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Volume 21 |
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Volume 20 |
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Medical and Scientific Meetings
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Issue 3-4 |
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Authors Index
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Volume 19 |
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Coverpage
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Issue 3-4 |
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Volume 18 |
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Issue 3 |
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Coverpage
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Issue 4 |
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Coverpage
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Volume 17 |
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Coverpage
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Issue 3-4 |
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Coverpage
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Medical and Scientific Meetings
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Volume 16 |
Issue 1-2 |
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Coverpage
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Medical and Scientific Meetings
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Issue 3-4 |
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Coverpage
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Medical and Scientific Meetings
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Volume 15 |
Issue 1-2 |
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Coverpage
News
Medical and Scientific Meetings
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Issue 3-4 |
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Coverpage
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Medical and Scientific Meetings
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Volume 14 |
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Issue 3-4 |
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Volume 13 |
Issue 1 |
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Issue 2 |
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Volume 12 |
Issue 1 |
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News
1 |
Methadone versus morphine
as a first-line strong opioid for cancer pain:
A randomized double-blind study
Snezana BOSNJAK, Snezana
SUSNJAR
This was the first randomized
study designed to compare the effectiveness
and tolerability of methadone (7.5 mg orally
every 12 hours and 5 mg every 4h as needed)
and morphine (15 mg slow-release every 12 hours
and 5 mg every 4 h as needed), as a first-line
opioid for severe pain caused by advanced cancer.
More than 80% of cancer patients develop pain
before death. Morphine is the standard first-line
strong opioid according to the WHO. Methadone
is an alternative second-line strong opioid.
Methadone has been stated to have a number of
potential advantages over morphine: improved
pain control (particularly in patients with
neuropathic pain), decreased toxicity (particularly
constipation) and lower development of tolerance.
In addition, the cost of treatment with methadone
is also lower, which is important for low-income
countries. So far, no studies have directly
compared methadone and morphine on a double-blind
basis.
A total of 103 patients, from 7 international
research centers, were randomized after stratification
by characteristics of the pain (neuropathic
vs. non-neuropathic) to receive methadone (49
patients) or morphine (54 patients). The study
duration was 4 weeks. The Institute for Oncology
and Radiology of Serbia participated with 34
patients and was nominated the best research
center on the basis of the quality of data.
The primary objective of the study was to evaluate
the difference in pain intensity and opioid-induced
toxicity (sedation, nausea and vomiting, confusion
and constipation), comparing the baseline score
with the score at week 4 for each study arm.
Methadone did not produce superior analgesic
efficiency or overall tolerability at 4 weeks
compared with morphine. The blind global satisfaction
ratings of both drugs by patients and investigators
did not show any difference between methadone
and morphine. However, patients receiving methadone
had more opioid toxicity-related dropouts. Methadone
is a useful alternative strong opioid in developing
countries because of its lower cost. Two-times
daily dosing regimen of methadone used in the
study proved to be effective and feasible. Close
monitoring of patients in the first week after
initiation of methadone treatment is mandatory.
References:
1. Bruera E, Palmer JL, Bosnjak S, Rico MA,
Moyano J, Sweeney C et al. Methadone versus
morphine as a first-line strong opioid for cancer
pain: A randomized double-blind study. J Clin
Oncol 2004;22:185-92. |
2 |
HPV-prophylactic vaccine:
A new way of prevention against cervical carcinoma
Aljosa MANDIC
This was the first randomized
study designed to compare the effectiveness
and tolerability of methadone (7.5 mg orally
every 12 hours and 5 mg every 4h as needed)
and morphine (15 mg slow-release every 12 hours
and 5 mg every 4 h as needed), as a first-line
opioid for severe pain caused by advanced cancer.
More than 80% of cancer patients develop pain
before death. Morphine is the standard first-line
strong opioid according to the WHO. Methadone
is an alternative second-line strong opioid.
Methadone has been stated to have a number of
potential advantages over morphine: improved
pain control (particularly in patients with
neuropathic pain), decreased toxicity (particularly
constipation) and lower development of tolerance.
In addition, the cost of treatment with methadone
is also lower, which is important for low-income
countries. So far, no studies have directly
compared methadone and morphine on a double-blind
basis.
A total of 103 patients, from 7 international
research centers, were randomized after stratification
by characteristics of the pain (neuropathic
vs. non-neuropathic) to receive methadone (49
patients) or morphine (54 patients). The study
duration was 4 weeks. The Institute for Oncology
and Radiology of Serbia participated with 34
patients and was nominated the best research
center on the basis of the quality of data.
The primary objective of the study was to evaluate
the difference in pain intensity and opioid-induced
toxicity (sedation, nausea and vomiting, confusion
and constipation), comparing the baseline score
with the score at week 4 for each study arm.
Methadone did not produce superior analgesic
efficiency or overall tolerability at 4 weeks
compared with morphine. The blind global satisfaction
ratings of both drugs by patients and investigators
did not show any difference between methadone
and morphine. However, patients receiving methadone
had more opioid toxicity-related dropouts. Methadone
is a useful alternative strong opioid in developing
countries because of its lower cost. Two-times
daily dosing regimen of methadone used in the
study proved to be effective and feasible. Close
monitoring of patients in the first week after
initiation of methadone treatment is mandatory.
References:
1. Greenlee RT, Hill-Harmon MB, Murray T, Thun
M. Cancer statistics, 2001. CA Cancer J Clin
2001;50:7-33.
2. Bosch FX, Lorincz A, Munoz N, Meijer CJ,
Shah KV. The causal relation between human papillomavirus
and cervical cancer. J Clin Pathol 55, 2002;55:244-65.
3. Munoz N et al. Epidemiologic classification
of human papillomavirus types associated with
cervical cancer. N Engl J Med 2003;348:518-27.
4. Schlecht NF et al. Human papillomavirus infection
and time to progression and regression of cervical
intraepithelial neoplasia. J Natl Cancer Inst
2003;95:1336-43.
5. Goldie SJ et al. A comprehensive natural
history model of HPV infection and cervical
cancer to estimate the clinical impact of a
prophylactic HPV-16/18 vaccine. Int J Cancer
2003;106:896-904.
6. Stanimirovic B, Kuljic-Kapulica N, Antic
N, Stanimirovic V, Vasiljevic M, Popovic-Lazic
J. HPV typing in cervical squamous intraepithelial
lesions(SIL)- our experience after 1000 studied
patiens. Archive of Oncology 1999;7(2):43-8.
7. Koutsky LA, Holmes KK, Critchlow CW et al.
A cohort study of the risk of cer- vical intraepithelial
neoplasia grade 2 or 3 in relation to papillomavirus
infec- tion. N Engl J Med 1992;327:1272-8.
8. Mandic A, Vujkov T. Human papillomavirus
vaccine as a new way of pre- venting cervical
cancer: A dream or the future. Ann Oncol 2004;15:197-200.
9. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression
of vaccinia recombinant HPV 16 L1 and L2 ORF
proteins in epithelial cells is sufficient for
assembly of HPV virion-like particles. Virology
1991;185:251-7 .
10. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller
JT. Papillomavirus L1 major capsid protein self-assembles
into virus-like particles that are highly immuno-
genic. Proc Natl Acad Sci USA 1992;89:12180-4.
11. Da Silva DM, Velders MP, Nieland JD, Schiller
JT, Nickoloff BJ, Kast WM. Physical interaction
of human papillomavirus virus-like particles
with immune cells. Int Immunol 2001;13(5):633-41.
12. Koutsky L, Ault K, Wheeler C, Brown D, Barr
E, Alvarez F et al. A controlled trial of human
papillomavirus type 16 vaccine. N Engl J Med
2002;347/21:1645-51.
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3 |
Diagnostic and therapeutic
management of primary cardiac lymphoma
Vladimir BALTIC
Primary cardiac lymphoma
(PCL) can be defined as non-Hodgkin's lymphoma
(NHL) that involves e heart and/pericardium,
or as NHL with tumor mass localized in heart
(1,2). Primary cardiac lymphoma accounts for
1.3% to 2% of all cardiac tumors and 0.5% of
extranodal lymphomas (1). Primary and secondary
lymphomas appear most frequently in case of
immunocompromised HIV-infected persons (3).
In HIV-infected persons the risk of development
of systemic non-Hodgkin's lymphoma is 60 to
200 times that in the general population. A
meta-analysis of cohort studies that included
14 936 HIV-infected persons showed that the
relative risk in the era of highly active antiretroviral
therapy (HAART), as compared with the pre-HAART
era, was 0.58 (4). Primary cardiac lymphomas
are most often localized in the right atrium
and rarely in other heart cavities or in valves.
As a rule neoplasia always involves pericardium
also. However, secondary lymphoma always involves
pericardium, epicardium or infiltrates into
myocardium (3,4). Pathognomonic clinical presentation
of PCL is not typical and depends on the size
and localization of primary lesion. Prognostic
factors are also difficult for identification.
Retrospective analysis of 60 immunocompetent
patients showed that the disease was presented
as right heart insufficiency (20%), pericardial
pain (17%), cardiac tamponade (12%), heart rhythm
abnormalities, vena cava superior syndrome (8%),
acute myocardial infarction, dyspnea, etc. (3).
Systemic symptoms were found in 17% of patients,
and elevated laboratory values for LDL and ESR
were registered in case of 16% and 20% of patients,
respectively. To diagnose the disease following
techniques can be used: cytological analysis
of pericardial exudates, echocardiography, CT,
MRI, and scintigraphy with Tc99mSESTAMIB. When
indicated angiography can also be used (3).
Transesophageal echocardiography and MRI are
the techniques of high specificity and sensitivity
(Figure 1,2) (4). ECG-gated MRI provides the
image of cardiac tumor mass that is isointensive
with the signal of normal myocardium T1W and
T2W images. The application of gadolinium contrast
medium elevates the signal intensity (Figure
3) (4).
 |
Figure
1. Echocardiogram Obtained at the Time
of Diagnosis. The apical four-chamber
view (Panel A) and the subcostal four-chamber
view (Panel B) show that right atrial
cavity is filled by mass of echoes, indicating
the presence of a tumor. RA denotes right
atrium, LA left atrium, RV right ventricle,
and LV left ventricle |

|
Figure
2. Cardiac MRI Studies. One frame from
a cine acquisition (in which the blood
appears bright), obtained in a paraseptal
long-axis view to the right of the intreventricular
septum (Panel A), shows a large, lobulated
mass extending into the right atrial cavity
from its attachment along the floor of
the chamber (straight arrow). The mass
protrudes partially into the tricuspid
orifice, which is demarcated by the closed
tricuspid-valve leaflet (curved arrow).
A small pericardial effusion is also visible
(arrowhead). A spin-echo image with T2
weighting (in which the blood appears
black), acquired in the orientation of
the four-chamber view near the inferior
surface of the heart (Panel B), shows
a bulky mass lesion (straight arrow) yhat
occupies most of the right atrial cavity
at this level. A small pericardioal effusion,
probably with some deposition of fibrin
along the pericardial surfaces, may be
contributing to apparent thickening of
the right atrial free wall (curved arrow).
A short-axis spin-echo image obtained
after the intravenous administration of
0.1 mmol of gadolinium per kilogram (Panel
C) shows extension of the tumor underneath
the basal portion of the interventricular
septum (arrow). The signal intensity in
the tumor is less strongly enhanced that
of the normal myocardium. AO denotes ascendings
aorta, SVC superior vena cava, RVO right
ventricular outflow tract, RA right atrium,
RV right ventricle, and LV left ventricle. |
 |
Figure
3. Endomyocardial -Biopsy Specimen. There
is a diffuse infiltrateof neoplastic cells
under the endocardium (Panel A, hematoxylin
and eosin, x125). Examination at a higher
magnification (Panel B) shows that the
cells have a high nuclear-to-cytoplasmic
ratio (hematoxylin and eosin, x500). In
situ hybridization studies show that most
of the lymphoma cells contain nuclear
Epstein-Barr virus-encoded RNA (Panel
C, x125). |
Endomocardial biopsy was
performed in 50% of patients to obtain histologically
confirmed diagnosis. Centroblasts and B-cell
immunoblasts (CD20+, Ki67+, CD3-, and EBV-)
were predominant (4).
The shown characteristics are typical for diffuse
B-cell NHL of high-grade malignancy. The prognosis
of disease course in patients with PCL associated
with HIV infection is poor. The results of present
clinical researching show that 50% to 73% of
patients affected with PCL, after the treatment
with poly-chemotherapy, develop CR that persists
longer than 33 months in 20% of all cases. The
applied treatment regimen consists of CHOP (cyclophosphamide,
hydroxydaunomicin [doxorubicin], Oncovin [vincristine],
prednisone) or CHOP combined with Rituximab
(CD20 monoclonal antibody) (4).
References:
1. McAllister HA, Fengolio JJ. Tumors of the
cardiovascular systems. In: Atlas of tumor pathology.
2nd Series. Fascicle 15. Washington, DC: Armed
Forces Institute of Pathology; 1978. p. 99-100.
2. Caiirins P, Butany J, Fulop J, Rakowski H,
Hasram S. Cardiac presentation of non-Hodgkin's
lymphoma. Arch Pathol Lab Med 1978;111:80-3.
3. Ceresoli GL, Ferreri AJM, Bucc E, Ripa C,
Ponzoni M, Villa E. Primary cardiac lymphoma
in immunocompetent patient. Cancer 1997;80:1497-506.
4. Kaplan LD, Afridi NA, Holmvang G, Yukerberg
LR. Case 31-2003: A 44-year- old man with HIV
infection and right atrial mass. N Engl J Med
2003,349:14;1367-77. |
4 |
Application of MCC-465
or doxorubicin (DXR) encapsulated in PEG immunolyposome,
in patients with metastatic stomach cancer
Vladimir BALTIC
Goren et al. prepared
immunoliposome for the first time in 1996 (Figure
1). This liposome was conjugated to MoAb against
HER-2 positive tumors. On the basis of their
and other authors' experience Matsamura et al.
(2003) prepared immunoliposome-encapsulated
form of DXR (Figure 1). The liposome was chemically
conjugated to PEG and F(ab')2 fragments of the
human monoclonal antibody GAH, which can recognize
antigen molecules on plasmatic membranes of
different types of tumor cells. The anti-tumor
activity of MCC-465 against GAH-positive human
stomach cancer B37 cells was clearly shown in
pharmacokinetic studies phase I.
 |
Figure
1. Schematic diagram of MCC-465
Taken from: Ann Oncol 2004;15(3):518. |
MTD for MCC-465 is 45.5
mg/m2 using the 3-week schedule. The authors
recommend MCC-465 dose of 32.5 mg/m2 for phase
II study.
References:
1. Matsumura Y, Goth M, Muro K et al. Phase
I and pharmacokinetics study of MCC-465. a doxorubicin
(DXR) encapsulated in PEG immunoliposome, in
patients with metastatic stomach cancer. Ann
Oncol 2004;15:517-25. |
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Books Received
Medical and Scientific Meetings
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Issue 2 |
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News
1 |
Revised Bethesda Guidelines
for hereditary nonpolyposis colorectal cancer
(Lynch syndrome) and microsatellite instability
Umar A, Boland
CR, Terdiman JP, Syngal S, de la Chapelle A,
R.schoff J et al. J Natl Cancer Inst 2004;96:261-8.
Attila FENYVESI
Microsatellite instability
is characterized by the size variation of specific
sequence of DNA bases or nucleotides, which
contains mono, di, tri, or tetra tandem repeats.
About 15% of colorectal cancers are characterized
by microsatellite instability. This feature
arises through defective DNA mismatch repair,
which is related either to a germinative mutation
or a failure to express a mismatch-repair gene
(1). Germ line mutation in one of several DNA
mismatch genes is found in hereditary nonpolyposis
colorectal cancer (HNPCC, also known as Lynch
syndrome). HNPCC is the most common hereditary
colon cancer syndrome, and is estimated to account
for about 2-4% of all colorectal cancers. HNPCC
is an autosomal dominant condition, characterized
by increased lifetime risk of early onset colorectal
cancer as well as excess of extracolonic cancers
(2). On the other hand microsatellite instability
is also present in sporadic colorectal cancers
where DNA mismatch repair deficiency is the
result of MLH1 mismatch repair gene inactivation
due to methylation suppression of the MLH1 promoter
region. Methylation of cytosine in CpG rich
gene promoter region leads to loss of gene expression
(3). In 1991, the International Collaborative
Group on Hereditary Nonpolyposis Colorectal
Cancer (ICG-HNPCC) developed the original Amsterdam
Criteria, established minimal clinical diagnostic
criteria to identifying kindreds that eventually
led to the association of the HNPCC syndrome
and for recruiting HNPCC patients for collaborative
studies (4). Revised, Amsterdam criteria II
took into account other types of HNPCC-associated
cancers, endometrial, small bowel, and renal
pelvis cancers (5). In 1996 US National Cancer
Institute (NCI) hosted an International Workshop
on HNPCC, which led to the development of the
Bethesda guidelines. The Bethesda guidelines
represent clinical and histopathologic criteria
for identification of colorectal tumors that
should be tested for microsatellite instability
(6). To consider revision and improvement of
the Bethesda guidelines, another HNPCC workshop
was held by the NCI in Bethesda, MD in 2002.
These Revised Bethesda Guidelines (Table 1)
were published in the form of a commentary in
February 2004, in the Journal of the National
Cancer Institute to update the original Bethesda
Guidelines on testing colorectal tumors for
microsatellite instability (7). The revised
criteria aim to simplify the decision process
for genetic testing in high-risk individuals,
and propose that tumors should be tested for
microsatellite instability (and if found to
be microsatellite instability positive, tested
for HNPCC mutations). The authors of the commentary
also make recommendations for the process of
molecular evaluation patients identified as
being at risk. The Workshop participants suggested
that additional mononucleotide markers should
be added to the panel of five (original NCI
microsatellite panel included BAT25, BAT26,
D2S123, D5S346, D17S250 [8]) microsatellites
to improve sensitivity in the evaluation of
microsatellite instability. Suggestions are
also made for future research priorities for
the clinical and molecular evaluation of microsatellite
instability.
References:
1. Haydon AMM, Jass JR. Emerging pathways in
colorectal-cancer development. Lancet Oncol
2002;3:83-8.
2. Lynch HT, de la Chapelle A. Hereditary colorectal
cancer. N Engl J Med 2003;348:919-32.
3. Narayan S, Roy D. Role of APC and DNA mismatch
repair genes in the development of colorec-
tal cancer. Molecular Cancer (Internet). 2003;2(1):41
Avilable from: http://www.molecular-can- cer.com/content/2/1/41
4. Vasen HF, Mecklin JP, Khan PM, Lynch HT.
The International Collaborative Group on Hereditary
Non-polyposis Colorectal Cancer (ICG-HNPCC).
Dis Colon Rectum 1991;34:1535-49.
5. Vasen HF, Watson P, Mecklin JP, Lynch HT.
New clinical criteria for hereditary nonpolyposis
col- orectal cancer (HNPCC, Lynch syndrome)
proposed by the International Collaborative
group on HNPCC. Gastroenterology. 1999;116:1453-6.
6. Rodriguez-Bigas MA, Boland CR, Hamilton SR,
Henson DE, Jass JR, Khan PM, et al. A National
Cancer Institute Workshop on Hereditary Nonpolyposis
Colorectal Cancer Syndrome: meeting highlights
and Bethesda Guidelines. J Natl Cancer Inst
1997;89:1758-62.
7. Umar A, Boland CR, Terdiman JP, Syngal S,
de la Chapelle A, R.schoff J et al. Revised
Bethesda Guidelines fo Hereditary Nonpolyposis
Colorectal Cancer (Lynch Syndrome) and Microsatellite
Instability. J Natl Cancer Inst 2004;96:261-8.
8. Boland CR, Thibodeau SN, Hamilton SR, Sidransky
D, Eshleman JR, Burt RW et al. A National Cancer
Institute Workshop on Microsatellite Instability
for cancer detection and familial predispo-
sition: development of international criteria
for the detection of microsatellite instability
in col- orectal cancer. Cancer Res 1998;58:5248-57. |
2 |
Ovarian cancer: Importance
of our own immune system
Ovarian cancer is the
sixth most common cancer in women worldwide
and the leading cause of death from gynecological
cancer (1,2). Seventy-five percent of all epithelial
cancers will have spread beyond the ovaries
at the time of diagnosis and more than half
of patients will have remission after surgical
debulking and primary chemotherapy; nevertheless,
overall five-year survival remains lower than
25 % percent (3,4). Tumor stage, residual disease
after surgical debulking, and the response to
chemotherapy are the factors that affect the
outcome of ovarian carcinoma (4,5). Do we have
organism defense system against these or some
other malignant cells or don't we? Is our immunity
system to weak to recognize and attack such
a malignant changes in these cells or we still
don't know the power of our immune system? Until
the end of the 19th century the possibility
that a tumor could be rejected merely by the
body's immune defense was just a vision, but
after 100 years of preclinical and clinical
research in the field the vision of cancer immunotherapy
became real and has, with multiple tools, successfully
entered clinical standard practice. Immune defense
against pathogens and tumors is mediated through
antigen-specific and nonspecific immune mechanisms.
Non-specific immune responses are procured by
cells of the macrophage and NK cell lineage
and/or by soluble factors such as inflammatory
cytokines. The functioning of the antigen-specific
immune system is based on a division of labor
between T cells and antibody-producing B cells
(6). Ovarian carcinoma may be recognized and
attacked by the immune system. The tumor may
contain a lymphocytic infiltrate, and these
tumor-associated lymphocytes exhibit oligoclonal
expansion, recognize tumor antigens, and display
tumor-specific cytolytic activity in vitro (7-11).
Lin Zhang and colleagues find a very interesting
relationship between tumorinfiltrating T cells
and clinical outcome in advanced ovarian cancer.
Their study indicates that the presence or absence
of intratumoral T cells correlates with the
clinical outcome of advanced ovarian carcinoma
after surgical debulking and adjuvant chemotherapy
(12). They performed immunohistochemical analysis
of 186 frozen specimens from advancedstage ovarian
carcinomas to assess the distribution of tumor-infiltrating
T cells and conducted outcome analyses. Molecular
analyses were performed in some tumors by real-time
polymerase chain reaction. Results of this study
are very interesting. CD3+ tumor-infiltrating
T cells were detected within tumor-cell islets
(intratumoral T cells) in 102 of the 186 tumors
(54.8%); they were undetectable in 72 tumors
(38.7 percent); the remaining 12 tumors (6.5
percent) could not be evaluated. There were
significant differences in the distributions
of progression-free survival and overall survival
according to the presence or absence of intratumoral
T cells (P<0.001 for both comparisons). The
five-year overall survival rate was 38.0 percent
among patients whose tumors contained T cells
and 4.5 percent among patients whose tumors
contained no T cells in islets. Significant
differences in the distributions of progression-
free survival and overall survival according
to the presence or absence of intratumoral T
cells (P<0.001 for both comparisons) were
also seen among 74 patients with a complete
clinical response after debulking and platinum-based
chemotherapy: the five-year overall survival
rate was 73.9 percent among patients whose tumors
contained T cells and 11.9 percent among patients
whose tumors contained no T cells in islets.
The presence of intratumoral T cells independently
correlated with delayed recurrence or delayed
death in multivariate analysis and was associated
with increased expression of interferon-g, interleukin-2,
and lymphocyte-attracting chemokines within
the tumor. The absence of intratumoral T cells
was associated with increased levels of vascular
endothelial growth factor (VEGF). This finding
also points to the importance of vascular density
in tumor and increase level of VEGF as another
important factor which could effect on treatment
and clinical outcome. They did not find the
association between the presence and absence
of T cells and age, histological type, or tumor
grade. Univariate analysis revealed that the
presence or absence of T cells (P<0.001)
and the extent of residual tumor (P<0.001)
correlated with overall survival but that tumor
grade (P=0.06 for the comparison of grade 1
with grade 3; P=0.30 for the comparison of grade
2 with grade 3), histological type of tumor
(P=0.41), inclusion or noninclusion of paclitaxel
in the chemotherapeutic regimen (P=0.74), and
age (<55 years vs.>55 years, P=0.25) did
not. The presence or absence of intratumoral
T cells and the extent of residual tumor but
not age, tumor grade, or type of first-line
chemotherapy were independent prognosticators
of progression- free survival and overall survival
in a multivariate analysis. The histological
type of the tumor predicted overall survival
but not progression-free survival. A very complex
network of interacting cells and molecules mediates
cellular immune responses against infectious
pathogens and cancer. Specificity of the system
is determined by the interaction of antigen
binding receptors (TCR) on tumor-specific T
cells. The latter are presented to the TCR as
peptides assembled into the antigen-presenting
groove of HLA-I or HLA-II antigens on the surface
of tumor cell and/or antigen presenting dendritic
cells (DC). T cells represent the only immune
mechanism that can see inside a cancer cell.
This is important because most cancer specific
proteins, including those determining the malignant
phenotype, are not expressed on the cell surface
and not accessible to antibodies. Subsequent
to fragmentation of tumor proteins in the proteasome
the resulting peptides associate with HLA-I
and 2-microglobulin in the endoplasmatic reticulum.
This peptide-HLA-b2-microglobulin complex is
than stable enough to integrate into the cell
surface where it can be recognized by TA-specific
cytotoxic T cells (CTLs) (13).
 |
Figure
1. Patterns of T-Cell Infiltration in
Ovarian Carcinoma (Zhang L, Conejo-Garcia
JR, Katsaros D, Gimotty PA, Massobrio
M, Regnani G et al. Intratumoral T Cells,
Recurrence, and Survival in Epithelial
Ovarian Cancer N Engl J Med 2003; 348:203-13) |
Panel A shows double
immunofluorescent detection of cytokeratin (fluorescein;
green) and CD3 (Texas red; red) demonstrating
the organization of cytokeratin-positive tumor
cells in well-defined tumor islets and the presence
of CD3+ tumor-infiltrating T lympho- cytes both
within tumor islets and in peritumoral stroma.
Panel B shows that T cells appear in tumor islets
as well as in tumor stroma; there is an abundance
of intratumoral T cells. In Panel C, no intratumoral
T cells were detected: T cells are restricted
exclusive- ly to the peritumoral stroma in this
specimen. In Panel D, real-time quantitative
poly- merase-chain-reaction analysis of the
constitutive CD3e chain of the T-cell receptor
in 16 tumors containing T cells and 10 tumors
without T cells reveals overexpression of CD3e
in the former, reflecting a greater number of
T cells. The y axis represents the expression
of CD3e in relation to glyceraldehyde-3-phosphate
dehydrogenase messenger RNA (mRNA). Panels E
and F show four-color flow-cytometric analysis
of T cells derived from a fresh stage III ovarian
carcinoma with use of monoclonal antibodies
against CD3, CD4, and CD8. Gating was carried
out on viable CD45+ leukocytes, which comprised
up to 35 percent of all cells harvested after
mechanical dispersion and enzymatic digestion
of solid tumor nodules. T cells represent the
most prevalent tumor-infiltrating immune cells.
The quantification of CD3+CD4+ T cells is shown
in Panel E, and the quantification of CD3+CD8+
T cells is shown in Panel F. Panels G, H, and
I show an immunohistochem- ical analysis of
CD4+ and CD8+ T cells in ovarian carcinoma.
Panel G shows the corre- lation of the number
of CD4+ T cells with that of CD8+ T cells according
to the immuno- histochemical analysis of tumors
containing T cells and those without T cells.
Both intra- tumoral and peritumoral T cells
were counted. A close correlation was noted
(R2=0.66). In the specimen shown in Panel H,
both intratumoral and peritumoral CD4+ T cells
are present. Intratumoral and peritumoral CD8+
T cells are present in the adjacent section
shown in Panel I. APC denotes allophycocyanin.
 |
Figure
2. Survival Analyses of Patients with
Ovarian Carcinoma, According to the Presence
or Absence of Intratumoral T Cells (Zhang
L, Conejo-Garcia JR, Katsaros D, Gimotty
PA, Massobrio M, Regnani G et al. Intratumoral
T Cells, Recurrence, and Survival in Epithelial
Ovarian Cancer N Engl J Med 2003; 348:203-13). |
Panels A and B show Kaplan-Meier
curves for the duration of progression-free
survival and overall survival, respectively,
according to the presence or absence of intratumoral
T cells in 174 patients with stage III or IV
epithelial ovarian cancer and complete, partial,
or no response to therapy. Panels C and D show
Kaplan-Meier curves for the duration of progression-free
survival and overall survival, respectively,
according to the presence or absence of intratumoral
T cells in 74 patients with stage III or IV
epithelial ovarian cancer and a complete response
to therapy. Panels E and F show survival curves
stratified according to the extent of residual
disease for the 74 patients with a complete
response to therapy, according to the presence
or absence of intratumoral T cells. Optimal
debulking was defined by residual tumor of less
than 1 cm, and suboptimal debulking by residual
tumor of 1 cm or more. P values were derived
with the use of the log-rank statistics.
References:
1. Greenlee RT, Hill-Harmon MB, Murray T, Thun
M. Cancer statistics, 2001. CA Cancer J Clin
2001;50:7-33.
2. Bosch FX, Lorincz A, Munoz N, Meijer CJ,
Shah KV. The causal relation between human papillomavirus
and cervical cancer. J Clin Pathol 55, 2002;55:244-65.
3. Munoz N et al. Epidemiologic classification
of human papillomavirus types associated with
cervical cancer. N Engl J Med 2003;348:518-27.
4. Schlecht NF et al. Human papillomavirus infection
and time to progression and regression of cervical
intraepithelial neoplasia. J Natl Cancer Inst
2003;95:1336-43.
5. Goldie SJ et al. A comprehensive natural
history model of HPV infection and cervical
cancer to estimate the clinical impact of a
prophylactic HPV-16/18 vaccine. Int J Cancer
2003;106:896-904.
6. Stanimirovic B, Kuljic-Kapulica N, Antic
N, Stanimirovic V, Vasiljevic M, Popovic-Lazic
J. HPV typing in cervical squamous intraepithelial
lesions(SIL)- our experience after 1000 studied
patiens. Archive of Oncology 1999;7(2):43-8.
7. Koutsky LA, Holmes KK, Critchlow CW et al.
A cohort study of the risk of cer- vical intraepithelial
neoplasia grade 2 or 3 in relation to papillomavirus
infec- tion. N Engl J Med 1992;327:1272-8.
8. Mandic A, Vujkov T. Human papillomavirus
vaccine as a new way of pre- venting cervical
cancer: A dream or the future. Ann Oncol 2004;15:197-200.
9. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression
of vaccinia recombinant HPV 16 L1 and L2 ORF
proteins in epithelial cells is sufficient for
assembly of HPV virion-like particles. Virology
1991;185:251-7 .
10. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller
JT. Papillomavirus L1 major capsid protein self-assembles
into virus-like particles that are highly immuno-
genic. Proc Natl Acad Sci USA 1992;89:12180-4.
11. Da Silva DM, Velders MP, Nieland JD, Schiller
JT, Nickoloff BJ, Kast WM. Physical interaction
of human papillomavirus virus-like particles
with immune cells. Int Immunol 2001;13(5):633-41.
12. Koutsky L, Ault K, Wheeler C, Brown D, Barr
E, Alvarez F et al. A controlled trial of human
papillomavirus type 16 vaccine. N Engl J Med
2002;347/21:1645-51.
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Medical and Scientific
Meetings
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Issue 3 |
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News
1 |
Response of Established
Human Breast Tumors to Vaccination with Mammaglobin-A
cDNA
Narayanan K, Jaramillo
A, Benshoff ND, Campbell LG et al. JNCI 2004;96(18):1388-96.
A novel breast cancer-associated
antigen, mammaglobin-A, is expressed in 80%
of primary breast tumors. The characterization
of immune responses against this highly expressed
breast cancer-specific antigen would be of value
in the development of new therapeutic strategies
for breast cancer. The authors developed an
in vivo model using human leukocyte antigen-A*0201/human
CD8+ (HLA-A2+/hCD8+) double-transgenic mice
to define the epitopes and to study the level
of protection acquired by mammaglobin-A cDNA
vaccination toward mammaglobin-A+/HLA-A2+ breast
cancer cell lines. Mammaglobin-A epitopes were
identified using an HLA class I peptide binding
prediction computer program, and their activity
was verified using gamma interferon ELISPOT
and cytotoxicity assays. The HLA-A2+/hCD8+ mouse
represents a valuable animal model to characterize
the HLA-A*0201-restricted CD8+ CTL immune response
to mammaglobin-A in vivo, and the data reported
here demonstrate the immunotherapeutic potential
of mammaglobin-A for the treatment and/or prevention
of breast cancer. |
2 |
Five-Year Outcomes After
Prostatectomy or Radiotherapy for Prostate Cancer:
The Prostate Cancer Outcomes Study
Potosky AL, Davis WW,
Hoffman RM et al. JNCI 2004;96(18):1358-67.
Men treated for clinically localized prostate
cancer with either radical prostatectomy or
external beam radiotherapy usually survive many
years with the side effects of these treatments.
Authors presents treatment-pecific quality-of-life
outcomes for prostate cancer patients 5 years
after initial diagnosis. At 5 years after diagnosis,
men treated with radical prostatectomy for localized
prostate cancer continue to experience worse
urinary incontinence than men treated with external
beam radiotherapy. However, the two treatment
groups were more similar to each other with
respect to overall sexual function, mostly because
of a continuing decline in erectile function
among the external beam radiotherapy patients
etween years 2 and 5. |
3 |
Probabilities of Death
From Breast Cancer and Other Causes Among Female
Breast Cancer Patients
Schairer C, Mink PJ,
Carroll L et al. JNCI 2004;96(17):1311-21.
Among cancer patients, probabilities of death
from that cancer and other causes in the presence
of competing risks are optimal measures of prognosis
and of mortality across demographic groups.
We used data on breast cancer patients from
the Surveillance, Epidemiology, and End Results
(SEER) Program in a competing-risk analysis.
The probability of death from breast cancer
versus other causes varied substantially ccording
to stage, tumor size, ER status, and age at
diagnosis in both white and black patients. |
Medical and Scientific
Meetings
Simposium Articles: Supportive Care in Canser Patients:
1st Belgrade Education Symposium, October 2, 2004,
Belgrade, Serbia and Montenegro
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Issue 4 |
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News
1 |
Progress in nanoscience,
nanotechnology, and nanomedicine
Ðuro KORUGA
In 2002 there were a few
international conferences on nanoscience and
nanotechnology in USA (Foresight conference),
Europe and Japan (First Japan-UK Nanotechnology
Summer School). Also, there were two meetings
in Serbia where nanotechnology and biomedicine
joint together: one international (SAUM, Belgrade)
and other domestic (Academy of Studenica, Studenica).
Big progress has been done in nanotechnology
in fabrication of nano-dendritic structure with
branches under 3 nm (1nm =10-9m). For the first
time researchers from National Institute for
Materials Science (Japan), Furuya and Hasegawa
produced this dendritic structure under electron
beam irradiation using the vapor deposition
properties of organometallic gases. Also, they
fabricated nano-dendric structures on the substrate
by delivering a gas containing the target element
to the vicinity of the substrate with a newly
developed gas delivery system while maintaining
a high vacuum in the electron microscope sample
chamber. The size of the structure as a whole
and the location of formation can be controlled
easily, and combinations of numerous types of
substrates and gas sources are possible. This
research result is expected to find wide application
in research and development of surface-effect
devices, nanosized catalyzed, biosensors, and
nanobiomedical devices.
Another significant progress has been done in
nanoscienece in the field nano-controllers.
Two researchers Lidija Matija and Srðan Ribar
found solution how to overcome problems with
classical control theory in nanoscience and
its application in nanotechnology. For the first
time in nanoscience they proposed application
of fractional calculus rather than classical
one. Currently dominant approach to nanotechnology
is from physics point of view. However, a chemical
approach to nanotechnology is more natural to
biological solutions. The first system has more
solid phase state, while the second one has
more liquid phase state. It is quite obvious
that new nanotechnological systems will be on
the border on these two phases. Fractal calculus
is basic scientific approach to develop control
system, which can control all three states:
liquid, liquid/solid, and solid. |
2 |
Low-grade cervical intra-epithelial
neoplasia: Does the regression depend on our
own gene map and human papillomavirus status?
Aljosa MANDIC
Authors from France published
in Obstetrics & Gynecology some interesting
results about patients with low-grade cervical
intra-epithelial neoplasia (CIN) who have a
very good chance of experiencing spontaneous
regression. Xavier Sastre-Garau and his colleagues
(1) analyzed the probability of regression of
these lesions according to the human leukocyte
antigen (HLA-DR) and human papilloma virus (HPV)
status. The human leukocyte antigen (HLA)-DRB1*13
allele frequency is lower in women with cervical
carcinoma than in the general population, suggesting
that this allele could exert a protective effect
against progression of cervical intraepithelial
neoplasia (CIN) associated with human papillomaviruses
(HPV). The study sample was composed of 86 women
with CIN1 who agreed to regular colposcopic
follow-up and no immediate treatment. Biopsy
specimens were taken under colposcopy for histology
and for the determination of HPV and HLA status.
Cases were classified into 3 groups: CIN1 regression,
persistence for at least 12 months, or progression
to CIN2 or CIN3.
The rate of spontaneous regression (95% confidence
interval) at 24 months was 51.6% (39-61.6%)
overall compared with 34.7% (13.4-50.8%) in
HPV16/18 positive cases and 59.9% (43.7-71.4%)
in HPV16/18-negative cases (P = .051). The rate
of regression was 71.8% (40.8-86.5%) in patients
with HLA-DRB1*13 and 45.9% (31.5-57.2%) in patients
with other genotypes (P = .03). Regression reached
90.5% (38.9-98.5%) at 18 months in DRB1*13 patients
with HPV16/18-negative-associated CIN (15.1%
of the cases). In multi-variable analysis, HLA-DRB1*13
allele and HPV16/18-negative status were independently
associated with an increased probability for
regression (adjusted hazard ratio 2.1 [1.0-4.1]
and 2.5 [1.2-5.4], respectively). They showed
that subset of approximately 15% of CIN1 highly
likely to show spontaneous regression can be
defined using two biologic parameters that characterize
the viral causative agent and the host.
REFERENCE
1. Sastre-Garau X, Cartier I, Jourdan-Da Silva
N, De Crémoux P, Lepage V, Charron D. Regression
of Low-Grade Cervical Intraepithelial Neoplasia
in Patients With HLA-DRB1*13. Gen Obstet Gynecol
2004;104:751-5. |
3 |
Endometrial cancer: Advanced
disease and chemotherapy
Aljosa MANDIC.
According to the Register of Cancer the standard
incidence rates of endometrial cancer in central
part of Serbia are 9.1 in 1996 and 12.3 in 1999
per 100 000. Endometrial cancer is still the
most curable among ten most common cancers in
women because PMB, as a leading clinical symptom,
occurs mostly when disease is still limited
to the uterine corpus (International Federation
of Gynecology and Obstetrics [FIGO] stage I
and II in which the probability of long-term
disease-free survival is high) (1). Patients
with endometrial cancer who have localized disease
are usually curable by hysterectomy and bilateral
salpingo-oophorectomy. Best results are obtained
with either of two standard treatments: hysterectomy
or hysterectomy and adjuvant radiation therapy
(when deep invasion of the myometrial muscle
[one half the depth] or grade 3 tumor with myometrial
invasion is present). Where is the place of
progestogen therapy in treatment of endometrial
cancer?
Progestogen therapy was subscribed widely in
the past. A meta-analysis of 6 randomized trials
involving a total of 3,339 women has shown no
survival benefit for adjuvant progestogen therapy
in endometrial cancer (2). A subsequently published
randomized trial of 1012 women also failed to
demonstrate any survival benefit (3). It is
shown that surgery and radiotherapy are the
two most combined modalities of treatment for
endometrial cancer in early stages of the disease.
Is there any place of chemotherapy in advanced
endometrial cancer?
US researchers have now, for the first time,
presented the final results of the pivotal trial
that first demonstrated the benefits of adding
cisplatin to doxorubicin in patients with endometrial
carcinoma.
J. Tate Thigpen (University of Mississippi School
of Medicine, Jackson, Missouri) and colleagues
showed, at the initiation of the study, doxorubicin
and cisplatin ranked as the most active agents
in endometrial carcinoma (4). This trial of
stage III, IV, or recurrent disease evaluated
whether combining these agents increases response
rate (RR) and prolongs progression-free survival
(PFS) and overall survival (OS) over doxorubicin
alone. 281 of patients were eligible for study.
Regimens were doxorubicin 60 mg/m2 intravenously
or doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2
every 3 weeks until disease progression, unacceptable
toxicity, or a total of 500 mg/m2 doxorubicin.
There were 12 (8%) complete (CR) and 26 (17%)
partial responses (PR) among 150 patients receiving
doxorubicin versus 25 (19%) CRs and 30 (23%)
PRs among patients receiving the combination.
The overall response rate was higher among patients
receiving the combination (42%) compared with
patients receiving doxorubicin (25%; P = .004).
Median PFS was 5.7 and 3.8 months, respectively,
for the combination and single agent. The PFS
hazard ratio was 0.736 (95% CI, 0.577 to 0.939;
P = .014). Median OS was 9.0 and 9.2 months,
respectively, for the combination and single
agent. Overall death rates were similar in the
two groups (hazard ratio, 0.928; 95% CI, 0.727
to 1.185). Nausea, vomiting, and hematological
toxicities were common. The combination produced
more grade 3 to 4 leukopenia (62% vs. 40%),
thrombocytopenia (14% vs. 2%), anemia (22% vs.
4%), and nausea/vomiting (13% vs. 3%).
Compared with doxorubicin alone, combination
treatment was associated with a significantly
improved overall response rate (42 percent vs.
25 percent) and increased progression-free survival
(5.7 months vs. 3.8 months), but, at the same
time, it had a negligible impact on overall
survival (9.0 vs.9.2 months), and increased
toxicity.
REFERENCE
1. Mandic A, Vujkov T. Endometrial cancer: Diagnostic
methods in postmenopausal vaginal bleeding.
Arch Oncol 2003;11(2):97-101.
2. Martin-Hirsch PL, Lilford RJ, Jarvis GJ.
Adjuvant progestagen therapy for the treatment
of endometrial cancer: review and meta-analyses
of published randomised controlled trials. Eur
J Obstet Gynecol Reprod Biol 1996;65(2):201-7.
3. COSA-NZ-UK Endometrial Cancer Study Groups.
Adjuvant medroxyprogesterone acetate in high-risk
endometrial cancer. Int J Gynecol Cancer 1998;8:387-91.
4. Thigpen JT, Brady MF, Homesley HD, Malfetano
J, DuBeshter B, Burger RA et al. Phase III Trial
of Doxorubicin With or Without Cisplatin in
Advanced Endometrial Carcinoma: A Gynecologic
Oncology Group Study. J Clin Oncol 2004;22:3902-8. |
4 |
Mammographic density and
breast cancer after ductal carcinoma in situ
Habel LA, Dignam
JJ, Land SR et al. JNCI 2004;96(19):1467-72.
Women with ductal carcinoma in situ (DCIS)
are at substantially increased risk for a
second breast cancer, but few strong predictors
for these subsequent tumors have been identified.
We used Cox regression modeling to examine
the association between mammographic density
at diagnosis of DCIS of 504 women from the
National Surgical Adjuvant Breast and Bowel
Project B-17 trial and risk of subsequent
breast cancer events. In this group of patients,
mostly 50 years old or older, approximately
6.6% had breasts categorized as highly dense
(i.e., =75% of the breast occupied by dense
tissue). After adjusting for treatment with
radiotherapy, age, and body mass index, women
with highly dense breasts had 2.8 (95% confidence
interval [CI] = 1.3 to 6.1) times the risk
of subsequent breast cancer (DCIS or invasive),
3.2 (95% CI = 1.2 to 8.5) times the risk of
invasive breast cancer, and 3.0 (95% CI =
1.2 to 7.5) times the risk of any ipsilateral
breast cancer, compared with women with less
than 25% of the breast occupied by dense tissue.
Our results provide initial evidence that
the risk of second breast cancers may be increased
among DCIS patients with highly dense breasts.
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5 |
The ubiquitin-mediated
protein degradation pathway in cancer: therapeutic
implications
Burger AM, Seth AK.
Eur J Cancer 2004;40(15):2217-29.
The highly conserved eukaryotic ubiquitin-proteasome
system (UP-S) plays a pivotal role in protein
homeostasis and is critical in regulating
normal and cancer-related cellular processes.
The hierarchical nature of the UP-S provides
a rich source of molecular targets for specific
intervention and has therefore arisen as a
promising approach to innovative anticancer
therapies. The first in class proteasome inhibitory
agent Bortezomib (Velcade) has recently obtained
regulatory approval for the treatment of multiple
myeloma. Ubiquitin-mediated degradation is
a complex process that is comprised of well
defined steps involving ubiquitin-activating
enzymes (E1s), ubiquitin-conjugating enzymes
(E2s) and ubiquitin ligases (E3s). Although
a single E1 activates the ubiquitin conjugation
machinery, a large number of E2 conjugating
enzymes and E3 ligases are now known to exist.
Proteins tagged with ubiquitin are subsequently
recognised by the proteasome for digestion
and fragmentation. The enzymatic nature, multitude
of E3s and their specific substrate recognition
predestines them as therapeutic targets. This
article will review known inhibitors of the
proteasome and their molecular mechanisms
as well as ongoing developments and promising
avenues for targeting substrate-specific E3
ligases that are likely to yield a new class
of therapeutics that will serve and complement
the armamentarium of anticancer drugs.
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6 |
The interplay between
Src and integrins in normal and tumor biology
Playford MP, Schaller
MD. Oncogene 2004;23(48):7928-46.
Src family nonreceptor protein tyrosine kinases
transduce signals that control normal cellular
processes such as cell proliferation, adhesion
and motility. Normally, cellular Src is held
in an inactive state, but in several cancer
types, abnormal events lead to elevated kinase
activity of the protein and cause pleiotropic
cellular responses inducing transformation
and metastasis. A prerequisite of the ability
of a cancer cell to undergo metastasis into
distant tissues is to penetrate surrounding
extracellular matrices. These processes are
facilitated by the integrin family of cell
adhesion molecules. As is the case with Src,
altered integrin activity or substrate affinity
can contribute to the neoplastic phenotype.
Therefore, understanding the interplay between
Src and integrin function has been of intense
interest over the past few years. This review
focuses on the role of Src and integrin signaling
in normal cells and how this is deregulated
in human cancer. We will identify the key
players in the integrin-mediated signaling
pathways involved in cell motility and apoptosis,
such as FAK, paxillin and p130(CAS), and discuss
how Src signaling affects the formation of
focal adhesions and the extracellular matrix.
FAK, paxillin and p130(CAS), and discuss how
Src signaling affects the formation of focal
adhesions and the extracellular matrix.
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7 |
Supportive care in cancer
patients
(The first Belgrade
Education Symposium under the auspices of the
Multinational Association of Supportive Care
in Cancer)
The international education Symposium "Supportive
care in cancer patients" was organized
in Belgrade (October 2nd, 2004), under the auspices
of the Institute for Oncology and Radiology
of Serbia and Multinational Association of Supportive
Care in Cancer (MASCC). The goal of the Symposium
was to promote supportive care discipline in
the region of Central and Eastern Europe. The
need for the course was identified through requests
from oncologists and other relevant clinicians
involved in the care of patients with cancer.
The main learning objectives were: (1) to increase
awareness and applicable knowledge of supportive
care, its goals and achievements, (2) to highlight
the concept of quality of life in oncology,
(3) to cover evaluation and management of common
physical symptoms (cancer pain, dyspnoea), complications
of cancer (bone metastases, anorexia/cachexia)
and of major toxicities induced by anticancer
treatment (nausea and vomiting, myelosuppression,
febrile neutropenia), and (4) to present philosophy
and the key concepts of end of life care. The
course was also intended to inspire and motivate
the audience with the best international lecturers.
Topics were reviewed and discussed by the many
leading international experts willing to donate
their time and experience to this symposium.
The Symposium had 154 participants, mainly physicians
(oncologists, internal medicine specialists,
general practitioners, geriatricians, young
doctors in training for general oncology), but
also nurses and other relevant clinicians (clinical
psychologists) from Serbia and Montenegro and
other European countries (Bosnia & Herzegovina,
Bulgaria, Greece, France, Slovenia). A total
of 68 completed evaluation forms were returned.
Using the 1-5 scale, the overall rating of the
Symposium topic was 4.63, of the content 4.65,
while the organization and duration were rated
4.65 and 4.40, respectively (Table 1). The topic
and the content of the Symposium were most frequently
described as 'systematization of the existent
knowledge' (20/68, 29.4%) or "stimulative
for further work" (20/68, 29.4%). The most
frequent responses to the question 'How would
you describe methods of work applied in the
Symposium?' were: "illustrative and easy
to remember" (24/63, 38.1%), 'usual' (22/63,
34.9%) or "up-to-date, but without active
involvement of participants" (10/63, 15.9%).
The technical facilities provided were described
as "satisfactory in the given conditions"
(27/66, 40.9%) as well as "pleasant and
inspiring" (22/66, 33.3%). Taking into
consideration the content, quality of presentation
as well as quality of slides / visual support
the speakers were given the average rating of
= 4. The overall rating of the quality of the
education offered at this Symposium was 4.50
(range 1: poor; 5: excellent): more than 90%
of participants graded the Symposium as very
good (24/68, 35.3%) or excellent (40/68, 58.8%).
Every effort was made to provide the participants
with congress material of high quality. All
presentations were published in the scientific
journal Archive of Oncology, the only journal
in our country specialized in oncology. Moreover,
MASCC has strongly supported us by sending free
copies of the official journal "Supportive
care in cancer" and copies of recently
published guidelines for the prevention and
treatment of cancer-therapy induced oral and
gastrointestinal mucositis.
In our opinion the education results achieved
justify organization of such symposiums in the
future. The broadening of the topics to include
evaluation and management of other physical
symptoms/complications of cancer (tumor-induced
nausea and vomiting, fatigue, intestinal obstruction),
other treatment toxicities (cancer-therapy induced
oral mucositis), psychological symptoms of cancer
(depression, delirium), as well as social and
spiritual support was suggested. Moreover, longer
duration of the Symposium was proposed as well
as more active involvement of participants through
thematic workshops. The Symposium was intended
to bring together oncologists, other relevant
clinicians, and representatives of the pharmaceutical
industry to facilitate cooperation and communication
between them. Moreover, the intention was also
to increase awareness in public of supportive
care as a discipline in oncology: successful
press conference was organized and the Symposium
received extensive media coverage on both national
and local TV. The message conveyed is that supportive
care is to be acknowledged as a discipline which
is capable of helping the patient and the family
achieve the best possible quality of life in
every phase of malignant disease, and consequently
an integral part of comprehensive cancer care.
Oncologists, other relevant clinicians, the
public in general, being banded together and
gathered around this Symposium, may further
negotiate with the regulatory authorities and
advocate for the successful removal of barriers
to effective supportive and palliative care.
The Symposium was supported by: Serbian Medical
Association-Section for Oncology, Ministry of
Health, Republic of Serbia, Ministry of Science
and Environmental Protection, Republic of Serbia,
French Ministry of Foreign Affairs, International
Association for Hospice and Palliative Care
(IAHPC), and European Association for Palliative
Care (EAPC), Center for Palliative Care in Eastern
Europe (EAPC-EAST).
Our warmest thanks go to all the lecturers,
participants and sponsors.
Svetislav JELIC, Chairman of the Symposium
Snezana BOSNJAK, Co-chairman |
8 |
Press Release: The 2004
Nobel Prize in Physiology or Medicine
Source: www.nobelprize.org
The Nobel Assembly at Karolinska Institutet
has today decided to award The Nobel Prize
in Physiology or Medicine for 2004 jointly
to Richard Axel and Linda B. Buck for their
discoveries of "odorant receptors and
the organization of the olfactory system"
(4 October 2004)
Summary. The sense of smell long remained
the most enigmatic of our senses. The basic
principles for recognizing and remembering
about 10,000 different odours were not understood.
This year's Nobel Laureates in Physiology
or Medicine have solved this problem and in
a series of pioneering studies clarified how
our olfactory system works. They discovered
a large gene family, comprised of some 1,000
different genes (three per cent of our genes)
that give rise to an equivalent number of
olfactory receptor types. These receptors
are located on the olfactory receptor cells,
which occupy a small area in the upper part
of the nasal epithelium and detect the inhaled
odorant molecules. Each olfactory receptor
cell possesses only one type of odorant receptor,
and each receptor can detect a limited number
of odorant substances. Our olfactory receptor
cells are therefore highly specialized for
a few odours. The cells send thin nerve processes
directly to distinct micro domains, glomeruli,
in the olfactory bulb, the primary olfactory
area of the brain. Receptor cells carrying
the same type of receptor send their nerve
processes to the same glomerulus. From these
micro domains in the olfactory bulb the information
is relayed further to other parts of the brain,
where the information from several olfactory
receptors is combined, forming a pattern.
Therefore, we can consciously experience the
smell of a lilac flower in the spring and
recall this olfactory memory at other times.
Richard Axel, New York, USA, and Linda Buck,
Seattle, USA, published the fundamental paper
jointly in 1991, in which they described the
very large family of about one thousand genes
for odorant receptors. Axel and Buck have
since worked independent of each other, and
they have in several elegant, often parallel,
studies clarified the olfactory system, from
the molecular level to the organization of
the cells.
The olfactory system is important for life
quality. When something tastes really
good it is primarily activation of the olfactory
system which helps us detect the qualities
we regard as positive. A good wine or a sunripe
wild strawberry activates a whole array of
odorant receptors, helping us to perceive
the different odorant molecules. A unique
odour can trigger distinct memories from our
childhood or from emotional moments - positive
or negative - later in life. A single clam
that is not fresh and will cause malaise can
leave a memory that stays with us for years,
and prevent us from ingesting any dish, however
delicious, with clams in it. To lose the sense
of smell is a serious handicap - we no longer
perceive the different qualities of food and
we cannot detect warning signals, for example
smoke from a fire. Olfaction is of central
importance for most species. All living organisms
can detect and identify chemical substances
in their environment. It is obviously of great
survival value to be able to identify suitable
food and to avoid putrid or unfit foodstuff.
Whereas fish has a relatively small number
of odorant receptors, about one hundred, mice
- the species Axel and Buck studied - have
about one thousand. Humans have a somewhat
smaller number than mice; some of the genes
have been lost during evolution.
Smell is absolutely essential for a newborn
mammalian pup to find the teats of its mother
and obtain milk - without olfaction the pup
does not survive unaided. Olfaction is also
of paramount importance for many adult animals,
since they observe and interpret their environment
largely by sensing smell. For example, the
area of the olfactory epithelium in dogs is
some forty times larger than in humans.
A large family of odorant receptors.
The olfactory system is the first of our sensory
systems that has been deciphered primarily
using molecular techniques. Axel and Buck
showed that three per cent of our genes are
used to code for the different odorant receptors
on the membrane of the olfactory receptor
cells. When an odorant receptor is activated
by an odorous substance, an electric signal
is triggered in the olfactory receptor cell
and sent to the brain via nerve processes.
Each odorant receptor first activates a G
protein, to which it is coupled. The G protein
in turn stimulates the formation of cAMP (cyclic
AMP). This messenger molecule activates ion
channels, which are opened and the cell is
activated. Axel and Buck showed that the large
family of odorant receptors belongs to the
G protein-coupled receptors (GPCR).
All the odorant receptors are related proteins
but differ in certain details, explaining
why they are triggered by different odorous
molecules. Each receptor consists of a chain
of amino acids that is anchored into the cell
membrane and traverses it seven times. The
chain creates a binding pocket where the odorant
can attach. When that happens, the shape of
the receptor protein is altered, leading to
G protein activation.
One type of odorant receptor in each olfactory
receptor cell. Independently, Axel and
Buck showed that every single olfactory receptor
cell expresses one and only one of the odorant
receptor genes. Thus, there are as many types
of olfactory receptor cells as there are odorant
receptors. It was possible to show, by registering
the electrical signals coming from single
olfactory receptor cells, that each cell does
not react only to one odorous substance, but
to several related molecules - albeit with
varying intensity. Buck's research group examined
the sensitivity of individual olfactory receptor
cells to specific odorants. By means of a
pipette, they emptied the contents of each
cell and showed exactly which odorant receptor
gene was expressed in that cell. In this way,
they could correlate the response to a specific
odorant with the particular type of receptor
carried by that cell.
Most odours are composed of multiple odorant
molecules, and each odorant molecule activates
several odorant receptors. This leads to a
combinatorial code forming an "odorant
pattern" - somewhat like the colours
in a patchwork quilt or in a mosaic. This
is the basis for our ability to recognize
and form memories of approximately 10,000
different odours. Olfactory receptor cells
activate micro regions in the olfactory bulb.
The finding that each olfactory receptor cell
only expresses one single odorant receptor
gene was highly unexpected. Axel and Buck
continued by determining the organization
of the first relay station in the brain. The
olfactory receptor cell sends its nerve processes
to the olfactory bulb, where there are some
2,000 well-defined microregions, glomeruli.
There are thus about twice as many glomeruli
as the types of olfactory receptor cells.
Axel and Buck independently showed that receptor
cells carrying the same type of receptor converge
their processes into the same glomerulus,
and Axel's research group used sophisticated
genetic technology to demonstrate in mice
the role of the receptor in this process.
The convergence of information from cells
with the same receptor into the same glomerulus
demonstrated that also glomeruli exhibit remarkable
specificity (see figure).

In the glomeruli we find not only the nerve
processes from the olfactory receptor cells
but also their contacts with the next level
of nerve cells, the mitral cells. Each mitral
cell is activated only by one glomerulus,
and the specificity in the information flow
is thereby maintained. Via long nerve processes,
the mitral cells send the information to several
parts of the brain. Buck showed that these
nerve signals in turn reach defined micro
regions in the brain cortex. Here the information
from several types of odorant receptors is
combined into a pattern characteristic for
each odour. This is interpreted and leads
to the conscious experience of a recognizable
odour.
Pheromones and taste. The general principles
that Axel and Buck discovered for the olfactory
system appears to apply also to other sensory
systems. Pheromones are molecules that can
influence different social behaviours, especially
in animals. Axel and Buck, independent of
each other, discovered that pheromones are
detected by two other families of GPCR, localized
to a different part of the nasal epithelium.
The taste buds of the tongue have yet another
family of GPCR, which is associated with the
sense of taste.
REFERENCE. Buck
L, Axel R. Cell 1991;65:175-87.
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Book Review
Book Recieved
Meetings and Congress Reports
Medical and Scientific Meetings
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Volume 11 |
Issue 1 |
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ONCOnet*
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TELEMEDICINE WORLDWIDE |
1 |
Telemedicine - Beyond 2000
(Conditions of Development)
Editor-in-chief,
Rashid L. Bashshur, Ph.D.
Telemedicine Journal and e-Health 2001;7(4):273.
In "Telemedicine
Journal and e-Health", Volume 7, Number
4, 2001, Editor-in-chief, Rashid L. Bashshur,
Ph.D. has written an editorial titled "Where
we are in Telemedicine/Telehealth, and where
we go from here". He has presented the
following excerpts taken form his introductory
remarks at the opening session of an international
symposium on the state-of-art in telemedicine
, conducted on the campus of the University
of Michigan on August 23-25, 2001:
- symposium prelude
- the promise of telemedicine
- accessibility enhancement
- cost containment
- quality improvement
- second generation of telemedicine
The paper is useful for understanding the philosophy
of telemedicine and telecare and is certainly
need to be read. On the author's opinion, the
most significant part is one with list of exclusive
conditions which must be observed to improve
telemedicine (access, cost and quality). This
part should convince all health professionals
dealing with telemedicine that despite low level
of present status of telemedicine in Serbia
and a lot of skepticism among health professionals
of real benefit of telemedicine in Serbia under
present conditions, must deal with the problems,
not to give up and wait until better times comes.
"I believe that the promises held by telemedicine
and the hoped for impact on access, cost, and
quality are not likely to be manifest unless
certain NOT mutually exclusive conditions are
observed: · * Enhanced access to healthcare
via telemedicine will be achieved only with
the ubiquitous distribution of telemedicine
systems/networks. The infrastructure must be
within the reach of rich and poor alike, consistent
with the Alma Ata declaration of healthcare
as a right in 1978, to which this country and
other countries are signers. In fact, the need
for increased access to healthcare, lower cost
for healthcare, and increased quality of such
care is generally inversely related to a population's
or region's economic status. To achieve enhanced
access, these systems must become more affordable,
and both the public and private sectors must
assume their respective shares in this investment.
* The key to cost containment is effective substitution
of telemedicine for traditional and more costly
arrangements. Normally, at least initially,
technology contributes to an increase in the
cost of care as it often adds to the diagnostic
and treatment armamentarium. This is the case
despite the fact that the increased capabilities
should improve diagnostic accuracy and health
outcomes. The production function for health
(or the combination of all services needed to
produce a unit of health-including doctor and
nurse time, diagnostic tests, therapeutic regiment,
and other services) must change to encompass
lesser intensity of service and increased efficiency.
* About quality of care, telemedicine's potential
contribution can be realized only through large-scale
diffusion of and conversion to telemedicine,
certainly beyond that observed to date. This
requires broad provider and institutional adoption
and acceptance. A more complete integration
of information technology into routine clinical
practice, greater use of information technology
and artificial intelligence in clinical decision-making,
and standardized electronic medical records
are essential. This integration is necessary
to create a critical mass and to derive the
full benefits of integrative technology related
to diagnosis and treatment, as well as the reduction
of diagnostic and treatment errors (after all
an error is simply quality compromised in some
fashion). By whatever name, these problems can
be reduced through greater reliance on accurate
information about patients, automated clinical
decision support, artificial intelligence and
professional interaction.
* Telemedicine will not realize its full potential
regionally, nationally, and certainly internationally
without greater investment in information technology.
The information highway has only reached some
places recently while in others its development
is nascent. Even in developed countries, there
are significant interstices between the highway
networks where the technology is not available.
The current disjuncture between the enormous
and everexpanding capabilities of information
technology and our ability to exploit these
capabilities must be bridged. Prudent investment
in information technology is challenging because
of its fast obsolescence, the technological
imperative (if it exists we must have it) on
the one hand, and our limited ability to utilize
these capabilities, on the other. Indeed, there
must be long-term commitment and investment
by the public and private sectors. The economic
"pay off," or return on investment,
must be deferred.
* Provider institutions must adapt administrative
policies to accommodate telemedicine and more
broadly health informatics and bio-informatics.
Institutional, organizational and national policies
must face new assumptions and new realities
derived from the development of telemedicine
and health informatics. The medical establishment
must rethink the manner in which it provides
services. It must also address the medical needs
of areas where such services are absent or in
short supply.
Summing up, the second generation of telemedicine
has made great strides in terms of technology,
geography, and interest when compared with the
first. There seems little doubt that this interest
and the advancing technology have assured its
future in some form or another. However, with
an informed public policy and smart private
action, we have the opportunity to derive more
benefits, assure a more prudent investment,
and improve health and well-being of people
everywhere. Perhaps one of the most unique and
significant attributes of telemedicine technology
is its integrative capacity, in establishing
networks, and in building partnerships. More
benefits and more dividends can be achieved
through establishing integrative telemedicine
systems that incorporate all diagnostic and
clinical services within healthcare institutions,
for states and provinces to develop comprehensive
and ubiquitous networks within their boundaries,
and for the countries of the world to share
healthcare resources. We must not think of telemedicine
only in terms of serving remote or otherwise
medically disenfranchised populations. To do
so would not only relegate telemedicine to a
second tier or level of medical care, but would
also ignore its capabilities for greater system
integration and coordination and more efficient
production of health."
Prepared by Svetozar
ZDRAVKOVIC |
2 |
New Telemedicine Center
Creates Virtual "Front-Door" to M.D.
Anderson
Kathleen CHARTER
Texas Medical Center News 2002 Nov 15; 24(21)
Six physicians made history
at The University of Texas M.D. Anderson Cancer
Center Oct. 22, when they "linked up"
in the first telemedicine consultation held
in the cancer center's new telehealth center.
Funded with a $2 million grant from the SBC
Foundation, SBC Communications' philanthropic
arm, the new center provides remote practitioners
with a virtual "front door" to the
cancer center. SBC Communications is the parent
company of Southwestern Bell. Houston M.D. Anderson
physicians Henry Mark Kuerer, M.D., Ph.D., a
surgical oncology assistant professor; Nuhad
K. Ibrahim, M.D., a breast medical oncology
associate professor; and George H. Perkins,
M.D., a radiation oncology assistant professor,
discussed treatment options for a 43-year old
Hispanic breast cancer patient with Orlando-based
M.D. Anderson affiliates Nikita Shah, M.D.,
a medical oncologist; Daniel Bucholz, M.D.,
a radiation oncologist; and Michael Kahky, M.D.,
a surgical oncolgist. "This has been a
dream for years by a number of us," said
John Mendelsohn, M.D., the cancer center's president.
"M.D. Anderson has a wealth of educational
opportunities to share, and this new door of
technology is our way to extend care to the
world." Since M.D. Anderson's clinical
telemedicine program's inception in 1994, nearly
1,500 activities have been conducted annually.
"It is one of the largest telemedicine
oncology programs in the world," said Margaret
Kripke, Ph.D., M.D. Anderson executive vice
president and chief academic officer. "With
this new center, we will continue training even
more of tomorrow's leading researchers today."
The 3,000 square-foot SBC Telehealth Center,
located in M.D. Anderson's Faculty Center, is
comprised of a 65-seat classroom, an administrative
conference room and the telemedicine room where
consultations are held. Rooms feature state-of-the-art
audiovisual and telecommunications equipment
that allows specialists to examine electronic
diagnostic images, pathology slides and other
data from a patient's medical record. In addition,
the classroom features a touch panel to independently
control classroom functions from the podium,
eye-level monitors which allow instructors to
maintain eye contact at all times, a "blue
screen" for special effects, television-friendly
lighting, and a rear-screen projection system
that will support a variety of formats, including
high-definition television. Adding to this new
telecommunications technology, and located across
the street in M.D. Anderson's main clinical
facility, is the newly updated SBC Auditorium
that seats 300. "M.D. Anderson views patient
care as multidisciplinary," Mendelsohn
said. "This new center will host patient-care
teams as they develop the best possible patient-care
plans." In addition to conducting long-distance
medical consultations, patient and professional
educational programs, and research exchanges
with affiliates in Orlando and Madrid, as well
as other institutions across the nation and
globe, the SBC Telehealth Center is bridging
the digital divide by making live Internet broadcasts
and "on demand" Internet video available
to worldwide audiences. The center's distance
education area will also provide interactive
television facilities for teaching graduate-level
courses from The University of Texas Graduate
School of Biomedical Sciences. "Having
the facilities on campus, in the same building
as our faculty offices, will save our educators
travel time and time away from patients,"
said Stephen Tomasovic, Ph.D., vice president
for educational programs. "With this well-equipped
telecommunication center in place, we are supporting
M.D. Anderson's mission of 'Making Cancer History,'"
Mendelsohn said.
Texas Medical
Center News [Internet] Texas Medical Center;©1996-2002
[cited 2003 Mar 25]. Available from http://www.tmc.edu/tmcnews/11-05-02/page_01.html). |
3 |
Telemedicine news - 1
In an effort to take
quality healthcare across India and into neighbouring
nations, a Calcutta-based private group has
decided to open several treatment centres equipped
with telemedicine facilities connecting all
the units with both Calcutta and an Ohio-based
hospital in the United States. To begin with,
B.M. Birla Heart Research Centre plans to open
15 treatment centres-cum-diagnostic facilities
in places like Siliguri, Burdwan, Midnapore,
Malda, Ranchi, Bhubaneswar, and a few towns
in the Northeast. The treatment centres will
have doctors and diagnostic facilities. "They
will be equipped with telemedicine connections,
through which experts in Calcutta can opine
on a patient's condition after a look at the
investigation results, including X-rays and
ECGs," said M.L. Pachisia of the Heart
Research Centre. If required, cases can be seen
by experts at the Cleveland Clinic in Ohio.
The Telegraph
- Calcutta, February 28, 2003
|
4 |
Telemedicine news - 2
Initial user feedback
on a futuristic experiment in France allowing
medical professionals in different locations
to view three-dimensional images of patients'
organs has been extremely positive. The 'Argonaute
3D' project allows a virtual representation
of an organ to be produced from traditional
two-dimensional scans, highlighting any tumours.
Doctors and other medical staff can then simultaneously
view the representation from any angle. Combined
with videoconferencing at the consultation stage,
the system allows all the necessary medical
professionals to view and discuss the problem
area before surgery takes place. The scheme
is a collaboration between telecommunications
company France Telecom and the Institute for
Research into Cancer of the Digestive System
(IRCAD) in Strasbourg.
Future Health
Bulletin, February 28, 2003 |
5 |
Telemedicine technology
news - 1
Titan Corp. is developing
a "sensor glove" designed to record
and transmit patients' vital signs almost instantly
to doctors who are helping make decisions on
medical treatment from half a world away. The
glove, which would be worn by medics in the
field, would record an injured soldier's pulse
rate, body temperature, blood pressure, and
blood-oxygen level. The information would be
relayed to doctors using wireless technology.
A short video by NBC KNSD/7 TV in San Diego
is available on the Titan Web site (requires
Real Player or Windows Media Player).
Augusta Chronicle,
December 26, 2002 |
6 |
Telemedicine technology
news - 2
Asthma sufferers could
soon benefit from a system which allows their
doctors to keep track of their condition via
mobile phone. The system connects an electronic
lung capacity measuring device, known as a peak
flow meter, to a mobile phone which gathers,
records, and submits accurate asthma data in
real-time to doctors. This system, the brainchild
of telemedicine firm e-San, will allow doctors
to receive immediate alerts of patients whose
conditions have deteriorated. For the duration
of the trial, 100 asthma patients in the Slough
area of the UK will be given a free mobile device
- O2's XDA, which is a combined phone and personal
digital assistant. There are around 3.5 million
asthmatics in the UK, which has one of the worst
records for the condition in Europe.
BBC News, March
3, 2003 |
7 |
Telemedicine technology
news - 3
Wellogic and WorldCare
recently announced the activation of a turnkey
telemedicine system that will enable WorldCare
clients to receive expert second opinion medical
consultations rendered by the WorldCare Consortium:
The Cleveland Clinic, Duke University Health
System, Johns Hopkins Medicine, and Partners
HealthCare System, which includes Massachusetts
General Hospital and Brigham and Women's Hospital.
Wellogic Consult will enable clinical users
in referring locations to assemble a complete
electronic patient record and securely transmit
the record to a reviewing hospital. Advanced
image compression, combined with advanced Web
services technology and deep user interface
design, makes Consult ideal for the transmission
of all components of an electronic patient record,
from text and scanned documents to DICOM images
and digitized radiology films, over any connection,
even dial-up.
PR Newswire,
March 3, 2003 |
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TELEMEDICINE JOURNALS |
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|
News
1 |
Prognostic value of magnetic
resonance imaging-guided stereotactic biopsy
in the evaluation of recurrent malignant astrocytoma
compared with a lesion due to radiation effect
McGirt MJ, Bulsara
KR, Cummings TJ, New KC, Little KM, Friedman
HS et al.
J Neurosurg 2003;98(1):14-20.
This study
was undertaken to determine the prognostic value
of differentiating between recurrent malignant
glioma and a lesion due to radiation effect
by performing stereotactic biopsy has not been
assessed. Between 1995 and 2001, 114 patients
underwent magnetic resonance (MR) imaging-guided
stereotactic biopsy to differentiate lesions
caused by a recurrence of malignant astrocytoma
and by radiation effect. All patients had previously
undergone tumor resection (World Health Organization
Grade III or IV) followed by radiotherapy. Disease
diagnosis based on biopsy and patient characteristics
were assessed as predictors of survival according
to results of a multivariate Cox regression
analysis. With the aid of stereotactic biopsy
the authors demonstrated prognostic significance
in differentiating recurrent malignant astrocytoma
from a lesion due to radiation effect in patients
presenting more than 5 months after having undergone
radiotherapy. In patients who presented earlier
than 5 months after radiothera- py, radiation
effect on biopsy was not associated with an
improved rate of survival compared with that
in patients harboring recurrent malignant astrocytoma. |
2 |
Activity and expression
of human telomerase in normal and malignant
cells in gastric and colon cancer patients
Nowak J, Januszkiewicz
D, Lewandowski K, Nowicka-Kujawska K, Pernak
M, Rembowska J et al.
Eur J Gastroenterol Hepatol 2003;15(1):75-80.
The aim of
this study was to investigate the expression
of three components of the telomerase complex
(hTR, hTERT and TP1), along with telomerase
activity in malignant and normal cells. Addition
of Ifosfamide and Etoposide to Standard Chemotherapy
for Ewing's Sarcoma and Primitive Neuroectodermal
Tumor of Bone Expression of hTERT, hTR and TP1
has been studied by the reverse transcriptase
polymerase chain reaction (PCR) technique. It
can be concluded that all the cancer cells tested
have higher telomerase expression and activity
than normal cells. Therefore, telomerase can
be a good cancer marker, provided that quantita-tive
analysis is carried out. |
3 |
Multiple Colorectal adenomas,
Classic adenomatous polyposis, and germ-line
mutations in MYH
Sieber MO, Lipton
L, Crabtree M, Heinimann K, Fidalgo P, Phillips
KSR et al.
N Engl J Med 2003;348:791-9.
Germ-line mutations
in the base-excision-repair gene MYH have been
associated with recessive inheritance of multiple
colorectal adenomas. Tumors from affected persons
displayed excess somatic transversions of a
guanine-cytosine pair to a thymineadenine pair
(G:C -->T:A) in the APC gene. Six patients
with multiple adenomas and eight patients with
polyposis had biallelic germline MYH variants.
In the group with multiple adenomas, about one
third of patients with more than 15 adenomas
had biallelic MYH mutations. In the polyposis
group, no patient with biallelic MYH mutations
had severe disease (>1000 adenomas), but
three had extracolonic disease. No clearly pathogenic
MTH1 or 0GG1 mutations were identified. Germ-line
MYH mutations predispose persons to a recessive
phenotype, multiple adenomas, or polyposis coli.
For patients with about 15 or more colorectal
adenomas - especially if no germ-line APC mutation
has been identified and the family history is
compatible with recessive inheritance - genetic
testing of MYH is indicated for diagnosis and
calculation of the level of risk in relatives.
Clinical care of patients with biallelic MYH
mutations should be similar to that of patients
with classic or attenuated familial adenomatous
polyposis. |
4 |
Addition of Ifosfamide
and Etoposide to Standard Chemotherapy for Ewing's
Sarcoma and Primitive Neuroectodermal Tumor
of Bone
Grier EH, Krailo
DM, Tarbell JN, Link PM, Fryer JH Ch, Pritchard
Jd et al.
N Engl J Med 2003;348:694-701.
Ewing's sarcoma
and primitive neuroectodermal tumor of bone
are closely related, highly malignant tumors
of children, adolescents, and young adults.
A new drug combination, ifosfamide and etoposide,
was highly effective in patients with Ewing's
sarcoma or primitive neuroectodermal tumor of
bone who had a relapse after standard therapy.
A total of 518 patients met the eligibility
requirements. Of 120 patients with metastatic
disease, 62 were randomly assigned to the standard-therapy
group and 58 to the experimental-therapy group.
There was no significant difference in five-year
event-free survival between the treatment groups
(P=8.81). Among the 398 patients with nonmetastatic
disease, the mean (±SE) five-year event-free
survival among the 198 patients in the experimentaltherapy
group was 69±3 percent, as compared with 54±4
percent among the 200 patients in the standard-therapy
group (P=0.005). Overall survival was also significantly
better among patients in the experimental-therapy
group (72±3.4 percent vs. 61±3.6 percent in
the standard-therapy group, P=0.01). The addition
of ifosfamide and etoposide to a standard regimen
does not affect the outcome for patients with
metastatic disease, but it significantly improves
the outcome for patients with nonmetastatic
Ewing's sarcoma, primitive neuroectodermal tumor
of bone, or primitive sarcoma of bone. |
5 |
Clinical trials and regulations
Snezana SUSNJAR
In January's issue of European Journal of
Cancer, Grossi F et al reported the geography
of clinical cancer research publications from
1995 to 1999 (EJC 2003; 39: 106-111). The authors
performed the Medline search to collect the
data concerning reported phase I, II and III
trials dealing with antineoplastic treatment
and supportive therapy, as well. More than 40
countries were included in this search. The
United States ranked first by both the number
of papers and the mean impact factor (IF) of
papers in which the trials were reported. According
to this analysis Yugoslavia was among the top
25 countries by number of reported papers (15).
The total IF for that period was 57, 296, and
mean IF was 3,18 which placed Yugoslavia in
top 10 countries after Canada, Netherlands,
UK, Australia, USA, Finland, Israel, France
and Austria. Although there is some experience
in conducting clinical trials in Serbia, still
legislative documents are lacking. Good clinical
practice (GCP) is an international, ethical
and scientific quality standard for designing,
conducting, recording and reporting of clinical
studies. The harmonization of different national
GCPs (USA, Europe, Japan) was finally achieved,
thus facilitating the mutual acceptance of clinical
data by different regulatory authorities. These
regulations, in accordance with European Union
Directives concerning clinical trials, are hopefully
expected to be incorporated into the Law on
pharmaceutical products in Serbia very soon.
However, there is substantial concern about
GCP has already become an obstacle to progress
for clinical trials in the treatment of breast
cancer (The Statement of Barcelona, EJC 2002;
38: 2210-3). Although GCP was basically created
to protect research subjects' confidentiality,
ensure that ethical principles are applied and
none of adverse events, especially serious side
effects of new drugs, to be overlooked, the
conduction of clinical trials according to GCP
rules became very difficult for researchers
and prohibitively expensive. Hence, the authors
called for common sense to be allowed to prevail
and introduced two watchwords: education (of
public, ethics committees and clinical scientists)
and partnership (between patients, clinical
researchers and the politicians responsible
for bureaucracy governing the development of
new drug). |
6 |
Morphine in cancer pain
management: a practical guide
Snezana SUSNJAR
Morphine is the strong opioid of choice
for the relief of chronic severe pain associated
with cancer. If given according to well-established
principles, morphine relieves pain in 80% of
patients. A practical guide for morphine administration
in cancer pain management was recently published
in the Journal of Supportive Care in Cancer
reviewing the clinical guidelines of the Harry
R. Horvitz Center (a World Health Organization
Center for palliative medicine). The pharmacokinetics
of morphine is presented in details and how
it is altered by age, renal and hepatic function,
concomitant medications, gender and ethnic differences.
The indications for morphine use in cancer pain
management are clearly stated. It is pointed
out that the morphine is indicated for severe
cancer pain, whether somatic, visceral or neuropathic
although morphine-poorly-responsive pain syndromes
do exist. The practical recommendations for
dose titration (initial morphine dose and rescue
doses for breakthrough pain) to achieve adequate
balance between analgesia and adverse effects
are particularly useful. One of the advantages
of morphine in comparison with other strong
opioids is the possibility of drug administration
by several different routes (oral, sublingual/buccal,
rectal, parenteral, epidural, intrathecal, vaginal
and topical). The article gives a detailed description
of the routes of morphine administration (indications,
advantages, disadvantages and dose conversions).
The major adverse effects of morphine (gastrointestinal,
neuropsychiatric, respiratory) are summarized
with the aim to help clinicians to prevent and
manage them effectively. Together with already
existing guidelines (1, 2) a practical guide
presented in this article could help clinicians
to further improve the effectiveness of cancer
pain management with morphine and the quality
of supportive care received by cancer patients.
Reference:
1. Hanks GW, de Conno F, Cherny N, et al. Morphine
and alternative opioids in cancer pain: the
EAPC recommendations. Br J Cancer 2001; 84:587-93.
2. Cherny N, Ripamonti C, Pereira J, et al.
Strategies to manage the adverse effects of
oral morphine: an evidence based report. J Clin
Oncol 2001;19:2542-54. rug). |
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Book Review
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 2 |
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News
1 |
A growing network of cancer-susceptibility
genes
Venkitaraman RA
N Engl J Med 2003;348:1917-9.
In the search for genes
that are relevant to disease, new contexts are
discovered for "old" molecules. Several
genes are particular- ly versatile, in that
they are individually responsible for more than
one disase. A study by Howlett et al. Provides
an interesting example: mutation of BRCA2, a
breast-cancer-susceptibility gene, may cause
Fanconi's anemia. Genetic instability is charac-
teristic of BRCA 2-deficient cells, which accumulate
broken and deformed chromosomes as they divide.
Similar abnormalities also occur in cells that
lack BRCA1, another breast-cancer-sus- ceptibility
gene. Genetic instability can be triggered by
the failure to repair breaks in double-stranded
DNA caused by ionizing radi- ation. BRCA2 and
BRCA1 protein are essential for recombination
but dispensable for end-joining. In dividing
cells deficient in either protein, breaks in
double-stranded DNA are repaired predomi- nantly
through error-prone mechanisms, leading to chromosomal
aberrations and an increased rate of mutation.
The centrality of DNA-repair reactions - as
mediated by RAD51 and BRCA2 - in preserving
chromosomal structure and preventing carcinogenesis
is emphasized by work exposing a connection
between suscepti- bility to breast cancer and
Fanconi's anemia, a rare, autosomal recessive
disease that confers an increased risk of acute
myeloid leukemia and squamous-cell carcinoma.
At least eight subtypes of Fanconi's anemia
(designated A, B, C, D1, D2, E, F and G), each
with a distinct genetic cause, have been recognized.
Germ-line mutations in six different genes (accounting
for all subtypes except B and D1) have been
identified. Two findings have cemented the connection
between breast-cancer proteins and Fanconi's
anemia. The first was the discovery that FANCD2,
the gene mutated in patients with the subtype
D2, links Fanconi's anemia proteins to BRCA1.
These findings suggest that BRCA2 is the gene
mutated in Fanconi's anemia D1 and, possibly
B. The serine-threonine kinases ATM (which is
mutant in patients with ataxia-telangiectasia)
and CHEK2 are enzymatic components of the machinery
by which cells sense and signal the presence
of breaks in double-stranded DNA. In this case,
the aberrations in DNA recombination that promote
carcinogenesis by causing genetic instability
may also be the Achilles? heel of the cancers
that arise in this setting.
 |
Figure
1. Cancer-Susceptibility Genes and DNA
Repair. Several genes (ATM, CHEK2, BRCA1,
and BRCA2) whose inactivation predisposes
people to breast and other cancers participate
in the error-free repair of breaks in
double-stranded DNA by homologous recombination.
The process starts when ATM and CHEK2
protein kinases signal the presence of
double-stranded breaks by phosphorylating
(red arrows) proteins such as BRCA1, inducing
their migration to sites where DNA is
repired. BRCA2 carries the DNA-recombination
enzyme RADS1 to the same sites. It is
guided there by the DNA-binding structures
formed between its carboxy terminal and
Dss1. The concetreted activity of these
proteins culminates in error-free DNA
repair by recombination. Two findings1,2
connect Fanconi's anemia proteins to this
pathway. First, a complex of Fancon's
anemia proteins - termed A, C, D2, E,
F, and G - triggers the ubiquitination
of the D2 protein alone and its colocalization
with BRCA1. Second, BRCA2 is mutated in
a small group of patients with Fanconi's
anemia. This work emphasizes the importance
of the homologous recombination pathway
in the pathogenesis of disorders involving
chromosomal instability. Ub denotes mono-ubiquitin. |
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2 |
A randomized trial of aspirin
to prevent colorectal adenomas in patients with
previous colorectal cancer
Sandler SR, Halabi
S, Baron AJ, Budingers S, Paskett E, Keresztes
R et al.
N Engl J Med 2003;348:883-90.
Experimental studies in
animals and observational studies in humans
suggest that aspirin and other nonsteroidal
antiinflamatory drugs (NSAIDs) may decrease
a risk of colorectal adenomas,the precursors
to most colorectal neoplasia.Randomized clinical
trials have demonstrated the reduction innumber
and size of adenomas in patients with familial
adenomatous polyposis (FAP) (Snadler RS et al.).
The Colorectal Adenoma Prevention Study and
Eastern Cooperative Oncology Group (ECOG) in
the M.D. Anderson Cancer Center randomly assigned
635 patients with colorectal cancer to receive
either aspirin 325 mg aspirin per day or placebo.
One or more adenomas were found in 17% of patients
in the aspirin group and 27% in patients of
the placebo group. Relative risk of recurrent
adenoma in the aspirin group was 0.65. The time
to the detection of a first adenoma was longer
in theaspirin group than in the placebo group
(hazard risk ratio for thedetection of a new
polyp, 0.64). Daily use of aspirin is associated
with a significant reduction inthe incidence
of colorectal adenomas in patients with previous
colorectal cancer.
 |
Figure
1. Kaplan-Meier Estimates of the Time
to a First Adenoma |
 |
Table
2. Number of Colonoscopic Examinations
after Randomization |
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3 |
Adjuvant treatment with
interferon alfa did not contribute to survival
or relapse-free survival in completely resected
locally advanced renal cell carcinoma
Davorin RADOSAVLJEVIC
Messing et al. (1) reported
in April issue of Journal of Clinical Oncology
the results of randomized, phase III trial of
adjuvant interferon alfa compared with observation
for 283 eligible patients with locally advanced
(pT3-4 and/or node positive disease) renal cell
carcinoma completely resected by radical nephrectomy
and lymphadenectomy. In the treatment arm interferon
was given daily for 5 days every 3 weeks for
up to 12 cycles. At median follow-up of 10.4
years, median survival was 7.4 years in the
observation arm and 5.1 years in the treatment
arm. Median recurrence-free survival was 3.0
years in the observation arm and 2.2 years in
the interferon arm. Although no lethal toxicities
were observed, severe (grade 4) toxicities including
Neutrogena, myalgia, fatigue, depression, and
other neurological toxicities occurred in 11.4%
of those randomly assigned to interferon treatment.
The results of the study are in accordance with
those from two other phase-III randomized trials
(2,3) which compared interferon alfa given as
adjuvant treatment with observation after complete
resection: none showed a delay in time to relapse
or improvement of overall survival associated
with interferon alfa therapy. Data are lacking
for study of interleukin-2 adjuvant therapy
in a randomized trial. Thus, the standard management
for localized tumors after nephrectomy remains
surveillance. Success of an adjuvant treatment
program depends on drugs capable of eradicating
metastases. The outcome of three adjuvant trials
(1-3) reflects the lack of effective systemic
therapy to treat metastatic disease. Three decades
of extensive clinical investiga- tions have
identified only two agents that have an effect
on survival for patients with metastatic disease.
Treatment with high-dose bolus interleukin-2
achieved durable responses in small proportion
of highly selected patients. A modest survival
benefit for interferon alfa therapy in metastatic
renal cell carcinoma was observed in two-phase
III trials comparing interferon alfa with vinblastine
or medroxyprogesterone. Given the high proportion
of patients with metastases and the associated
poor survival, this malignancy must be regarded
as a priority for studies in tumor biology and
development of novel, mechanism-driven therapy
(4).
Reference:
1. Messing EM, Manola J, Wilding G et al. Phase
III study of interferon alfa-NL as adjuvant
treatment for resectable renal cell carcinoma:
An Eastern Cooperative Oncology Group/Intergroup
Trial. J Clin Oncol 2003; 21:1214-22.
2. Porzsolt F. Adjuvant therapy of renal cell
cancer with interferon alfa-2a. ProcAmSocClin
Oncol 1992;11:202, (abstr 622).
3. Pizzocaro G, PivaL, Costa A et al. Adjuvant
interferon to radical nephrectomy in Robson`s
stage II and III renal cell cancer: A multicenter
randomized study with some biological evaluations.
Proc Am Soc Clin Oncol 1997;16:318a (abstr.
1132).
4. Motzer RJ: Renal Cell Carcinoma: A Priority
Malignancy for Development and Study of Novel
Therapies (editorial). J Clin Oncol 2003; 21:1193-4.
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4 |
National Comprehensive
Cancer Network-Guidelines for the management
of prostate cancer
Douglas Scherr,
Peter W. Swindle, Peter T. Scardino
Guidelines for the management
of prostate cancer issued by the National Comprehensive
Cancer Network (NCCN) assembled a Prostate Cancer
Panel composed of 17 leading experts in field
of prostate including urologists, radiation
oncologists and medical oncologists provide
a basis for rationale treatment decisions. These
guidelines represent concensus recommendations
and evidence based for physicians in prostate
cancer treatment. The initial stratification
point in the guidelines is based on the anticipated
life expectancy of the individual patient (>5
or <5 years) and whether the patient is symptomatic
from the prostatic cancer. If the life expectancy
is > 5 years, the recommended intervention
is based on clinical stage, prostate-specific
antigen (PSA) level, Gleason score, and presence
of symptoms. These assessments establish the
patient's risk of recurrence after therapy (low,
intermediate, high or very high). The guidelines
also describe the appropriate use of observation
("watchful waiting") vs. active intervention
in certain patients. After radical therapy,
patients should be monitored with PSA determinations,
digital rectal examination and bone scans. Patients
who exhibit increasing PSA levels after radiotherapy
are candidates for surgery as the additional
option. If PSA begins to increase after prostatectomy,
androgen ablation, radiotherapy or observation
is treatment of choice. Systemic salvage therapy
generally consists of androgen ablation; the
benefit of total androgen blockade vs. monotherapy
remains controversial. Relapse after initial
androgen ablation is treated with an antiandrogen,
if none had been administered previously. Patients
refractory to further hormonal therapy are observed
or receive palliative therapy, including chemotherapy.
The NCCN guidelines serve to provide a framework
on which physicians can base optimal treatment.
Specific disease characteristics, life longevity
and personal preferences of the patient are
fundamental for treatment recommendation.
(Source: Urology
2003;61 (Suppl 2A), 14-24) |
Meetings and Congress
Reports
Medical and Scientific Meetings
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Issue 3 |
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Medical
Meeting
XXXX
Annual Meeting of the Oncologists of Serbia
XVII Meeting of Oncology and Radiology of Serbia
Institute for Oncology and Radiology
of Serbia
Srbian Medical Association
November 5-7, 2003 - Belgrade, Yugoslavia |
148 |
LOCALLY ADVANCED BREST
CANCER: ABSTRACTS
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183 |
THYROID CANCER: ABSTRACTS
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196 |
CURRENT RADIOTHERAPY: ABSTRACTS
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219 |
MISCELLANEOUS
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XVII
Meeting of Oncology Nurses and Technicians of
Republic of Serbia |
223 |
CONFERENCE
REPORTS AND ABSTRACTS |
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Issue 4 |
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News
1 |
Adjuvant ovarian function
supression under reinvestigation
Snezana SUSNJAR
The role of adjuvant endocrine
therapy is well established for the treatment
of endocrine-responsive breast cancer (BC) patients.
Adjuvant ovarian function suppression (OFS)
was the first endocrine treatment proved to
be efficacious in breast cancer. Adjuvant chemotherapy
showed to be superior in younger thus premenopausal
patients compared to older ones, which is explained
by the fact that chemotherapy very often leads
to amenorrhea in younger patients. However,
it seems that the benefit from adjuvant chemotherapy
is more dependent on age than on menopausal
status (1). Furthermore, women aged <35 years
with steroid receptor (SR) - positive disease
treated with adjuvant chemotherapy alone seemed
to have the worst outcome in comparison with
other patients (1).
According to EBCTCG analysis published in 1998
(2), tamoxifen is as effective in premenopausal
as is in postmenopausal SR - positive breast
cancer patients. Due to this report, tamoxifen
± chemotherapy was accepted as one of standard
adjuvant treatments in premenopausal endocrine-responsive
patients. The latest report of ZEBRA (3) and
ABCSG 05 trials (4), revealed that adjuvant
LH-RH analogs given to these women alone or
with tamoxifen might have equal effect to or
might be superior to adjuvant CMF (cyclophosphamide,
methotrexate, and fluorouracil) chemotherapy.
Due to inconclusive data presented in current
trials, these are the main open questions waiting
to be resolved:
1. What is the role of ovarian suppression,
e.g. does it add to the benefit of combined
chemotherapy + tamoxifen?
2. Does adjuvant chemotherapy add to the efficacy
of combined OFS + tamoxifen?
3. What is the best mode of OFS, e.g. is permanent
OFS superior to temporary OS?
4. What is the role of aromatase inhibitors
in combination with OFS in premenopausal patients?
To address these questions tailored treatment
investigation for premenopausal endocrine-responsive
patients was designed. Three complementary studies,
coordinated by International Breast Cancer Study
Group (IBCSG), are being conducted (5,6): SOFT
(Suppression of Ovarian Function Trial) for
those women whose doctors prefer to use tamoxifen
and TEXT (Tamoxifen and Exemestane Trial) and
PERCHE (Premenopausal Endocrine Responsive Chemotherapy
Trial) for patients who are considered for OFS
from the beginning of adjuvant treatment. Eight
thousand premenopausal SR-positive breast cancer
patients are intended to be included in these
trials.
Many oncologists and patients are concerned
about the consequence of the early menopause
related mainly to the osteoporosis, lipid metabolism
and cardiovascular complications and sexual
activity. How to get over it is another important
issue need to be further investigated in order
to ensure good quality of life to these women.
References:
1. Craig Henderson: Endocrine Therapy, Chemotherapy,
of Both as Adjuvant Systemic Treatment of Patients
With Early Breast Cancer, in: Educational book,
Annual Meeting of American Society of Clinical
Oncology. J Clin Oncol 2001;Suppl: 53-60.
2. Early Breast Cancer Trialists' Collaborative
Group: Polychemotherapy for early breast cancer:
an overview of the randomised trials. Lancet
1998;352:930-42.
3. Jonat W, Kaufmann M, Sauerbrei W, Blamey
R, Cuzick J, Namer M et al. Goserelin Versus
Cyclophosphamide, Methotrexate, and Fluorouracil
as Adjuvant Therapy in Premenopausal Patients
With Node-Positive Breast Cancer: The Zoladex
Early Breast Cancer Research Association Study.
J Clin Oncol 2002;20:4628-35.
4. Jaskesz R, Hausmaninger H, Kubista E, Gnant
M, Menzel C, Bauernhofer T et al. Randomized
Adjuvant Trial of Tamoxifen and Goserelin Versus
Cyclophosphamide, Methotrexate, and Fluorouracil:
Evidence for the Superiority of Treatment with
Endocrine Blockade in Premenopausal Patients
With Hormone-Responsive Breast Cancer - Austrian
Breast and Colorectal Cancer Study Group Trial
5. J Clin Oncol 2002;20(24):4621-7.
5. Gelber RD, Castiglione-Gertsch M, Coates
AS, Goldhirsch A for the International Breast
Cancer Study Group (IBCSG), Breast International
Group (BIG) and North American Breast Intergroup.
Tailored Treatment Investigation for Premenopausal
Women with Endocrine Responsive (ER+ and/or
PgR+) Breast Cancer: The Open Questions. The
Breast 2003;12 Suppl 1:S43(Abstr P103).
6. Francis P, Fleming G, Nasi ML, Pagani O,
Perez E, Walley B, for the International Breast
Cancer Study Group (IBCSG), Breast International
Group (BIG) and North American Breast Intergroup.
Tailored Treatment Investigation for Premenopausal
Women with Endocrine Responsive (ER+ and/or
PgR+) Breast Cancer: The SOFT, TEXT and PERCHE
Trials. The Breast 2003;12 Suppl 1:S44 (Abstr
P104). |
2 |
Step forward in tumor's
cytogenetics: Vulvar and vaginal cancer
Vulvar and vaginal
cancer are a rare gynecologic malignancy. Vulvar
cancer accounts for 5% of all female genital
cancers and 1% of all malignancies in women
(1). The most common histology of vulvar cancer
is squamous cell carcinoma accounting for about
87% of these lesions. Malignant melanoma is
the second most common cancer occurring in the
vulva, accounting for about 6% of lesions. Other
less common histological types include Bartholin's
gland adenocarcinoma, sarcoma, basal cell carcinoma,
and invasive Paget's disease (2).Changes in
genetic code of normal cells, which become abnormal
with malignant potential and abnormalities of
tumor's cells karyotypes, nowadays are still
gray fields of molecular oncology. Only few
cases had been analyzed by chromosome banding
techniques and karyotyped, and also the number
subjected to molecular cytogenetic analysis
remains low. F. Micci and colleagues, Norwegian
Radium Hospital, Department of Cancer Genetics,
analyzed cytogenetically 51 tumors of vulva
and vagina, and found karyotypic abnormalities
in 37 (3). All tumors were analyzed by G-banding,
sometimes supplemented by multicolor fluorescence
in situ hybridization, and a subset of tumors
was also analyzed by comparative genomic hybridization.
The two cytogenetically abnormal cases of Paget's
disease both had two clones, one with gain of
chromosome 7 as the sole change, the other with
loss of the X chromosome among, in one case,
other aberrations. Researches also found 31
cytogenetically abnormal squamous cell carcinomas,
and different clonal karyotypic abnormalities
were seen. Intratumor heterogeneity with multiple
clones was observed in 11 cases. The clones
were cytogenetically unrelated in eight tumors
but related in three, indicating that in the
latter clonal evolution had taken place from
a single malignantly transformed cell. The main
chromosomal imbalances were gains of, or from,
chromosome arms 3q, 5p, 8q, 9q, and 19q, and
loss from 11q. Breakpoint clusters were seen
in 11q13-23, 2q22-35, and 19q13, as well as
in the centromeres and pericentromeric bands
of chromosomes 3, 8, 9, 13, 14, and 22.
References:
1. DiSaia PJ, Creasman WT. Invasive carcinoma
of the vulva. In: Clinical gyne- cologic oncology.
St. Louis: Mosby-Year Book; 1997. p. 202-32.
2. Giselle B. Ghurani and Manuel A. Penalver:
An update on vulvar cancer. Am J Obstet Gynecol
2001;185:294-9.
3. Micci F. Cytogenetic characterization of
tumors of the vulva and vagina. Genes Chromosomes
Cancer 2003;38(2):137-48.
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3 |
Is HE4 new biomarker for
early detection of ovarian cancer or CA125 is
still alone?
Epithelial ovarian cancer
belongs to the most common and most deadly of
all types of ovarian carcinomas. Ovarian cancer
is the sixth most common cancer in women worldwide
and the leading cause of death from gynecological
cancer. The three screening techniques available
at this time (pelvic examination, CA-125 level,
and vaginal ultrasound) do not actually diagnose
ovarian cancer but only suggest its presence.
As a biomarker, CA125 is still the best available
diagnostic test for epithelial ovarian cancer.
Unfortunately it is not so specific and it is
not very effective in identifying early stage
disease. It is useful in diagnosing late stage
cancers, and in detecting the recurrence of
tumors after chemotherapy and radiation. Also
it could give false-positive results in some
cases. Recently Scientists at the Pacific Northwest
Research Institute (PNRI) in Seattle, Washington,
announced a new biomarker for ovarian cancer.
The researchers describe a molecule, HE4, associated
with ovarian cancer cells. They performed experiments
to explore whether quantitation of HE4 protein
levels in serum can be used as a biomarker for
ovarian carcinoma. Because the molecule is secreted
readily into the blood, its presence should
be detectable when simple and inexpensive clinical
blood tests are developed. A double determinant
("Sandwich") ELISA was constructed
and shown to detect a signal at the 160-pg level.
Blinded studies on sera from postmenopausal
patients with ovarian carcinoma and controls
indicate that the specificity and sensitivity
of the HE4-based ELISA is equivalent to that
of the CA125 assay. The new biomarker HE4 proved
to be at least as effective as CA125. There
where no false-positive results occurred, HE4's
sensitivity to ovarian carcinoma was 40% higher
than that of CA125. The possibility that a simple
and inexpensive blood test can be developed
for clinical use is already being studied in
a licensing agreement with Fujirebio Diagnostics
Inc., the creator of CA125 but still there are
many things to be done before it really showed
some benefits in early diagnosis of ovarian
cancer.
References:
1. Boyle P, Maisonneuve P, Autier P. Towards
cancer control in women. J Epidemiol Biostat
1998;3:137-68.
2. Landis SH, Murray T, Bolden S, Wingo PA:
Cancer statistics, 1999. CA Cancer J Clin 1999;49:8-31.
3. Hellstr.m I, Raycraft J, Hayden-Ledbetter
M, Ledbetter JA, Schummer M, McIntosh M et al.
The HE4 (WFDC2) Protein Is a Biomarker for Ovarian
Carcinoma". Cancer Res 2003;63:3695-700. |
4 |
Mechanism of paclitaxel
resistance: Bcl-2 down-regulation?
Aljosa MANDIC
Chemotherapy is the standard
adjuvant therapy following cytoreductive surgery
in treatment of the advanced ovarian carcinoma.
In new therapy standards emerged after the publication
of a trial by the Gynecologic Oncology Group
(GOG) in 1996 and the first reports of a intergroup
trial in 1998 that confirmed GOG. The results
demonstrated that patients treated with cisplatin/paclitaxel
regiment had significantly higher response rates,
progression-free survival and overall survival
compared with the previous standard treatment
of cisplatin and cyclophosphamide (1,2) Consensus
statements were published in 1998, recommending
that optimal treatment of advanced disease following
cytoreductive surgery was chemotherapy with
a taxane and platinum compound (3). Paclitaxel
belong to the group of taxanes. Paclitaxel is
an antimicrotubule agent that promotes the assembly
of microtubules from tubulin dimers and stabilises
microtubules by preventing depolymerisation.
This stability results in the inhibition of
the normal dynamic reorganisation of the microtubule
network that is essential for vital interphase
and mitotic cellular functions (4). Decrease
in sensitivity of the tumor cell to the chemotherapy
is one of the most important problems that occur
nowdays effecting results of chemotherapy. Investigate
the mechanism of the resistance is also one
of the goal in modern oncology. C. Ferlini and
colleagues, Laboratory of Antineoplastic Pharmacology,
Department of Obstetrics and Gynaecology, Universit.
Cattolica Sacro Cuore, Rome, Italy reported
about Bcl-2 down-regulation as a novel mechanism
of paclitaxel resistance. Mitochondrial was
investigated as an additional target of taxanes.
Isolated mitochondria were incubated in the
presence of taxanes with or without stimulation
of the mitochondrial respiratory state. To evaluate
the binding of [14C]paclitaxel to isolated mitochondria,
mitochondrial proteins were precipitated yielding
18.6 ± 2.1 cpm/µg of protein. After stimulation
of the respiratory state, binding of [14C]paclitaxel
increased up to 163.2 ± 46.7 cpm/µg of protein.
CPM values after Bcl-2 immunoprecipitation were
62.8-fold higher than those of the control antibody,
thereby indicating the involvement of Bcl-2
in paclitaxel binding. A panel of A2780 cell
lines resistant to increasing doses of paclitaxel
alone or to high doses of paclitaxel/cyclosporine
A (A2780 TC cells) was established. In both
cases, Bcl-2 expression was consistently down-regulated,
whereas levels of other members of the Bcl-2
family, such as Bax and Bcl-x, did not change
in paclitaxel-resistant cell lines. When A2780TC
cells were stably transfected with a Bcl-2 construct,
paclitaxel sensitivity was partially restored,
thereby supporting a direct role of Bcl-2 down-regulation
in the maintenance of drug-resistance. Than
they examined Bcl-2 by immunohistochemistry
in a small subset of ovarian cancer paclitaxel-resistant
patients and it was noticed that the protein
is down-regulated in this clinical setting with
respect to the expression levels found in drug-sensitive
tumors (5). This very interesting findings point
to Bcl-2 as an additional intracellular target
of taxanes and that its down-regulation is involved
in taxane resistance.
References:
1. McGuire WP, Hoskins WJ, Brady MD et al. Cyclophosphamide
and cisplatin compared with paclitaxel and cisplatin
in patients with stage III and stage IV ovarian
cancer. N Engl J Med 1996;334:1-6.
2. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton
KD. European, Canadian randomised trial of paclitaxel
in relapsed ovarian cancer: high-dose versus
low-dose and long versus short infusion. J Clin
Oncol 1994;12:2654-66.
3. Berek JS, Bertelsen K, du Bois A. Advanced
epithelial ovarian cancer:1998 consensus statements.
Ann Oncol 10Suppl 1:1999:87-92.
4. Mandic A, Vujkov T, Malbasa Z. Paclitaxel
or docetaxel combined with plat- inum in advanced
ovarian cancer. J BUON 2003;8:19-22.
5. Ferlini C, Raspaglio G, Mozzetti S, Distefano
M, Filippetti F, Martinelli E et al. Bcl-2 down-regulation
is a novel mechanism of paclitaxel resistance.
Mol Pharmacol 2003;64(1):51-8. |
5 |
Characteristics of Hodgkin's
lymphoma after infectious mononucleosis
Vladimir BALTIC
Characteristics of Hodgkin's
lymphoma after infectious mononucleosis The
etiology of Hodgkin's lymphoma is unknown. However,
some epidemiological studies have revealed there
is a several fold increase risk of Hodgkin's
lymphoma shortly after EBV-induced infectious
mononucleosis, the typical clinical manifestation
of primary Epstein-barr virus (EBV) infection
in adolescence. Hjalgrim et al. have compared
the incidence of Hodgkin's lymphoma in Danish
cohort of 17,045 patients with the serum-positive
EBV infection and 26,614 patients lacking serological
evidence of the infection, to the Swedish cohort
of 21,510 patients with infectious mononucleosis.
The follow-up for Hodgkin's lymphoma started
on 1 April, 1968 and terminated on 31 December,
1997. During the period 46 patients with Hodgkin's
lymphoma were registered in both groups, but
the histological confirmation of the disease
was obtained in 32 patients. In all paraffin
sections, using a sensitive immunohistochemical
technique, the presence of EBV latent membrane
protein was demonstrated in Reed-Sternberg cells.
The relative risk of EBV positive and EBV negative
Hodgkin's lymphoma after infectious mononucleosis
is graphically shown in Figure 1.revious colorectal
cancer. As it can be seen, there is a causal
relationship between the EBV-induced infectious
mononucleosis and EBV-positive Hodgkin's lymphoma
in young adults. Hodgkin's lymphoma has been
assessed to develop in 1 of 1,000 patients affected
by infectious mononucleosis.
 |
Taken
from: N Engl J Med, 2003:349;14:1330 |
References:
1. Epstein-Barr virus and Kaposi's sarcoma herpesvirus/human
herpesvirus 8. Vol 70. IARC monographs on the
evaluation of carcinogenic risks to humans.
Lyon: IARC Press; 1997.
2. Mueller NE. Epstein-Barr virus and Hodgkin's
disease: an epidemiological paradox. Epstein
Barr Virus Rep 1997;4:1-2.
3. Hjalgrim H, Askling J, Sorensen P et al.
Risk of Hodgkin«s disease and other cancers
after infectious mononucleosis. J Natl Cancer
Inst 2000;92:1522-8.
4. Hjalgrim H, Rostgaard K, Askling J et al.
Hematopoietic and lymphatic can- cers in relatives
of patients with infectious mononucleosis. J
Natl Cancer Inst 2002;94:678-81.
5. Zhou XG, Sandvey K, Li PJ et al. Epstein-Barr
virus (EBV) in Chinese pediatric Hodgkin disease:
Hodgkin disease in young children is a EBV-related
lym- phoma. Cancer 2001;92:1621-31.
6. Hjalgrim H, Askling J, Rostgaard K et al.
Characteristics of Hodgkin«s lym- phoma after
infectious mononucleosis. N Engl J Med 2003;349:1324-32. |
Meetings and Congress
Reports
Medical and Scientific Meetings
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Volume 10 |
Issue 1 |
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News
1 |
Obstacle to cancer therapy
Cancer cells are wily.
Drug therapies may temporarily halt tumor growth,
but all too often the agents lose their effectiveness
as the cells genetic versatility allows them
to become resistant. Researcher hoped that so-called
antiangiogenesis therapies, which are aimed
at preventing the growth of the new vessels,
needed to nourish tumors rather than at the
tumors themselves, might circumvent this problem.
But recent work suggests that tumors may be
able to get around angiogenesis inhibitors,
too. The latest example comes from Joanne Yu,
Robert Kerbel and their colleagues at Sunnybrook
and Women's College Health Sciences Center in
Toronto, Canada. They report that tumors in
which the p53 tumor suppressor gene has been
inactivated, which happens in 50% of human cancers
are much less responsive to angiogenesis inhibitors
than comparable tumors in which the gene is
still functional. Researchers already knew that
cancer cells could counteract the inhibitors
by pouring out more of the factors that promote
new blood vessel growth. But loss of the p53
gene apparently renders tumor cells better able
to survive in the low-oxygen conditions present
in tumors deprived of an ample blood supply.
James Pluda who just left the National Cancer
Institute in Frederick, MA where he oversaw
antiangiogenesis trials, for MedImmune Inc.
in Gaithersburg, MA describes the Kerbel team's
experiments as "a very nice piece of work"
one that will help researchers decipher results
from clinical trials of angiogenesis inhibitors.
Already some 40 agents are being used worldwide
against a wide range of cancers. Neither Pluda
nor others expect the new results to preclude
development of the inhibitors. But, Pluda notes,
the findings "give us something to look
at if patients whose cancers initially respond
then progress". However, Kembel's team
outline additional strategies that might get
around the problem of tumor resistance to antiangiogenesis
therapy such as upping the dose of the inhibitors
of giving them with drugs that specifically
target hypoxic cancer cells. The trick to defeating
cancer this work shows once again will be to
outmaneuver the huge enemy.
Strategies for Cancer Gene Therapy
Many gene therapy protocols to date have concentrated
upon treatments for cancer. Though many cancers
have a genetic predisposition, they all involve
acquired mutations, and as they progress their
cells become less differentiated and more heterogeneous
with respect to the mutations they carry. In
general cancers have at least one mutation to
a prooncogene (yielding an oncogene) and at
least one to a tumor suppressor gene, allowing
the cancer to proliferate. The range of different
cancers encountered and the mutations they carry,
have led to a variety of strategies for gene
therapy namely, immunopotentiation, oncogene
inactivation, tumor suppressor gene replacement,
molecular chemotherapy and drug resistance genes.
The aim of immunopotentiation is to enhance
the response of the immune system to cancers,
thereby leading to their destruction. Passive
immunotherapy aims to increase the pre-existing
immune response to the cancer whilst active
immunotherapy initiates an immune response against
an unrecognized or poorly antigenic tumor. This
strategy usually involves harvesting tumor infiltrating
lymphocytes and treating them to express increased
cytokines e.g. IL-2 and TNF-alpha. Oncogene
inactivation uses the same techniques employed
for dominantly inherited monogenic diseases.
The oncogene may be targeted at the level of
DNA, RNA, transcription or protein product.
Despite multiple genetic abnormalities, restoration
of the tumor suppressor gene, such as p53, can
be sufficient to cause cellular apoptosis and
arrest tumor growth. Moreover, expression of
p53 is synergistic with chemotherapeutic drugs
such as cisplatin. And adjacent tumor cells
that have not been transduced are killed in
what is termed the bystander effect. The p53
gene has been identified as important in a range
of cancers and though less elegant than oncogene
inactivation techniques, this method has proved
robust enough to be included in a number of
clinical trials. Other tumor suppressor genes
may also prove useful, e.g. BRCA1sv. An alternative
means of killing a tumor cell is to transduce
a gene coding for a toxic product, known as
molecular chemotherapy. The gene of choice is
usually herpes simplex virus thymidine kinase
(HSV/TK) which converts the pro-drug ganciclovir
into toxic metabolites. The effected cell is
supported via the gap junctions of adjancet
cells until the toxin burden is too great killing
both the affected cell and its neighbors. An
advantage to this system is that all the transduced
cells will be killed, allowing allogenic tumor
cells to be prepared in advance. Phases of human
trials are preliminary designed to demonstrate
safety and efficacy and will not provide complete
cures. The patients chosen have advanced metastatic
cancer and early results are comparable to single
agent chemotherapy. Colleagues at M.D Anderson
Cancer Center in Houston, Texas have the great
success in the field of cancer gene therapy.
Proprotein convertases and the pathophysiology
of human disease: prospective considerations
From the apparent variety of physiologically
important substrates that may require proteolytic
activation by proprotein convertases, we can
presume that reduced, excessive or ectopic production
of one or the other of these enzymes will cause
serious pathological conditions in humans, manifesting
either as generalized physiological imbalances
or as localized anomalies. The clinical symptoms
that such abnormal expression could induce will
probably be very pleotropic due to the relatively
broad distribution of many of these enzymes.
For example, excessive or deficient production
or activation of hormones or their receptors
have been implicated in the pathogenesis of
endocrinopathic disorders. Considering the really
critical role of proprotein convertases in prohormone
processing these enzymes must contribute to
the pathophysiology of several very serious
endocrine diseases such as ACTH deficiency,
Cushing's disease, disorders of glucose metabolism
and hyperparathyroidsm. Probably, cancer, atherosclerosis
and psoriasis are three pathologies in which
the contribution of growth factors appears to
be crucial. Most polypeptide growth factors
are fragments of larger precursor proteins and
many are generated by cleavage after sequences
of basic residues that could be recognized by
proprotein convertases. Numerous growth-regulatory
molecules play critical roles in inducing the
fibroproliferative response that contributes
to the formation of the advanced lesions of
atherosclerosis. These molecules determine whether
the potentially occlusive fibrous plaque lesions
of atherosclerosis will progress, regress or
remain unchanged. The group includes PDGF, EGF,
FGF, colony-stimulating factors, TGF-beta and
TNF. Psoriasis, number of neurological disorders,
hypertension, viral (HIV infection) and bacterial
infections are examples of pathologies. The
multifunctional nature of furin, ubiquitously
expressed proprotein convertase has been implicated
in many physiological and pathological process
as a cancerogenesis, tumor progression. This
multifunctional nature of furin has opened a
way for extensive analysis of furin as a therapeutic
target. Laboratory at LSUHSC, New Orleans has
developed a potentially therapeutically useful
inhibitor which a represents a compound for
further development. This compound exhibits
therapeutically effect on tumor progression
and metastasis.
Something about cancer meetings
Very soon, Oncogenetics 2002 will be held during
May 2002 in Dublin, Ireland. Sessions will cover,
genomic analysis, gene expression, pathways,
proteomics, bioinformatics and epigenetic in
cancer research. Details are available on the
American Association for Cancer Research (AACR)
website, www.aacr.org. Progress and New Hope
in the Fight Against Cancer, a public forum
highlighting the latest Discoveries is the title
of meeting on 6th April 2002 in San Francisco,
California. There will be possibility for meeting
the world's research experts, connect with advocacy
and support groups. The 93rd Annual Meeting
of American Association for Cancer Research
will be in held Moscone Convention Center, San
Francisco, California, April 6-10, 2002. The
AACR Annual Meeting provides the ideal environment
for the cross-fertilization of ideas on cutting-edge
basic, translational and clinical cancer research.
See website of AACR mentioned above.
Newly designated National Cancer Institute of
USA director roundly applauded by cancer community
The cancer community is expressing unanimous
approval of President's of the USA appointment
of Andrew von Eschenbach, MD as director of
the National Cancer Institute (NCI). Dr. von
Eschenbach was director of the Genitourinary
Cancer Center and Prostate Cancer Research Program
at the University of Texas M.D. Anderson Cancer
Center. |
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Dr. Miroslav
S. SARAC
Louisiana State University Health Sciences
Center New Orleans
Department of Biochemistry and Molecular Biology
New Orleans, LA 70112, U.S.A
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Meetings and Congress
Reports
Books Received
Medical and Scientific Meetings
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Issue 2 |
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News
1 |
Early diagnosis of recurrent
breast cancer with FDG-PET in patients with
progressive elevation of serum tumor markers
Suarez M, Perez-Castejon
MJ, Jimenez A, Domper M, Ruiz D, Montz R, Carreras
JL.
Q J Nucl Med 2002;46(2):113-21.
Background: The aim of
this work is to assess the diagnostic value
of positron emission tomography (PET) with 18F-fluorodeoxyglucose
(FDG), in the early detection of tumour recurrence
in already treated breast cancer patients in
apparent complete remission and with a progressive
elevation of tumour markers CEA and/or CA 15.3
without any other clinical or instrumental signs
of relapses. Methods: The author studied 45
women (mean age 58+/-12, range 35-80 years)
with histological diagnosis of breast cancer
who underwent a tumour marker-guided whole body
FDG-PET. All patients were in remission, without
any other clinical or instrumental signs of
relapses, except for the progressive elevation
of CA 15.3 and/or CEA, tested during the follow-up.
FDG-PET results were controlled by pathology
when histological sampling was possible, by
other conventional imaging modalities (US, X-rays,
CT, MRI) and/or by clinical follow-up up to
12 months at least. Results: FDG-PET findings
were evaluated in 38 patients: 27 resulted positive.
Among these 27 PET positive patients 24 were
true positive and 3 false positive. Tumour marker
guided FDG-PET was also able to discover 3 unknown
neoplasms not visualized by other modalities.
PET revealed 54 sites of intense focal FDG uptake.
The anatomical distribution of these sites was
19 skeleton, 18 lymph node basins, 5 liver,
5 pelvic region, 1 lung, 1 pericardium, 1 pleura,
1 contralateral breast, 2 peritoneum and 1 thyroid
bed. Forty-eight of these 54 sites of FDG accumulation
were confirmed to be metastases. FDG-PET resulted
negative in 11 patients and only in 2 of them
the other diagnostic modalities were able to
discover metastatic lesions; we had 9 true negative
and 2 false positive results. On the basis of
our investigation the performances of tumour
marker guided FDG- PET per patient are as follows:
sensitivity 92% (24/26), specificity 75% (9/12),
positive predictive value 89% (24/27), negative
predictive value 82% (9/11), accuracy 87% (33/38).
Conclusions: This study demonstrated the clinical
utility of tumour marker-guided PET in the follow-up
of breast cancer patients. This diagnostic approach
allowed to modify the clinical management in
those patients in whom a tumor relapse or unexpected
primary neoplasm was discovered. |
2 |
Image fusion between 18FDG-PET
and MRI/CT for radiotherapy planning of oropharyngeal
and nasopharyngeal carcinomas
Nishioka T, Shiga
T, Shirato H, Tsukamoto E, Tsuchiya MDK, Kato
T et al.
Int J Radiat Oncol Biol Phys 2002;53(4):1051-7.
Purpose: Accurate diagnosis
of tumor extent is important in three-dimensional
conformal radiotherapy. This study reports the
use of image fusion between (18)F-fluoro-2-deoxy-D-glucose
positron emission tomography (18FDG-PET) and
magnetic resonance imaging/computed tomography
(MRI/CT) for better targets delineation in radiotherapy
planning of head-and-neck cancers. Methods and
materials: The subjects consisted of 12 patients
with oropharyngeal carcinoma and 9 patients
with nasopharyngeal carcinoma (NPC) who were
treated with radical radiotherapy between July
1999 and February 2001. Image fusion between
18FDG-PET and MRI/CT was performed using an
automatic multimodality image registration algorithm,
which used the brain as an internal reference
for registration. Gross tumor volume (GTV) was
determined based on clinical examination and
18FDG uptake on the fusion images. Clinical
target volume (CTV) was determined following
the usual pattern of lymph node spread for each
disease entity along with the clinical presentation
od each patient. Results: Except for 3 cases
with superficial tumors, all the other primary
tumors were detected by 18FDG-PET. The GTV volumes
for primary tumors were not changed by image
fusion in 19 cases (89%), increased by 49% in
one NPC, and decreased by 45% in another NPC.
Normal tissue sparing was more easily performed
based on clearer GTV and CTV determination on
the fusion images. In particular, parotid sparing
became possible in 15 patients (71%) whose upper
neck areas near the parotid glands were tumor-free
by 18FDG-PET. Within a mean follow-up period
of 18 months, no recurrence occurred in the
areas defined as CTV, which was treated prophylactically,
except for 1 patient who experienced nodal recurrence
in the CTV and simultaneous primary site recurrence.
Conclusion: This preliminary study showed that
image fusion between 18FDG-PET and MRI/CT was
useful in GTV and CTV determination in conformal
RT, thus sparing normal tissues. |
3 |
Virtual endoscopy: current
perspectives
Kuwayama H, Limuro
M, Kitazumi Y, Luk G.
J Gastroenterol 2002;37 Suppl 13:100-5.
Virtual endoscopy is a
new method for evaluating the gastrointestinal
tract using either thin-section computed tomography
(CT) or magnetic resonance imaging (MRI). The
acquired data are then subjected to computer
manipulation to render images simulating the
conventional endoscopic view. CT and MR imaging
data can provide information that is not accessible
endoscopically. These important features include
information on tissue extending through and
beyond organ walls and the anatomic context
of the entire gastrointestinal tract, which
permits correct anatomic localization of the
lesion. Many clinical studies have shown that
it is a safe, noninvasive, well-tolerated alternative
to conventional endoscopy. Virtual endoscopy
may have potential as a method of screening
for colorectal cancer. This review describes
the technique, reviews reported results, and
discusses the present and future applications
of this technique, focusing on CT colography
(CTC).
Source: http://www.ncbi.nlm.nih.gov |
ONCOnet*
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TELEMEDICINE WORLDWIDE |
1 |
What's New in the World
of Telemedicine - 1
http://tie2.telemed.org/news
Medem, Inc. has launched
a service that allows doctors to per form online
consultations with their patients through a
Medem- operated secure electronic mail network.
The service would allow doctors to set their
own fees (if any), which would have to be paid
out of the patient's pocket. Results of a Medem
survey indicated that most physicians planning
to offer the online service expect to use the
level of their patients' co-payments as a baseline
for setting online consultation fees, or approximately
$20-30. Research shows that primary care physicians
expect to perform five to ten online consultations
per week. Since doctors are already doing much
of this work via telephone without reimbursement,
it is likely that many will opt into this service,
which at the above rates could provide roughly
$5,000 to $15,000 of extra income per year.
Medem would receive $2.50 per consultation for
which a patient is billed.
(Source: amednews.com,
July 8/15, 2002) |
2 |
What's New in the World
of Telemedicine - 2
http://tie2.telemed.org/news
In the region of Extremadura,
Spain, a Grand Opening Celebration was held
to recognize the success of a (still ongoing)
telemedicine pilot project between the Health
Center of Olivenza and the Provincial Hospital
San Sebastian. Teleconsultations in dermatology,
cardiology, radiology, and vascular surgery
are being conducted. In February and March of
2002, 187 teleconsults were conducted. The average
waiting time for a patient to be seen by a specialist
dropped from a range of 8-26 weeks down to a
maximum of one week during the pilot. In addition
the number of transfers was significantly reduced.
The Extremadura Minister announced plans to
expand the current telemedicine pilot to include
additional specialty services, and the objective
for 2003 is to establish telemedicine capability
in all regions.
(Source: Business
Wire, May 30, 2002) |
3 |
What's New in the World
of Telemedicine - 3
http://tie2.telemed.org/news
Amal Cancer Centre
in Amman, Jordan recently opened a telepathology
section. The new section will help in the diagnosis
of cancer and other diseases through direct
contact and consultation with specialists at
telepathology centers at Rotterdam and Leiden
Universities in the Netherlands. Physicians
in Jordan and Holland will conduct diagnostic,
support, or educational services in anatomic
or clinical pathology by viewing gross or microscopic
images.
(Source: The Jordan
Times, June 23, 2002) |
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TELEMEDICINE JOURNALS |
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Book Review
Meetings and Congress Reports
Medical and Scientific Meetings
Extended Abstracts: Symposium on Manuscript Peer Reviewing
in Biomedical Journals
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Issue 3 |
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Medical
Meeting
XXXIX
Annual Meeting of the Oncologists of Serbia
XVI Meeting of Oncology and Radiology of Serbia
Institute for
Oncology and Radiology of Serbia
Srbian Medical Association
November 14-15, 2002 - Belgrade, Yugoslavia |
125 |
PLENARY LECTURES
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129 |
TREATMENT OF ELDERLY ONCOLOGY
PATIENTS
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151 |
TRANSLATIONAL REASEARCH
IN BREAST CANCER
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173 |
NOVELTIES IN NEURO-ONCOLOGY
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189 |
BIOPSY OF SENTINEL LYMPH
NODES IN EPITHELIAL MALIGNANT TUMORS
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205 |
EDUCATIONAL SYMPOSIUM:
THE SKILL OF COMMUNICATION AT SCIENTIFIC MEETINGSS
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221 |
MISCELLANEOUS
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XV
Meeting of Oncology Nurses and Technicians of
Republic of Serbia |
229 |
CONFERENCE
REPORTS AND ABSTRACTS |
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Issue 4 |
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News
1 |
Nobel prize for "Physiology
or Medicine" 2002: when a worm brings you
under the spotlights
Nobel prize for
physiology or medicine was awarded to: Sydney
Brenner, University of California, Berkeley,
John Sulston, Cambridge, and Robert Horvitz,
Cambridge, Massachusetts.
The Laureates have identified
key genes regulating organ devel- opment and
programmed cell death and have shown that corresponding
genes exist in higher species, including man.
Sydney Brenner (Berkeley, CA) established C.
elegans as a novel experimental model organism.
This provided a unique opportunity to link genetic
analysis to cell division, differentiation and
organ development, and to follow these processes
under the microscope. Brenner`s discoveries
carried out in Cambridge, UK laid the foundation
for this year's prize. John Sulston (Cambridge,
UK) mapped a cell lineage where every cell division
and differentiation could be followed in the
development of a tissue in C. elegans. He showed
that specific cells undergo programmed cell
death as an integral part of the normal differentiation
process, and he identified the first mutation
of a gene participating in the cell death process.
Robert Horvitz (Cambridge, MA) has discovered
and characterized key genes controlling cell
death in C. elegans. He has shown how these
genes interact with each other in the cell death
process and that corresponding genes exist in
humans. For more information on this and other
Nobel prizes see www.nobel.se. |
2 |
New concepts in combination
oncological therapeutics
Will a single agent, chosen
on the basis of molecular profiling, be sufficient
to remove the selective advantage enjoyed by
cancer cells? Not according to current thinking.
Combined oncological therapeutics will be defined
using many interventions. Potentially, combination
non-specific cytotoxic agents might initially
cytoreduce large bulk tumor masses. Clinical
and preclinical synergy of classical DNA-directed
non specific cytotoxic agents with targeted
therapies (12,13) suggests that classical cytotoxic
agents modulate important cellular signaling
pathways so, when com- bined with targeted agents,
they will lead to enhanced clinical efficacy.
Concepts of dose-response should be considered
and exploited to reduce exposure to toxic agents.
Careful phase I biomarker-targeted trials could
confirm unique mechanisms of classical cytotoxic
agent action discovered in vitro that may lead
to innovative and unexpected combination therapies.
Combination cancer therapeutics might require
identification of mutated upstream signal transduction
genes using high throughput genomic profiles,
and identification of downstream signals with
high throughput proteomic profiles with therapeutic
targets individually selected. New epidermal
growth factor receptor tyrosine kinase inhibitors
(e.g. ZD1839/Iressa, cetuximab) will expand
the repertoire of signal transduction targets.
Many angiogenesis inhibitors that variously
target vascular endothelial growth factor receptor
tyrosine kinase, fibroblast growth factor receptor
tyrosine kinase and the a v b 3 integrin may
be useful antineoplastic agents. The challenge
of understanding or predicting efficacy with
these agents will be to reproducibly quantify
whether drug-induced phosphorylation of other
downstream signal transduction intermediates
is translated into the clinical setting. Moreover,
we are now challenged with redefining the concept
of clinical efficacy-is lack of tumor proliferation
and metastatic spread without ablation sufficient
to define efficacy? Will all of this come to
pass? Only innovative well-designed translational
investigations will reveal the answer. But the
future today is far brighter than it was 10
years ago. And "combination chemotherapy"
will take on a totally different nuance and
mean- ing than it has today. |
3 |
Virtual colonoscopy
Schairer C, Mink PJ,
Carroll L et al. JNCI 2004;96(17):1311-21.
Studies in populations at varied risk show reproducible
sensitivity of 90% for polyps 10 mm or greater
with 93% specificity and per-patient sensitivity
of greater with 93% specificity and per-patient
sensitivity of 96-100%. Sensitivity for polyps
6-9 mm is about 80%, with detection of smaller
polyps being poor. These results nearly equal
the rates for colonoscopy. The addition of computer-aided
detection, now in early trials, should improve
accuracy. Accepted indications, based on published
data, include: follow-up after incomplete colonoscopy,
obstructing neoplasm in the distal colon, and
contraindications to colonoscopy. Individuals
carry a lifetime risk of colorectal cancer of
6% with an increased incidence after age 50.
Colorectal cancer is the second most common
cause of cancer death in the USA. Slow progression
in the adenoma-to-carcinoma sequence suggests
that dis- ease is largely preventable by regular
screening. Less than a third of eligible patients
undergo screening. Screening strategies for
colon cancer include: fecal occult blood-testing,
which fails to detect 95% of polyps (colonoscopy,
which can miss 6% of adenomas of 10 mm or larger(
and double-contrast barium enema, which can
miss up to 20% of polyps over 10 mm. Only an
estimated 6% of patients in a screening population
will be found to harbour an adenoma of 10 mm
or greater. Furthermore only about 3% of all
adenomas progress to cancer. Screening with
colonoscopy, as some advocate, would not seem
prudent given the low but definite risk of perforation
and associated risks of sedation and bleeding.
Advantages of screening with CTC include avoidance
of an invasive procedure and sedation. CTC also
more accurately localises masses and detect
clinically significant extracolonic abnormalities.
The major disadvantage is the inability to biopsy
polyps. False-positive results can cause unnecessary
follow-up colonoscopy. Flat adenomas, which
may account for 8-33% of adenomas and more frequently
harbour high-grade dysplasia, are harder to
detect. |
4 |
European bodies reach
an uneasy truce on embryonic stem-cell research
Schairer C, Mink
PJ, Carroll L et al. JNCI 2004;96(17):1311-21.
On September 30 in Brussels, after a bitter
dispute with the European Parliament over
research involving the use of human embryonic
stem cells, the European Union (EU) Council
of Science Ministers eventually approved the
Sixth Framework Research Programme. But the
approval, which will allow the 5-year, 17.5
billion Euro programme to launch officially
in early November, unexpectedly included a
1-year moratorium on stem- cell research funding.
The Council - the central decision-making
body of the EU - and the Parliament had reached
an unwritten agreement in June over the approval
of the Framework Programme, which allowed
EU funding of stem-cell research in countries
where it was not prohibited (Lancet 2001;
358: 1972). However, the Council adopted a
unilateral decision in late July - under the
Danish presidency of the EU - to embargo such
financing until the end of 2003. The Parliament
protested the Council's decision on grounds
that it was not a consensus agreement and
the moratorium did not have par- liamentary
approval. Several members of the Parliament's
Committee on Industry, External Trade, Research
and Energy, headed by socialist Carlos Westendorp,
threatened that, if the moratorium went forward
without consultation, Parliament could block
the programme's entire budget - or even sue
the Council via the EU Court of Justice. The
Committee went as far as querying the constitutional
legality of the Council decision. The threat
prompted representatives from the two parts
to negotiate again and to reach an agreement.
This stipulates that "further provisions
on the funding of research activities involving
the use of human embryos and human embryonic
stem cells will be established before the
end of 2003, on the basis of a new proposal
(based on an in-depth ethical, technical,
and political study) from the European Commission
and in consultation with the European Parliament".
Until then, says the statement Commission
"will not propose to finance such research
projects, unless they involve (already established)
banked or isolated human embryonic stem cells
in culture". The new commitment also
stipulates that "proposals for [funding]
research projects involving (human embryonic
stem cells) will be submitted to a regulatory
committee (where al EU countries will be represented)".
Commenting on this latest compromise, which
Italy was the only country to oppose, Westendorp
noted: "What we`ve learned from all this
is that any future agreement with the Council
must be confirmed in writing."
. News. Ann Oncol 2002; 13:1694.
2. Brenner DE. New concepts in combination
oncological thera- peutics. Ann Oncol 2002:13:1698.
3. Gollub MJ. Virtual colonoscopy. Lancet
2002;360:964.
4. Bosch H. European bodies reach an uneasy
truce. Lancet 2002; 360:1080.
|
Books Review
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Volume 9 |
Issue 1 |
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ONCOnet*
|
TELEMEDICINE WORLDWIDE |
1 |
American Telemedicine Association's
advisories for consumers who choose to use the
internet to obtain information about healthcare
or seek medical treatment
http://www.atmeda.org/news/
The American Telemedicine
Association (ATA) is a non-profit association
established in 1993 and headquartered in Washington,
DC. ATA promotes the deployment of telemedicine
to improve the delivery of health care for all
individuals. Its members include physicians,
allied health professionals, technologists and
healthcare administrators. A Board of Directors,
elected by the membership, governs the Association.
ATA maintains a Web site at www.atmeda.org.
ATA provides these advisories for consumers
who choose to use the Internet to obtain information
about healthcare or seek medical treatment:
1. Consumers should make sure that Web sites
used to obtain information about health and
medicine are provided by a reliable and credible
source such as recognized and credentialed health
care providers, and use sources that are based
on qualified authorities. The source of the
information should be clearly labeled and annotated.
The ATA endorses the concept of professional
societies accrediting Web sites that provide
consumers health and medical information.
2. In some cases commercial interests such as
a drug manufacturer may sponsor or contribute
information to a Web site. Consumers should
look for assurances that the information provided
in these cases is objective and does not favor
the sponsor's products.
3. At this time consumers should exercise caution
in using Web sites that offer online diagnosis
of an individual's medical condition and prescribed
treatment and medication for the diagnosed condition.
There are currently no recognized accreditation
or regulatory authorities overseeing the operation
of these sites.
4. It is a widely recognized conflict of interest
for health professionals that prescribe medicines
to have any direct financial relationship with
an entity that sells those medications. Therefore,
consumers are cautioned against obtaining prescribed
medicines from Web sites that offer both diagnosis
of condition and direct sales of the prescribed
medicine.
5. Medical professionals in almost all developed
nations are required to obtain credentials from
a recognized authority in order to practice
medicine. For example, health professionals
in the United States are issued a license to
practice medicine by individual state authorities.
Consumers seeking medical treatment from health
professionals over the Internet should receive
clear assurances that they will be interacting
with a qualified professional holding the appropriate
credentials and that the professional is able
to legally practice medicine in the consumer's
location.
6. Clinical consultation over the Web by credentialed
providers should include procedures that protect
the patient including:
- Informed consent;
- Information security and privacy protection
measures; and
- Documentation of the clinical encounter.
Specialty medical societies are encouraged to
develop guidelines to ensure that clinical consultations
provided over the Internet are consistent with
accepted medical practices. |
2 |
A brief view on current
status of telemedicine in Serbia
Svetozar Zdravkovic
Serbia belongs to the
group of middle developed countries. This fact
determines the level of development of telecommunication
infrastructure, which can hardly be regarded
as a satisfactory one: small number of base
ISDN connectors, insufficient number of qualitative
leased lines, telephone switchboard systems
and units are on average much longer in operation
than in other countries of the region, mobile
telephone operators use network with GSM protocol
which offers transfer rate of 9800 b/sec for
data exchange which is insufficient for computer
communications (except for e-mail), 2 MB connectors
are more dream than reality. Although the statement
of Serbian Prime Mminister of providing significant
investments in the development telecommunication
infrastructure is very encouraging, the change
of current status will need at least several
years. According to all mentioned facts, the
one of the possible solutions can be the selection
of Academic Computer Network as a telecommunication
backbone for the purpose of telemedicine. There
are several reasons for this suggestion:
- Academic Computer Network exists, functions
and connects all university centers in Serbia
(in Belgrade, Novi Sad, Nis, Kragujevac, Subotica,
Zrenjanin), where all main clinical centers,
institutes and other specialized health institutions
are concentrated;
- investment in further development is with
the highest cost-benefit rate
- possibility for connection with health institutions
abroad, because Academic Computer Network has
recently become a part of European Academic
Computer Network.
Managers of the Academic Computer Network are
willing to help, so physicians and all professionals
in health service who are involved in telemedicine
should work together and make possible faster
development of telemedicine services.
Our experience in the use of telemedicine modest.
There are a few health institutions with such
experience: Military Medical Academy in Belgrade,
Institute of Oncology Sremska Kamenica, Military
Hospital in Nis and Clinical Medical Center
in Belgrade. Mostly used telemedicine services
are telepathology and teleconferencing for the
purpose of medical education and consultations
(teleeducation and teleconsultation). Live video
broadcasting of medical procedures (such as
laparoscopic surgery done by the Institute of
Oncology in Sremska Kamenica) for the purpose
of teleconsulatations does not meet the regulated
conditions, such as minimum transfer rate of
384 Kb/sec. This leads to the possibility of
establishing video computer conferencing center
which should serve only for medical needs and
which would be accessed by Academic Computer
Network (provided Quality of Service - it could
ensure transfer rate of minimum 384 Kb/sec.
between any two peers of connection). The development
of telemedicine services has the priority in
the high developed countries (USA, Canada, countries
of European Community, Japan), because telemedicine
reduces the expenses of medical care, improves
prevention and protection with better, faster
and more direct health education. As the country
with developed health culture, we should follow
this trend and join more activities in developing
telemedicine in our country. |
3 |
American Telemedicine Aassociation's
special interest group for telepathology - Clinical
guidelines for telepathology
http://telepathology.upmc.edu/ata/taskforce.html
Special Interest Group
for Telepathology:
Yukako Yagi - Chair |
Mark Newberger |
Ronald Weinstein, MD
- Co Chair |
Ikuo Tofukuji |
John Gilbertson, MD |
Jason Kaar, JD |
Bulert Celasun,
MD
|
Bruce Williams DVM |
Mike J Becich, MD, PhD |
George Naxera |
Robert Dawson, MD |
Paul Fontelo, MD |
James McGee, MD, PhD |
Katsushige Yamashiro,
MD |
Bruce Dunn, MD |
Francisco G. La Rosa,
MD |
General Information:
[email protected]
Our Mission
CONTENT OF
"CLINICAL GUIDELINES FOR TELEPATHOLOGY"
1 Introduction
2 Scope
3 The Practice of Telepathology: Responsibilities
of the Pathologist
3.1 Primary Diagnosis Telepathology
3.1.1. Technicians, Technologists and Pathologist's
Assistants in Primary Diagnosis Telepathology
3.2. Second Opinion Telepathology
3.2.1. Responsibilities of the Referring Pathologist
3.2.2. Responsibilities of the Consulting
Pathologist
4 Training and Quality Control
4.1 Training of Pathologists
4.2 Training of Technicians, Technologists
and Pathologist's Assistants
4.3 Quality Control
5 Documentation and Archiving
6 Data Integrity and Security
A Draft Version
2.4; May 20, 1999; The American Telemedicine
Association
1 Introduction
This is a working draft of clinical guidelines
for telepathology written with the expectation
that others will rewrite it and add to it.
To keep this document generally applicable
it steers clear of technical specifications
or implementation issues and concentrates
on the responsibilities of the pathologist
in telepathology.
2 Scope
For the purpose of this document, Telepathology
will be defined as electronic, multimedia
communication between pathologists for the
purpose of primary diagnoses and diagnostic
consultation second opinion. It may also be
extended to include similar diagnostic communication
between other physicians (non-pathologists)
and a laboratory staff by qualified laboratory
personnel - trained technicians, technologists,
or a pathologist's assistants - and a remote
pathologist and when the laboratory personnel
is under the supervision of a pathologist.
The concepts discussed in this document should
be generally applicable to all three types
of telepathology; static (store and forward),
dynamic (synchronous), and hybrid (static-dynamic)
implementations.
3 The Practice of Telepathology: Responsibilities
of the Pathologist
Pathologists have been sending each other
cases for diagnostic second opinion for many
years. This collaboration has traditionally
involved the sending of stained slides, unstained
slides, tissue blocks, wet tissue, pathology
reports and cover letters via courier or through
conventional mail. The system has worked well,
and is the "gold standard" by which
diagnoses are compared between institutions.
In defining guidelines for second opinion
telepathology, pathologists should borrow,
whenever possible, from the workflows and
responsibilities set up in the courier based
system.
Guidelines for primary opinion telepathology
should be driven from best practices in conventional
laboratory procedures. It is understood that
pathologists often work in central offices
geographically separated from both the clinics
(where cytology and surgical samples are obtained)
and the histology laboratories (where cytology
preparations and tissue are processed and
slides are made).
Sections 3.1 and 3.2 detail proposed responsibilities
of pathologists and laboratory personnel in
both primary diagnosis telepathology (section
3.1) and second opinion telepathology (section
3.2). Though the discussion is framed in a
telepathology environment involving multiple
institutions, the responsibilities are similar
if telepathology occurs within a single institution.
3.1 Primary Diagnosis Telepathology
In telepathology, specimens at a referring
site are diagnosed by pathologists at a remote
site. In primary diagnosis telepathology,
the diagnostic effort and responsibility resides
entirely with the pathologist at the remote
site. The medical responsibilities for a site
initiating a telepathology session for primary
diagnosis, are similar to those of a laboratory
sending glass slides by courier or conventional
mail to another pathologist for primary diagnosis
in a traditional environment. These include:
1. The laboratory must identify the case appropriately.
Traditionally this has meant, at a minimum,
local accession number and the patient's name
as well as some indication of what material
has been sent (the number or slides, blocks,
reports, etc.) In the telepathology environment
this must be extended to the appropriate documentation
of images and information sent.
2. The laboratory must insure that all appropriate
clinical information is conveyed to the remote
pathologist. Traditionally this has usually
meant an appropriately filled out requisition
and/or the surgeon's operative report, however
it can include additional information (for
example, X-rays in bone pathology cases) or
direct access to the clinicians involved depending
on the situation and pathologists medical
judgement. If, in the judgement of the pathologists
involved, the system cannot provide adequate
clinical information to the remote pathologist,
telepathology should not be used to render
a diagnosis or telepathology should be supplemented
by other mechanisms.
3. The laboratory must insure that the remote
pathologist has adequate access to appropriate
diagnostic material. In a practice setting
in which primary telepathology diagnoses are
rendered, and a pathologist is not present
at a referring site, a methodology must be
employed which insure that video sampling
of gross tissues and glass slides is inclusive.
4. In addition to the medical responsibilities
discussed above, the laboratory has responsibilities
for data handling, archiving and security
as discussed below.
3.1.1. Technicians, Technologists and Pathologist's
Assistants in Primary Diagnosis Telepathology
Pathologist's Assistants, technologists and
technicians have traditionally worked under
the supervision of Pathologists in anatomic
pathology laboratories. Appropriately trained
personnel (pathologist's assistants, technologists
and technicians) should be able to present
cases and relevant materials, via telepathology,
to other pathologists at remote sites.
1. Presenting Personnel should be adequately
trained in the use of telepathology equipment
and the limitations of telepathology
2. A pathologist should supervise the support
personnel, and support personnel should have
access to other pathologists throughout the
telepathology session.
3.1.2. Responsibilities of the Pathologist
in Primary Diagnosis Telepathology
In primary diagnosis telepathology, diagnostic
effort and responsibility resides entirely
with the pathologist at the remote site. If
the remote pathologist supervises referring
site, the pathologist takes on the roles and
responsibilities of both referring and consulting
pathologist in Section
3.2. Second Opinion Telepathology
In second opinion telepathology, diagnostic
effort and responsibility resides with both
the pathologists at the local site (referring
pathologist) and the pathologist at the remote
site (consulting pathologist).
3.2.1. Responsibilities of the Referring
Pathologist
The medical responsibilities for a pathologist
initiating a second opinion telepathology
session are similar to those of a pathologist
sending glass slides by courier to a consulting
pathologist in a traditional environment.
These include:
1. The referring pathologist must identify
the case appropriately. Traditionally this
has meant, at a minimum, local accession number
and the patient's name as well as some indication
of what material has been sent (the number
or slides, blocks, reports, etc.) In the telepathology
environment this must be extended to the appropriate
labeling of images and documentation of the
number of images sent.
2. The referring pathologist must insure that
all appropriate clinical information is conveyed
to the consulting pathologist. Traditionally
for second opinion this has usually meant
a cover letter and a copy of the referring
pathologist's report, however it can include
additional information (for example, X-rays
in bone pathology cases) depending on the
situation and the referring pathologist's
medical judgement. If in the judgement of
the referring pathologist, the telepathology
system proposed for the consultation can not,
adequately provide all of the appropriate
clinical information to the consulting pathologist,
telepathology should not be used for the consultation
or telepathology should be supplemented by
other mechanisms.
3. The referring pathologist must insure that
the consulting pathologist has adequate access
to appropriate diagnostic material. One of
a pathologist's cardinal responsibilities
is to appropriately sample specimens so as
to arrive at the accurate diagnosis. The pathologists
traditionally sub-sample gross specimens into
blocks, and those blocks are then sub-sampled
in the creation of slides. In traditional
courier based consultations, it is not uncommon
to have, on the judgement of the referring
pathologist, only a subset of slides sent
to the consulting pathologist. In some implementations
of telepathology, a further level of sub sampling
in which images representing selected fields
from a slide are sent to the consulting pathologist.
In these implementations, it is the responsibly
of the referring pathologist to select these
fields appropriately.
4. The referring pathologist must render a
final report on a case. As in traditional
pathology consultations, it is the responsibility
of the referring pathologist, when receiving
an opinion from a consulting pathologist,
to reconcile his or her understanding of the
case - and any clinical or pathological information
not available to the consulting pathologist
- with the opinion of the consulting pathologist
and then reach an appropriate diagnosis. This
responsibility should also exist in consultations
based on telepathology. The use of telepathology
should not relieve the referring pathologist
of the responsibly to render to a final report
on a case.
5. In addition to the medical responsibilities
discussed above, the referring pathologist
has responsibilities for data handling, archiving
and security as discussed below.
3.2.2. Responsibilities of the Consulting
Pathologist
A pathologist receiving a case via telepathology
has a number of medical responsibilities similar
to those of a pathologist receiving a case
via courier:
1. The consulting pathologist should insure
that he/she has received all materials sent
by the referring pathologist. This has traditionally
been done, in the courier-based model, by
comparing the material listed in the cover
letter (or other documentation) to the material
received.
2. The pathologist must insure that appropriate
standard operating procedures are in place
at the referring site to insure that all the
clinical information or pathologic material
(tissue, blocks, etc.) necessary to adequately
examine a case is available. If in the judgement
of the consulting pathologist, the telepathology
system proposed can not provide the necessary
information to the consulting pathologist,
telepathology should not be used for the consultation
or telepathology should be supplemented by
other mechanisms. If clinical information
deemed necessary by the consulting pathologist
is not available by any mechanism, an unqualified
opinion should not be rendered.
3. In the traditional courier-based consultation,
it is the responsibility of the consulting
pathologist to determine if the material sent
by the referring pathologist is of adequate
quality to render a diagnosis. For example,
it has been up to the consulting pathologist
to determine if the slides proffered were
adequately cut and/or stained. The quality
needed for a diagnosis depends directly on
the skill of the consulting pathologist and
the diagnostic question involved. Consistent
with the traditional, courier-based practice,
it is the responsibility of the consulting
pathologist to determine if the image quality
is adequate for diagnosis. If the consulting
pathologist feels that image quality and/or
video image sampling are not adequate, he/she
should request that the glass slides and or
blocks be sent for analysis. This is consistent
with traditional, courier-based practice.
4. The consulting pathologist should transmit
his/her opinion/diagnosis to the referring
pathologist in a mutually agreed upon manner.
Observations that could effect patient care
in a time sensitive manner should be transmitted
directly to the referring pathologist.
5. In addition to the medical responsibilities
discussed above, the consulting pathologist
has responsibilities for data handling, archiving
and security as discussed below.
4 Training and Quality Control
4.1 Training of Pathologists
Because the effectiveness and accuracy of
telepathology depends critically on the skill
and judgement of the pathologist, both referring
and consulting pathologists practicing telepathology
should be trained in telepathology.
1. Training should occur on the individual
systems that the pathologist uses.
2. Training should occur also in general telepathology/imaging
principles and limitations. The implementation
of this training is an issue that requires
discussion and consensus. Possibilities could
include general web-based seminars and tests
supported by the ATA, CAP, USCAP, etc. followed
by practical examinations provided be the
same organizations. (The CAP has similar programs
ongoing for standard glass slide pathology.)
4.2 Training of Technicians, Technologists
and Pathologist's Assistants
In an environment in which a technologist,
a technician, or a pathologist's assistant
is supervised by a local or a remote pathologist,
he/she should be trained specifically in telepathology
techniques.
4.3 Quality Control
Pathologists providing consultation by telepathology
should be required to have at least 10% of
their cases re-examined by another pathologist,
comparing the transmitted images to the microscopic
slide and any discrepancies should be noted.
5 Documentation and Archiving
The telepathology interaction is a vital part
of a patient's care and as such must be documented
in the medical record. To this end:
1. A diagnostic consultation by telepathology
shall generate a formal report by the consulting
pathologist. This report shall become a permanent
part of the patient medical record. It is
recommended that all reports, letters, clinical
information and possibly static (still) images
transmitted from the referring site to the
pathologist as part of the telepathology encounter
should be archived at the consultant's institution.
This practice is consistent with that applied
to courier based consultations.
2. All reports, letters, clinical information
and static (still) images involved in a diagnostic
consultation by telepathology, as well as
the consultant's report, shall be archived
as part of the medical record at the referring
institution. This practice is consistent with
those applied to courier based consultations.
(Because image archiving requires special
equipment not available at all institutions,
the referring institution may allow the consulting
institution or a third party to archive telepathology
information, as long as the archiving is done
under the rules or the referring institution.)
3. The telepathology encounter, and the general
opinion of the consulting pathologist, shall
be documented in the final report of the referring
pathologist. This practice is consistent with
those applied to courier based consultations.
4. Dynamic, real time images generated during
a telepathology session need not be archived.
Static (still) images shall be archived at
that same image quality, file size and format
that was used in the telepathology encounter.
Static (still) images should be archived for
at least as long as the glass slides involved
in the case.
For cases in which diagnoses are based exclusively
by static images, the entire image file should
be archived.
6 Data Integrity and Security
By its nature, the telepathology encounter
involves transmission and storage of confidential
patient information. Though it is understood
that no security system is foolproof and that
the specific security mechanisms needed will
depend on the specific telepathology implementation,
parties engaging in telepathology shall insure
that the telepathology system provides reasonable
privacy and confidentiality by security measures
including:
1. Message Security: A telepathology shall
occur over secure networks, or shall be adequately
encrypted. It is the responsibility of the
consulting laboratory to provide a secure
station for receiving diagnostic reports.
Verifiable digital signatures may be allowed.
2. System Authentication: When appropriate,
the system should authenticate itself unambiguously
to all users, for example, using a third party
certificate and private key.
3. User Authentication: The referring pathologist,
consulting pathologist and all other persons
using the system (administrators, assistants,
etc.) shall be adequately authenticated to
each other and to the system. This authentication
should involve, at a minimum, a user name
and password.
4. Activity Logs: All accesses to the system
shall be logged by user and by case. The logs
shall be reviewed on a regular basis and the
review documented.
5. Access Restriction: Within the security
policy of the individual institution, the
system should limit access to legitimate users.
6. Archiving: The system shall have adequate
back up and archive mechanisms in place.
|
4 |
What is Telemedicine?
The basic question
today, when high technology has involved in
medicine very deep, is: What is telemedicine
and what kind of services we call telemedicine
services? One answer on that question is made
by Jonathan D. Linkous in his article published
on official web site of American Telemedicine
Association (ATA) with title: Toward a rapidly
evolving definition of telemedicine.
Toward a rapidly evolving definition of telemedicine
Jonathan D. LINKOUS
http://www.atmeda.org/news/newres.htm
Last Spring an article was published in the
ATA News Digest regarding the market size for
telemedicine. The article described several
market research reports that are available that
depict the size of the market for telemedicine
and make projections for the market in the future.
Since that time, a number of comments were provided
to ATA regarding the market reports including
criticisms of what the reports included, or
did not include when determining market size.
This gives rise to a perennial point of discussion
regarding the definition of telemedicine.
Most of the market reports use a "traditional"
definition of telemedicine that is largely based
on hub and spoke systems, interactive video
or sophisticated store-forward technology, and
the provision of data sent telephonically to
a specialist for interpretation. Several surveys
have even ignored teleradiology and concentrated
solely on face-to-face video consults. This
most certainly captured the definition of telemedicine
as perceived 12 to 24 months ago. However, recent
technology innovations and soon-to-be-deployed
new approaches call for broadening the traditional
thinking about what should be included as part
of telemedicine.
This should not be a surprising development
as telemedicine has been in a constant state
of change over the past five years. Recent innovations
in the use of computer-driven diagnostic systems,
micro-sensors, and interactive medical technology
will probably push the definition even further.
So why even bother being concerned about the
definition? This is an important issue for several
reasons: defining allowable services to be reimbursed
under Medicare and other forms of insurance;
defining eligible services to be included within
existing grant and loan programs; and defining
the services affected by state medical licensure
laws. For vendors of services and products it
is important to identify the current and future
market. For medical centers it is important
in determining which department (information
services vs. medicine) has control over.
ATA has used the following broad definition
of telemedicine: "Telemedicine is the use
of medical information exchanged from one site
to another via electronic communications for
the health and education of the patient or healthcare
provider and for the purpose of improving patient
care." Note that this is not restrictive
as to what information is transmitted, how it
is transmitted, or how the information is used
once received.
Thus, what is and is not telemedicine? For example,
while comprehensive home care monitoring services
with a multi-mode device is considered telemedicine,
is a wireless heart monitor or a portable emergency
notification system? Is it telemedicine if the
patient data is generated but instead of transmitting
the raw data to a physician, it is read and
analyzed by a computer? Are miniaturized biosensors
that take vital signs or test for the presence
of various conditions and transmit the data
considered telemedical peripheral devices? Clearly,
the types of products and services considered
part of telemedicine is evolving. The telemedicine
of today is relatively simple. The telemedicine
of tomorrow gets more complex as the possibilities
expand. |
5 |
Protecting the privacy
of patients' health information summary of the
final regulation
http://aspe.hhs.gov/admnsimp/final/pvcfact1.htm
Overview: Each time a patient sees a doctor,
is admitted to a hospital, goes to a pharmacist
or sends a claim to a health plan, a record
is made of their confidential health information.
For many years, the confidentiality of those
records was maintained by our family doctors,
who kept our records sealed away in file cabinets
and refused to reveal them to anyone else. Today,
the use and disclosure of this information is
protected by a patchwork of state laws, leaving
large gaps in the protection of patients' privacy
and confidentiality. There is a pressing need
for national standards to control the flow of
sensitive patient information and to establish
real penalties for the misuse or disclosure
of this information. President Clinton and Congress
recognized the need for national patient record
privacy standards in 1996 when they enacted
the Health Insurance Portability and Accountability
Act of 1996 (HIPAA). That law gave Congress
until August 21, 1999, to pass comprehensive
health privacy legislation. After three years
of discussion in Congress without passage of
such a law, HIPAA provided HHS with the authority
to craft such privacy protections by regulation.
Following the principles and policies laid out
in the recommendations for national health information
privacy legislation the Administration submitted
to Congress in 1997, the Administration drafted
regulations to guarantee patients new rights
and protections against the misuse or disclosure
of their health records and the President and
Secretary Donna E. Shalala released them in
October of last year. During an extended comment
period, HHS received, electronically or on paper,
more than 52,000 communications from the public.
This final rule provides the first comprehensive
federal protection for the privacy of health
information. However, because of the limitations
of the HIPAA statute, these protections do not
fully achieve the Administration's goal of a
seamless system of privacy protection for all
health information. Members of both parties
in Congress will need to pass meaningful, comprehensive
privacy protection for American patients that
would extend the reach of the standards being
finalized today to all entities that hold personal
health information. For other HHS Press Releases
and Fact Sheets pertaining to the subject of
this announcement, please click here for our
Press Release and Fact Sheet search engine at:
http://www.hhs.gov/search/press.html
Note by editors: More details about this
matter will be found in next issues of Archive
of Oncology |
6 |
Telepsychiatry
http://www.telemedtoday.com/articlearchive/articles/telemedicine_articles.htm
Current Telepsychiatry
Activity in the U.S., Australia, Canada, and
Norway
Terry WHEELER and Ace ALLEN
Telemedicine Today's last full survey of telepsychiatry
was in the summer of 1994 (Vol. 2, no. 2). At
the time, we identified 9 programs in the U.S.
that were actively seeing patients, as well
as one in Canada and one in Norway. The five
most active programs were Norfolk (NE) Regional
Medical Center (about 420 consultations/year);
U. of SC (about 288/year); E. Montana (about
116/year); E. OREGON (about 48/year); and U.
of KS (40/year). Total consultations in 1994
among the 9 U.S. programs: about 948. A lot
has happened in the ensuing years. Last year's
Telemedicine Today survey of active telemedicine
programs, done cooperatively with the Association
of Telemedicine Service Providers, documented
25 programs in the U.S. doing 3,460 telemental
health consultations in 1996 (Vol. 5, no. 4).
Among the 19 programs in the U.S. we were able
to interview for this current survey, we found
that an aggregate total of about 720 consultations/month
are being done - or about 8,640/year. This is
nearly a 10-fold increase since 1994. |
7 |
Telecardiology
http://www.telemedtoday.com/articlearchive/articles/telecardiology.htm
Telecardiology has
been here for a long time. Telephones, and modifications
of telephones, have been conceived of and used
for auscultating heart and breath sounds for
over 70 years. More sophisticated techniques
for transmitting heart sounds more accurately
have been used since the 1960's FAXes are used
for transmitting EKGs, ad EKG tracings (rhythm
strips and 12-lead) can be transmitted easily
over phone lines. However, not until the past
10 years has the technology been available for
doing echocardiograms -- often the gold standard
test for diagnosis -- over a distance. meanwhile,
for most telemedicine systems, cardiology is
one of the most requested applications. It is
an area of medical care that is particularly
anxiety-inducing for many rural practitioners,
who greatly appreciate expert backup for those
newborns with oddball murmers, and those late-night
E.R. visits. This issue takes a close look at
five programs around North America doing tele-echocardiography.
One program is doing this along with a full
interactive history and physical, including
tele-stethoscopy. We've chosen these programs
because they represent different strategies
for delivering cardiac care (see Table). Two
are store-and-forward systems, three are real
time. One is broadband, one ISDN, one fractional
T1, two use standard phone lines. Each one of
these programs has taken a critical look at
the important issue of efficacy -- of whether
in fact the telecardiology technology can reliably
transmit the information needed to make good
clinical decisions. A few of the programs have
also looked (more or less formally) at costs
and benefits. The strong consensus is that tele-echocardiography,
both real time and tore-and-forward, and telestethoscopy
are effective ways of transmitting diagnostic-quality
information. There is an emerging body of data
that suggests they are quite cost-effective,
as well. Currently only real-time tele-echocardiography
is reliably reimbursed; this may change as efficacy
studies of the store-and-forward options accumulate. |
8 |
Teledermatology
http://www.telemedtoday.com/articlearchive/articles/teledermfinland.htm
Kuopio, Finland.
Real Time and Store-and-Forward Teledermatology
Since late 1994, teledermatology has been deployed
between Mäntyharju Municipal Health Center,
Mikkeli Central Hospital, and Kuopio University
Hospital. Supported in part by contributions
from the Etelä-Savo Hospital District and the
Finnet telephone companies, it is an ISDN-mediated
system running at 128 to 384 Kbps, using PictureTel
2000 equipment with far-end camera control and
autofocus. A second camera is used for still-image
captures at approximately 2x the resolution
(704 x 576 lines) of the video image. Initial
trials found that the higher bandwidth was necessary
for most consultations. While most cases (now
totaling nearly 100) have been done interactively
and with the still-image capture system, some
cases have been handled in pure store-and-forward
mode by taking photos of lesions, developing
and scanning them, then sending them as compressed
GIF or JPEG files over the Internet as email
attachments. This process will be greatly foreshortened
in the future by using digital cameras (see
Store and Forward Teledermatology at OHSU, last
issue - Ed.). The technology as currently constituted
appears most suitable for eczemas, most ulcers,
and nodular or bullous diseases, where the information
obtained is frequently diagnostic. For skin
tumors, the technology may be most useful for
advising the general practitioner how to proceed
with a biopsy, or when to triage to a specialist.
To date, patients have not been billed, and
consultations are on demand, rather than regularly
scheduled. Contact: Dr. Raimo Suhonen, Chief,
Dep't of Dermatology, Mikkeli Central Hospital,
50100 Mikkeli, Finland; [email protected];
http://personal.eunet.fi/fimnet/sll/raimo/ |
9 |
Current status of telesurgery
http://telemedtoday.com/articlearchive/articles/telemedicine_articles.htm
Telesurgery is the
provision of surgical care over a distance,
with direct, real-time visualization of the
operative field. It may be categorized as follows:
1) Telepresence surgery. Uses a computerized
interface to transmit the surgeons actions at
a surgical workstation to the operative site
at the remote surgical unit, with haptic (force
feedback) input to transmit to the surgeon the
tactile environment of the operative field
2) Telerobotics. Remote control with a robotic
arm, usually in conjunction with a laparoscope,
without haptic feedback
3) Telementoring. An experienced surgeon acts
as a preceptor for a remote inexperienced surgeon
by observing the surgeon via interactive video.
Teleproctoring is an extension of telementoring,
referring to documentation of performance for
privileging purposes. Related fields: virtual
reality and computer generated educational and
training scenarios. |
|
TELEMEDICINE JOURNALS |
|
|
News
1 |
A revolution in cancer
biology
Bogomir DIMITRIJEVIC,
Institute for Nuclear Sciences "Vinca",
Laboratory for Radiobiology and Molecular Genetics,
Belgrade, Yugoslavia
Traditionally,
tumors have been categorized on the basis of
histology. Achievements of this analytical approach
limit our ability to adequately classify and
diagnose malignant diseases. DNA microarrays
offer analysis of thousands of genes at once
and provide molecular profile of an individual
patient's tumor. When such profiles are analyzed
with pattern recognition software designed for
cluster analysis, new classes of cancer emerge
that transcend distinctions based on histological
appearance alone. The ultimate goal is to move
beyond correlation and classification and to
reach new insights into molecular pathology
and to set the stage for more rational therapeutic
approaches and drug design.
The preliminary version of the human genome
sequence is already available and is being continually
refined. This foundation should engage the next
(and greatest) challenge of biology and medicine
- the comprehensive understanding of the structure
and function of the cell and the organism thus
addressing questions of life, death and disease.
Living systems are much too complex to be studied
on one gene or one protein at a time. For this
reason biomedical science deals with this complexity
by studying the activity of many genes or proteins
in parallel, the approach known as molecular
profiling.
The current focus of molecular profiling is
the large-scale analysis of gene expression
using new DNA array technology. The goals in
the practice of oncology range from insights
into pathogenesis, cancer diagnosis and prediction
of clinical outcome to identification of therapeutic
targets. There have been several reports recently
published that show how DNA arrays can be applied
to the analysis and classification of cancer.
It is very realistic that this trend will follow
an exponential growth. Published results are
not only breathtaking demonstration of great
potentials of the new technology; at least one
of them has explicit clinical value. Namely,
gene expression profiling of diffuse large B-cell
lymphoma (DLBCL) provided means to distinguish
patients with distinct disease outcome. Conventional
methods for classification of cancer were unable
to distinguish between any DLBCL subtypes. This
has been accomplished with specialized microarrays
(lymphochips) for the study of non-Hodgkin's
lymphoma. Therefore, gene expression profiling
was able to subdivide a single diagnostic category
of lymphoma into two apparently distinct diseases.
This appears to be the first step in the approach
that will generate information needed to tailor
treatment to the individual patient. A realistic
possibility for personalized therapy deserves
pompous designation - a revolution in cancer
biology. |
2 |
Are you ready for the revolution
or when did you ask last time the World Wide
Web about the Human Genome Project?
Dimitar JAKIMOV,
Dragana CETOJEVIC-SIMIN, Institute of Oncology
Sremska Kamenica, Yugoslavia
The
beginning of new millennium is an interesting
phenomenon, especially when you have some big,
important and revolutionary staff to think and
talk about. This phenomenon seams like some
kind of acceleration of the historical happenings,
up to the levels of unpleasantness, particularly
when it happens in a domain such as fundamental
science is. Genome sequencing projects carried
out by groups around the World represent one
of the biggest scientific challenges that has
ever been undertaken.
To mark the publication of the initial sequencing
and analysis of the human genome, the journal
Nature set up special section on the human genome
- the Genome Gateway - a web site that provides
a comprehensive overview of current knowledge,
upholding the principle at the heart of the
Human Genome Project: free and unrestricted
access to all genome related material through
these web pages. The section comprises a huge
set of papers that, for the most part, report
the findings of the international consortia
of scientists that make up the Human Genome
Project. More than 2,500 authors from 20 laboratories
contributed to these papers. It also delves
into the opportunities offered to biologists
by the genome and explores the approaches and
tools needed to exploit these opportunities.
The News and Views articles provide the context,
communicate the excitement, and present a critical
evaluation of the papers.
This is a short overview of the content you
can find on the specified internet addresses.
Everyone's genome!
"The human genome underlies the fundamental
unity of all members of the human family, as
well as the recognition of their inherent dignity
and diversity. In a symbolic sense, it is the
heritage of humanity". Universal Declaration
on the Human Genome and Human Rights (http://www.unesco.org/human_rights/hrbc.htm)
Biology as a data-rich subject is a relatively
new phenomenon. The genomic data has the potential
to be (indeed, is already) a powerful integrative
force across the spectrum of biological sciences.
These information needs to be navigable by the
whole research community in order to be maximally
effective and it also needs to be accessible
and comprehensive. The Nature's Genome Gateway
is contribution to this process.
Humans are much more than simply the product
of a genome, but in a sense we are, both collectively
and individually, defined within the genome.
The mapping, sequencing and analysis of the
human genome are therefore a fundamental advance
in self-knowledge; it will strike a personal
chord with many people. And application of this
knowledge will, in time, materially benefit
almost everyone in the world.
Sequencing and cell cycling
Every organism must have cells that can replicate
indefinitely. Can the draft human genome sequence
tell us how the cell cycle works and how it
evolved?
Genome sequencing has revealed surprisingly
little about the cell cycle. The two main conclusions
of comparative analysis were drawn well before
the first eukaryotic genome was sequenced: the
machinery that regulates the cell cycle has
been highly conserved in eukaryotic evolution,
and the size of protein families such as the
Cdks and cyclins has expanded as organisms have
become bigger and acquired more cell types.
Comparing sequenced genomes has strengthened
but not altered these conclusions. Disappointingly,
comparing fully sequenced genomes does not explain
how differences have evolved between the cell
cycles of different organisms. For example,
a conserved pathway (the mitotic exit network)
is required for cytokinesis in budding and fission
yeast, but is required to complete mitosis in
budding but not in fission yeast. Men live,
and must avoid cancer, for thirty times as long
as mice, and it is much easier to induce mouse
cells to proliferate indefinitely in vitro.
Can comparing the sequence and expression of
two genomes reveal the source of these differences?
Getting a positive answer to such questions
will require a marked improvement in our ability
to turn raw sequence data into biological knowledge.
Genomics and cancer
Identification of the genes that cause oncogenesis
is a central aim of cancer research. All cancers
are caused by abnormalities in DNA sequence.
Throughout life, the DNA in human cells is exposed
to mutagens and suffers mistakes in replication,
resulting in progressive, subtle changes in
the DNA sequence in each cell. Occasionally,
one of these somatic mutations alters the function
of a critical gene, providing a growth advantage
to the cell in which it has occurred and resulting
in the emergence of an expanded clone derived
from this cell. Additional mutations in the
relevant target genes, and consequent waves
of clonal expansion, produce cells that invade
surrounding tissues and metastasize. Cancer
is the most common genetic disease: one in three
people in the western world develop cancer,
and one in five die from it. Around 30 recessive
oncogenes (tumour suppressor genes) and more
than 100 dominant oncogenes have been identified.
In the past, the most successful way to identify
such genes was to narrow their location to a
small part of the genome using mapping strategies,
and then to screen candidate genes in the region
for mutations in cancer cases. However, this
strategy has its limitations. Mapping information
can be confusing or misleading. Moreover, some
cancer genes leave no obvious 'identifiers'
in the genome and therefore cannot be readily
positioned using such maps (for example, dominant
oncogenes that are activated by single nucleotide
substitutions leading to a single amino-acid
change). These mutated genes are essentially
invisible to conventional detection and their
identification has usually depended upon selection
of likely candidates on the basis of the biological
features associated with cancer.
How will the genome sequence help us to identify
the remaining cancer genes? One possibility
is to generate a longer list of plausible candidates
by searching for paralogues of known cancer
genes.
Was this really a useful way of generating likely
candidate cancer genes? Mutated cancer genes
do recur in certain gene families (for example,
signaling kinases and GDP binding proteins),
but these families are often large and, in most
cases, only a minority of members are implicated
in cancer. In fact, the diversity of structure
and function of cancer genes is striking. For
example, hardly any of the known recessive oncogenes
have strong homology to any other, and their
proteins are associated with diverse biological
and biochemical functions. Moreover, many close
relatives of important cancer-related genes
(for example, the genes for p73 and p63, which
show sequence similarity to TP53 are not known
to be mutated in cancer (although it is possible
that they are significantly altered by changes
in expression). So we may learn more about the
mutations driving cancer if we are not too heavily
influenced by past experience. Instead, we should
persevere in exploring every gene or protein,
whatever its structure or putative function,
as a possible candidate.
By simply mining the genome sequence for similarity
to known cancer genes, we may miss an opportunity.
In addition to many more gene sequences, the
working draft contains information concerning
the organization of genes, their structures
and ordering along the chromosomes. Cancers
are characterized by disruption and disorganization
of genomes. Perhaps we could use the genome
sequence as a template against which we can
detect structural alterations of the genome
in cancer cells.
To do this we need to compare the working draft
(and ultimately the finished sequence) with
corresponding sequences from cancer cell genomes.
However, there is very little cancer genome
sequence available, and what is available is
patchy. The largest body of sequence from cancer
genomes originates from programs that sample
clones in complementary DNA libraries constructed
from neoplastic tissues (for example, the Cancer
Genome Anatomy Project (CGAP, http://www.ncbi.nlm.nih.gov/CGAP/)).
In principle, we could try and compare these
with the working draft for the somatic base
substitutions and small insertions and deletions
that often result in inactivation of tumour
suppressor genes or activation of dominantly
acting oncogenes. In practice, however, these
databases contain relatively little sequence
and do not sample most transcripts in any single
tumour. Moreover, the available sequence is
mostly from untranslated regions of genes (whereas
the cancer-causing mutations cluster in the
coding regions). Even if the rare, meaningful
somatic mutations could be detected, they would
be buried in the debris of sequence errors (both
in the cDNA libraries and in the genomic sequence)
or camouflaged in a forest of innocuous polymorphisms.
Elucidating the complexity of cancer at the
genomic level will require much more sequence
data from cancer genomes, which will need to
be configured appropriately for the task at
hand. So, the working draft will not immediately
reveal the natures of the abnormalities in cancer
cell genomes. To facilitate these analyses we
will need the finished sequence, which will
form a structural framework for a new generation
of massive-scale comparisons of cancer cell
and normal genomes. Ultimately, it may also
prompt a shift away from strategies that depend
upon primary genomic localization and allow
systematic genome-wide searches for mutations.
New technology will be required; there is no
single technology at present that will detect
all the types of abnormality (large deletions,
rearrangements, base substitutions, small insertions
and deletions, amplifications, and epigenetic
changes such as methylation) that are present
in cancer cells. Sequencing of genomic libraries
constructed from cancer genomes would come closest
to this goal, but given the diversity of cancers
and the effort and cost required to obtain reasonable
coverage of a human genome this is a daunting
challenge.
Immunology in the genomic view
The outstanding problems facing immunology are
whole system issues: curing allergic and autoimmune
disease and developing vaccines to stimulate
stronger immune responses against pathogenic
organisms and cancer.
The human genome sequence contains a list of
all the parts controlling beneficial and harmful
immune responses. To identify these parts, the
immediate hurdles of gene identification and
genome assembly will need to be overcome. The
ultimate challenge will be to bridge the gulf
between a list of sequences and whole organism
biology.
In contrast to the 'reverse genetics' strategies,
which create mutants in predicted immunological
genes using a bottom-up strategy, perhaps the
greatest contribution made to immunology by
the genome sequence lies in facilitating 'forward
genetics' approaches. These start with an altered
immunological trait and proceed from the top
down to identify the causative gene. The trait
may be a difference between strains of mice
or a difference in human families. Research
efforts can be focused on genes with key roles
in immunological processes, regardless of sequence
or expression pattern.
The complete list of parts provided by the human
genome sequence will, on its own, not solve
the major questions facing immunologists. Rather,
it will form the basis of experiments designed
to understand how the parts fit together to
control immune responses.
Available resources
There are a number of resources currently available
for perusing the human genome. 'Human Genome
Central' attempts to gather together the most
useful web sites. See: http://www.ensembl.org/genome/central/and
http://www.ncbi.nlm.nih.gov/genome/central
The best starting point for the uninitiated
will be a site such as those of NCBI, Ensembl
or the University of Santa Cruz (UCSC). These
sites offer a mixture of genomic viewers and
web-searchable datasets, and allow analysis
of the human genome sequence without the need
to run complex software locally.
For more involved analysis, it might be necessary
to download some of the data locally. Useful
downloadable sequence-oriented datasets include
protein datasets (available from Ensembl and
NCBI) and the assembled DNA sequence for regions
of the genome, available at UCSC. Other genomic
datasets are also available, such as the global
physical map from The Genome Sequencing Center
in St Louis and the single nucleotide polymorphism
(SNP) database from NCBI. Raw sequence data
is available from the International Nucleotide
Database (GenBank/EMBL/DDBJ), but this data
is generally more difficult to handle because
it is very fragmentary, can contain contaminating
nonhuman DNA and may include misleading information
such as incorrect map assignment.
This loose network of sites will probably coalesce
into a more coordinated network of sites offering
informative web pages and resources. NCBI, Ensembl
and UCSC are developing new, more accessible
resources that will become available within
the next year.
Conclusion: Add to favorites!
On this web site, accompanying the description
of the sequence, there are a lot of data-mining
papers that interrogate the genome from distinct
biological perspectives. These range from broad
topicsócancer, addiction, gene expression, immunology
and evolutionary genomics to the more focused:
membrane trafficking, cytoskeleton, cell cycle
and circadian clock. The findings reported by
these authors are likely to be indicative of
many people's experiences with the draft human
genome: frustrating and rewarding in equal measures.
A suite of interwoven maps is one of the features
available on line. The key map for the entire
project is the whole-genome clone-based physical
map constructed by the International Human Genome
Mapping Consortium. It provided the scaffold
upon which the sequence was assembled. The cytogenetic
map plots landmarks across the genome and anchors
the physical map to the underlying chromosomal
positions. A comparison of the genetic and physical
maps charts the rate of recombination or exchange
between each pair of our 46 chromosomes ó that
occurs as the genome is passed on through generations.
Finally, the International SNP asingle nucleotide
polymorphismo Map Working Group documents 1.42
million polymorphic sites in the genome, providing
for the first time a variant in virtually every
gene and in each genomic region. This map of
human variation will facilitate efforts to reconstruct
our evolutionary history and dissect the genetic
basis of human traits and disease. Analysis
of the draft genome sequence itself provides
the first panoramic view of the landscape of
our genome.
One principle at the heart of the Human Genome
Project, reflected in the Universal Declaration
on the Human Genome and Human Rights, is free
and unlimited access to the sequence. In keeping
with this principle, the entire content of this
section, plus additional features and commentary,
is available without restriction.
References 1. Available from: http://www.nature.com/genomics |
3 |
Nuclear Myosin
Rajko IGIC, Department
of Anesthesiology and Pain Management, Cook
County Hospital, Chicago, IL, USA
Motility
of the cells or intracellular particles is very
important phenomenon in biology. It represents
one of the crowning achievements of evolution
(Lodish et al, 1995).
Some cells move and reach locations more favorable
for growth, such as migrations of embryonic
cells that form the organs of multicellular
organisms, while most of the cells in the body
do not migrate. Nevertheless, they exhibit changes
in their morphology. For example, the contraction
of muscle cells, movements of microvilli and
filopodia, the separation of chromosomes, and
the transport of membrane vesicles. These functions
are mediated within cells by molecules called
"motor proteins," including the muscle
protein myosin.
It has been suspected for long that cellular
nucleus must also have a motor protein responsible
for movements of various nuclear particles.
The researchers have found that nuclear processes,
such as transcription, involve large molecular
complexes and require energy (Alberts, 1998),
and that the abundance of actin in the nucleus
(Rando et al., 2000) suggests a role for myosin
in the nucleus. However, exact nature of this
motor protein was not known.
A few months ago, a nuclear motor protein was
identified by the researchers at the University
of Illinois at Chicago led by Professor Primal
de Lanerolle (Dragovic-Pestic et al, 2000).
They showed the presence of a protein called
myosin I in the nucleus. Nuclear myosin I is
similar to muscle myosin, but it contains a
unique 16-amino acid aminoterminal extension.
The authors showed that this extension is essential
for targeting myosin I to the nucleus. They
have also shown that this myosin is in a complex
with RNA polymerase II. Other experiments showed
that nuclear myosin I plays an active role in
RNA synthesis.
These results are very exciting because they
provide an important insight into the molecular
mechanisms required to express genes. They also
suggest similarities between muscle contraction
and transcription. A great deal is known about
the role of myosin in muscle contraction and
it may be possible to apply this knowledge to
better understanding the regulation of gene
expression. Because transcription is essential
for cell growth and division, improved understanding
of transcription at the molecular level may
provide new ways to treat cancers and other
proliferative diseases.
References
1. Alberts B. The cell as a collection of protein
machines: preparing the next generation of molecular
biologists. Cell 1998;92:291-4.
2. Dragovic-Pestic L, Stojiljkovic Lj, Philimonenko
AA, Nowak G, Ke Y, Settlage RE et al. A Myosin
I isoform in the Nucleus. Science 2000;290:337-41.
3. Lodish H, Baltimore D, Berk A, Zipursky SL,
Matsudaira P, Darnell J. Molecular Cell Biology,
3 ed. New York: Scientific American Books; 1995.
p. 991.
4. Rando OJ, Zhao K, Grabtree GR. Searching
for a function for nuclear actin. Trends Cell
Biol 2000;10;92-7. (Illustrated by H. Fazlic). |
4 |
Fundamental Research in
Serbia - YES or NO
Pavle Milenkovic
and Nevenka Stojanovic, Institute for Medical
Research, Belgrade, Yugoslavia
Most
of the governments in the world believe that
only applied research programs will lead to
the progress. It is not recognized that already
existing fundamental research is always the
basis for successful applied research. The so-called
strategic research programs are sometimes in
fact misleading and do not distinguish basic-fundamental
research from the basic strategic research.
Fundamental research is concerned with foundation
of new knowledge. The basic-fundamental strategic
research is oriented to the formation of new
frontiers leading to applicable product. This
does not mean that fundamental research is not
potentially applicable but the period of recognition
is too long and is often not foreseen by the
government and mostly by the scientists as well.
The examples are numerous. The structure of
DNA became, after 40 years, the basis for genetic
engineering and forensic medicine. The magnetic
resonance imaging is now widely used but the
scientific basis was founded in the fifties.
More than seventy percent of clinical tools
used in cardiology are based on fundamental
research not initially aimed to be utilized
in cardiology. Several pharmaceutical companies
realized that basic research might be the basis
for new ideas and therefore new drugs. The examples
also involve the development of hemopoietic
growth factors as useful drugs during the period
of about 20 years period, starting from initial
description, research on function, isolation,
and large-scale production by recombinant technology.
In Serbia, research is continuously supported
through the projects founded by Ministry of
Science and Technology. The limited economic
resources are faced with around 15,000 researchers
located at universities and institutes. It is
obvious that financial support of the researches
has been aimed to prevent the leaking of the
scientific basis to better positions in more
developed countries. But in the economic reality
the appropriate support of research projects
failed, inevitably causing the overall results.
Therefore, new changes in our society and expected
economic renewal in future need a new strategy
in the foundation and funding of scientific
research. However, the long-term strategic plan
for development of Serbia does not exist. Last
year, the National Advisory Board for science
and technology promoted a document on strategy
of scientific and technologic development. It
emphasized that strategic applied research had
a priority in the future. Although this seems
reasonable for the country of this size and
economy, as the long-term national interest
it might be dangerous. The experience of more
developed countries demonstrate that fundamental
research has good impact on productivity, that
new technology depends mainly on the advances
in fundamental research and that there is an
interdependence between national strength in
industry and strengths in fundamental research.
In global world economy there is an obvious
question: Does the engagement of a small country
in basic research seem to be the waste of financial
resources? Financial support of fundamental
research might be expensive and of high risk
in cost/benefit relation. However, the benefits
are obvious and in fact strategic.
By minimizing fundamental research we shall
be faced, in near future, with the technologies
developed in more advanced countries, which
we might not even understand. Continuous education
of high quality young scientists is essential
if we want survival of science in Serbia. Fundamental
research is a critical part of research education
and the basis for new knowledge.
References
1. dos Remedios C. The value of fundamental
research. A discussion paper prepared for the
IUPAB council. available from: URL: http://
www: iupab.org
2. Koenig R. Help needed to rebuild science
in Yugoslavia. Science 2000;290:690-93. |
5 |
Eminent scientist of the
year award
Dubravka STRIBER
DEVAJA, Svetozar ZDRAVKOVIC, Institute of Oncology
Sremska Kamenica, Yugoslavia
The
International Research Promotion Council (IRPC)
is an international organization committed to
promote academic and research achievements of
scientists and
researchers in different branches of science.
Along with other awards the IRPC - Asia Pacific
Chapter has decided to further its aims by selecting
and conferring "Eminent Scientist of the
Year" award and "Outstanding Research
Team" award in the field of science and
medicine. This is done by the Award Selection
Committee of IRPC comprised of eminent scientists
and after careful assessment of the achievements
of the research team. By decision of IRPC the
Institute of Oncology Sremska Kamenica was awarded
international reward for 2000 in the field of
medicine for the article "Hospital Cancer
Data Registry". The award consists of the
gold medal for the main author and medal showing
the emblem of IRPC to the research team, Certificate
of Excellence award winner. The authors of the
article: Dubravka Striber Devaja, B.S.E.E, Svetozar
Zdravkovic, B.S.E.E. and Prof. Vladimir Vit.
Baltic, M.D. Ph.D. were selected for the title:
Eminent Scientist of the Year 2000 & Millennium
Golden International Award Winner. "Recent
Advances & Research Updates" is published
exclusively for IRPC as the special issue of
the journal. The authors of the article from
the Institute of Oncology Sremska Kamenica are
the first from similar medical institutions
in Yugoslavia who won this award. |
6 |
Diskobolos 2001
Dubravka STRIBER
DEVAJA, Svetozar ZDRAVKOVIC, Institute of Oncology
Sremska Kamenica, Yugoslavia
Every
year JISA (Yugoslav Association of Information
Technology) assigns the Diskobolos reward for
the best solutions in the field of Information
Technology (IT). At the end of the year the
JISA pronounce the best achievement of the year.
Diskobolos picture reminds us of the new optical
storage era we use in IT field. The Judges for
the Diskobolos prize are twelve most eminent
IT experts and members of JISA. On December
21, 2000 the Institute of Oncology Sremska Kamenica
was awarded the year's main informatics reward
in the field of national health DISKOBOLOS 2000
for the article: "Telemedicine and multimedial
interactive communication in the Internet environment".
The authors of this article are: Dubravka Striber
Devaja, Svetozar Zdravkovic, Vladimir Vit. Baltic,
Vladimir Ivanovic. The Institute of Oncology
is the first medical institution which won the
award twice, in 1999 and 2000. Last year the
Institute of Oncology Sremska Kamenica was awarded
DISKOBOLOS 1999 for the realization of the project:
Registries of malignant tumours". |
7 |
Report on the quality control
system audit at the Institute of Oncology Sremska
Kamenica
Branislava Jovanovic,
Sava Marjanov, Institute of Oncology Sremska
Kamenica, Yugoslavia
Mrs.
Pamela Bankes, a quality controller from British
Standard Institution (BSI) visited the Institute
of Oncology Sremska Kamenica on February 22-23,
2001 and carried out the audit of the established
quality control system - BS EN ISO:1994.
The quality control system at the Institute
of Oncology Sremska Kamenica was initiated in
1996 and its successful implementation was confirmed
with the award of BSI Certificate on April 22,
1998.
In 1999, the Institute of Oncology entered a
Yugoslav contest for quality system award -
the statute of Oscar for Quality - and won the
fourth place and Medal for Quality.
Mrs. Pamela Bankes carried out the audit of
quality control system in all organizational
units at the Institute and did not find any
nonconformity with the established system. Her
general assessment was that the Institute succeeded
to maintain the effective quality system during
the past period. She also gave recommendations
for the improvement of the system.
The implemented improvements of the quality
control system at the Institute were demonstrated
in: the objectives of the quality system, as
defined in the Policy of Quality and their implementation,
the re-evaluation by the management, as a process
of re-checking of all data obtained from the
quality system and identification of all possibilities
for continuos improvement, the internal audit
of quality system, performed twice a year, the
analysis of the complaints expressed by customers-patients,
to recognize the most troublesome processes
and give recommendations for their improvements
the analysis of nonconformity trend, identification
of basic causes and implementation of recommended
activities their for correction and prevention.
At the end of her visit, Mrs. Pamela Bankes
expressed her great pleasure that the Institute
of Oncology is among the institutions certified
by BSI for Qualify Control System. The next
audit to be performed by BSI is foreseen for
August, 2001. By that time, the Institute of
Oncology should conform its certified quality
system with the new version of quality standards
ISO 9000:2000. |
Book Review
Book Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 2 |
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ONCOnet*
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TELEMEDICINE WORLDWIDE |
1 |
THE FINAL REPORT FROM THE
7th INTERNATIONAL INTER UNIVERSITY SCIENTIFIC
MEETING ACADEMY OF STUDENICA
Closing Statement
7th International Inter
University Conference on Telemedicine took place
in Monastery Studenica between May 23rd and
26th of 2001. About 80 international participants
presented over 30 orig- inal papers and 3 invited
lectures. The Conference Proceedings is published
as the 4th - "Annals of the Academy of
Studenica" in the form of CD-ROM.
The participants thank to the Institute of Oncology
for organizational effort and relaxing atmosphere
that set the stage for successful and dynamic
exchange of research results and experiences
from various fields of Telemedicine.
The Academy announces the best paper award to
Mark L. Manwaring for the original contribution
related to the Remote monitoring of intracranial
pressure. The best national paper award goes
to the paper "Telemedicine and Multimedia
interactive communication in internet environment"
authored by Dubravka Striber Devaja, Svetozar
Zdravkoviæ and Vladimir Vit. Baltiæ for the
contribution to the national telemedicine practice.
High interest for the Conference shows that
we are catching up with contemporary telemedicine
developments and confirms the need for introducing
the telemedicine to the national health care
system. Future developments require both considerable
investment to the communication and medical
infrastructure and multidisciplinary research
projects.
The Conference participants support foundation
of YUTEM-the Yugoslav Telemedicine Association
that should bring all interested parties together
in an effort to develop modern national Telemedical
infrastructure to the benefit of patients. We
are looking forward to meeting again and presenting
the initial results of the pilot projects of
YUSTEM-Yugoslav Telemedical System. |
|
For the
Programme Committee
Full Prof. Dr. Zoran Jovanovic
Full Prof. Dr. Veljko Malbasa
Ass. Prof. Dr. Miroslav Despotovic
|
2 |
Openinig Address
Dear Conference President
V.V. Baltic and and Co-President Professor P
Spasic,
The Officers, Board of Directors, and Members
of the American Telemedicine Association send
our very best wishes for a successful Telemedicicine
Conference in Studenica. The program for your
conference promises to be very interesting and
exciting. The topics which you plan to discuss
are at the forefront of the field of telemedicine.
We are confident that the presentations at the
Conference will lead to significant advancements
in the field of telemedicine and will also help
move forward the agenda for glob- al telemedicine.
This will be of benefit to people throughout
the world.
Congratulations on organizing this splendid
conference. Very best wishes for every possible
success at what will certainly be an unforgettable
international conference.
Most sincerely yours, |
|
Ronald S. Weinstein, M.D.
Secretary, American Telemedicine Association
Washington, D.C., USA
|
3 |
SINERGIJA
Dubravka STRIBER
DEVAJA, Svetozar ZDRAVKOVIC
On the occasion of the
return to Serbian informatics environment Microsoft
and its partners from Serbia organized a conference
named Synergy in the Sava Center on June 7,
2001. It was attended by several thousands of
participants interested to hear lectures, and
get information about recent achievements and
the newest products from the field of informatics
technology presented by Microsoft. The guests
and participants were welcomed and addressed
by Mr. Zoran Djindjic, Serbian Prime Minister,
Mr. Michael Lacombe, vice president of Microsoft,
Mr. Ian Wise from Compaq Computer and Microsoft
representatives Mr. Goran Radman and Mr. Dejan
Cvetkovic. The lectures were organized in four
sections covering productivity, infrastructure,
management and development - or to use the words
of the organizer - technologies of today in
service for future. A very interesting lecture
on new technology for development of Internet
web applications based on "web services"
and named Microsoft.NET (Microsoft dot net)
was presented by Rafael Lukawiecki, Project
Botticelli. Microsoft is planning to open its
offices in Yugoslavia as soon as possible and
to secure its copyright and intellectual ownership
on its products as a primary task. It is, among
other things, precon- ditioned by the average
income of our citizens which, according to Microsoft
representatives for this region, must be higher
if the company wants to make profit. On the
other hand, Mr. Radman said that daily rate
of any Microsoft software package, when paid
on installments, is not higher than a price
for a cup of coffee. Microsoft will help the
development of information systems in government
institutions by the unification of software
solutions. The company plans to open its agency
offices and all those who have Microsoft registered
software programs shall have all privileges
of legal users as everywhere. These plans leave
open enough space for a sound competition. The
development of Internet and existing telecommunication
system in Serbia were also discussed. The government
of Serbia is the one to make the next move.
The appearance of Microsoft on our market is
certainly positive and encouraging and we hope
that the state of Serbia will not be too idle
to use all benefits from this cooperation because
the information systems and Internet present
the future of any country, including Serbia. |
4 |
3D Monitor about
to appear
http://mikro.co.yu/mkvesti
or http://mkvesti.listbot.com
News of Journal "Mikro", June 4,
2001;3(106)
Recently founded company Actuality Systems,
Riding, Massachusetts is going to present its
new 20 inches, spherical monitor at the Society
Information Display conference to be held in
San Hose. The monitor, temporarily named Helios,
is designed for tridimensional display of a
picture showing much more details than a traditional
flat monitors. The users will be able to circle
around the screen and watch the picture from
any angle within the range of 360 degrees. The
company says that 3D monitor will find its use
in molecular and medical structures visualization,
mechanical modeling, aeronautical and astronomical
shots for flight control purposes and satellite
positioning, and of course - for fun! Actuality
Systems company was founded in 1997 as a progeny
of the Massachusetts Technology Institute. |
|
TELEMEDICINE JOURNALS |
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News
1 |
Intracellular signaling
pathways: main object of molecular oncology
Alexander G. TATOSYAN,
Cancer Research Center Moscow, Russia
The
harmonic functioning of a multicellular organism
is determined by the ability of its cells to
interact as well as their adequate response
to environmental changes. Surface receptors
are those "sense organs" which react
to extracellular factors and inform the cell
as appropriate. Specific interaction between
the external signals, called "impulse",
generated on the cellular membrane is amplified
and transmitted inside the cell through certain
signal chains. Some of the signals are sent
to the nucleus, where they initiate the expression
of particular genes. The cells' response to
the signal stimulus may be different such as
cell division (or, on the contrary, repression
of this process), differentiation, proliferation,
apoptosis, hormone secretion and others. The
maintenance of a normal cellular phenotype results
from an equilibrium between these processes.
When this equilibrium is disrupted, the cell
is at risk of entering a state of malignant
transformation. There is a great diversity in
the intracellular signaling pathways in cells.
Because of their extraordinary complexity, our
knowledge of these pathways is very fragmentary
and decoding them is still at an early stage.
We know that signaling pathways probably function
in networks in which there are interconnections,
and points of convergence and divergence. To
understand the structure and the regulation
of these networks is one of the major goals
of modern biology: intracellular signaling is
a topic that concerns nearly all of the research
undertaken in functional molecular biology.
It is studied particularly during oncogenesis
and in several diseases apart from cancer. In
its simplified form the signal transduction
mechanism in the cell is a direct interaction
between specific proteins in strictly determined
order. A number of key proteins may be used
in several signal transduction pathways. Different
types of kinases and mines the intracellular
signal trunsduction. During any malignant transformation,
the reverse picture is observed - the signal
system undergoes specific changes to make the
transformed cell independent of environmental
conditions and surrounding tissues. This is
evident when one examines genes that are altered
in cancers; many alterations are found in proteins
that transmit signals, such as transcription
factors, receptors, intracellular effectors,
etc. Cancer, as many other diseases, is a disease
of cellular signaling. Understanding how "intracellular
signaling" functions requires even a partial
knowledge acquired about this very complex network
to be constantly integrated at the more complex
level of the whole cell. Therefore, it is important
to make continuously the links between signaling
and intracellular transport, signaling and cellular
differentiation, and signaling and morphogenesis,
signaling and cell cycle. Protooncogenes and
suppressor genes play an essential role in the
transmission of signals that control these processes.
Understanding their precise role in normal cells
is an important step in the understanding of
cellular dysfunction in the regulation of the
proliferation and differentiation during oncogenesis.
On other hand the development of methods to
analyze structural and functional anomalies
of carcinogenic molecular factors represents
an ultimate goal of the basic researches undertaken
in order to progress in the diagnosis and the
treatment of cancer. The introduction of innovative
treatments resulting from research into the
clinics for the benefit of the patients constitutes
an essen- tial mission of molecular oncology
at present period. |
2 |
Ask nature- cyanobacteria
in cancer drug research
Dragana CETOJEVIC-SIMIN,
Institute of Oncology Sremska Kamenica, Yugoslavia
Despite
the fact that natural products are the most
successful source of drug leads, their use in
drug discovery has fallen out of favour. Of
the new drugs approved between 1983 and 1994
up to 80% of antibacterials and anticancer drugs
were derived from natural products (including
taxol, docetaxel and camptothecin). Thay are
likely to continue to be sources of new commercially
viable drug leads. The chemical novelty associated
with natural products is higher than that of
any other source: 40% of the chemical scaffolds
in a published data- base of natural products
are absent from syntetic chemistry. Biologically
active natural products are generally small
molecules with drug-like properties and are
capable of being absorbed and metabolized by
the body, what additionally lowers the develop-
ment costs. Microalgae are widespread group
of photosynthetic organisms. Cyanobacteria,
procariotic microalgae, produce a wide array
of low molecular weight secondary metabolites
with biological activity. Experimental studies
in animal models have demonstrated an inhibitory
effect of Spirulina fusiformis on oral carcinogenesis.
Cryptophycin 1 is a remarkably potent antiprolif-
erative compound that shows excellent antitumor
activity against mammary, colon and pancreatic
adenocarcinomas in mouse xenographs. At picomolar
concentrations it blocks cells in the G2/M phase
of the cell cycle by apparent action on microtubules
resulting in powerfull antitumor activity, many-fold
greater than paclitaxel or the vinca alkaloids.
Tubercidin stabilizes micro- tubules against
vinblastine- induced depolimerization, a taxol-
like effect. Curacin A is a potent antimitotic
agent, inhibitor of micro- tubule assembly.
Tolyporphin, Welwitinindolinone and Welwistatin
bind to P-glicoprotein, circumventing multiple
drug resistance and may be useful in the treatment
of drug-resistant tumors. With the ability to
manipulate the yealds and the diversi- ty of
metabolites through changes in culture conditions,
microal- gae should be examined more closely
for their ability to provide novel chemical
diversity for drug discovery.
References
1. Harvey A. Strategies for discovering drygs
from previously unexplored natural products.
Drug Discovery Today 2000;7:294- 300.
2. Adams GD. Heterocyst formation in cyanobacteria.
Curr Opin Microbiol 2000;3:618-24.
3. Kondo T, Ishiura M.The circadian clocks of
plants and cyanobacteria. Trends Plant Sci 1999;5:171-6. |
3 |
DA-125 a novel anthracycline
derivative showing high-affinity DNA binding
and topoisomerase II inhibitory activities,
exerts cytotoxicity via c-Jun N-terminal kinase
pathway
Sang GK, Mina S,
Keon WK et al. Cancer Chemother Pharmacol 200l;47:511-8.
DA-12 (8S,10S)-8-(3-Aminopropanoyloxyacetyl)-10-
[(2,6- dideoxy-2-fluoro- -L-talopryranosyl)oxy]-
7,8,9,10 - tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-nephthacene-doe
hydrocloride is a novel anthracycline derivative
with anticancer activity. |
4 |
The potential clinical
value of GML and the p53 gene as a pre- dictor
of chemosensitivity for colorectal cancer
Hashimoto Y, Ueda
K, Minami K, et al. Int J Clin Oncol 200l;6:90-6.
GML expressio and p53
mutation in colorectal cancer may be useful
predictive genetis markers for sensitivity to
MMC an 5-FU, respectively. |
Book Review
Book Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 3 |
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ONCOnet*
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TELEMEDICINE WORLDWIDE |
1 |
The 13th symposium of cardiologists
of Yugoslavia
Svetozar ZDRAVKOVIC
The 13th Symposium of
cardiologists of Yugoslavia was held in Novi
Sad October 17-20, 2001. Among the sessions
about cardiology and cardiosurgery, one interesting
session about telemedicine was held on October
19, 2001 with the title "Telemedicine in
cardiology - after birth ...". There were
four lec- tures in the field of cardiology mostly
describing transfer of EKG signals over mobile
telephony system, aspects of DICOM standards
in EKG devices and teleconsultations between
Clinic of car- diology and outpatient departments.
The special lecture was done by Institute of
oncology Sremska Kamenica, Dubravka Striber
Devaja and Svetozar Zdravkovic with the title:
"Telemedicine on the Institute of oncology
Sremska Kamenica - our experiences". As
the institution with some results in using telemedicine,
the organizer of the Symposium has called the
Institute to present its experiences, although
the session has concern only cardiological aspects
of telemedicine. The lecture was well accepted
from audience both from physicians and engineers.
In the discusion after lecrurers, the conclusion
was made to improve cooperation among medical
institutions themselves on one side, and medical
institutions and proffesional companies dealed
with technology used in telemedicne on other
side. The use of telemedicine in Yugoslavia
is still from case to case, so a real effort
had to be done from everybody included in telemedicine
to reach the objective - telemedicine in everyday
practice. |
2 |
Telemedicine guidelines
and technical standards affecting telemedical
transmissions
http://www.americantelemed.org/news/newres.htm
As telemedicine
matures, various policies are being adopted
that affect the equipment and services used
in telemedicine. The following information provides
links to various clinical guidelines and technical
standards that are used in telemedicine applications.
Clinical Guidelines:
- Telehomecare Clinical Guidelines (http://www.americantelemed.org/news/guidelines.html)
- Clinical Guidelines for Telepathology (http://telepathology.upmc.edu/ata/guideline.htm)
- ACR Teleradiology Guidelines (http://www.acr.org/departments/stand_accred/standards/
pdf_standards/diag/telerad.pdf)
Technical Standards
- DICOM (Digital Imaging and Communications
in Medicine) is the industry standard for transferral
of radiologic images and other medical information
between computers. (http://www.rsna.org/REG/practiceres/dicom/index.html)
- HL7 is a standard for the electronic interchange
of clinical, financial and administrative information
among independent health care oriented computer
systems; e.g., hospital information systems,
clinical laboratory systems, enterprise systems
and pharmacy systems. (http://www.mcis.duke.edu/standards/HL7/hl7.htm)
- H.320 encompasses a set of standards for narrow
band visual telephone systems and terminal equipment,
commonly used in interactive live video applications
for telemedicine. Developed by the International
Telecommunications Union (ITU) H.320 specifies
technical requirements for narrow band visual
telephone systems and terminal equipment, typically
for videoconferencing and videophone services.
It describes a generic system configuration
consisting of a number of elements, definition
of communication modes and terminal types, call
control arrangements, terminal aspects and interworking
requirements. The full standards are available
for purchase from ITU at http://www.itu.int/itudoc/itut/rec/h/h320.html.
- The Association for the Advancement of Medical
Instrumentation has a standards program consists
of over 100 technical committees and working
groups that produce Standards, Recommended Practices
and Technical Information Reports for many medical
devices. Information about the program and standards
that have been created are available at http://www.aami.org/standards/index.html. |
3 |
DICOM: The value and importance
of an imaging standard
http://www.rsna.org/practice/dicom/index.html
DICOM (Digital Imaging
and Communications in Medicine) is the industry
standard for transferral of radiologic images
and other medical information between computers.
Patterned after the Open System Interconnection
of the International Standards Organization,
DICOM enables digital communication between
diagnostic and therapeutic equipment and systems
from various manufacturers.
Such connectivity is important to cost-effectiveness
in health care. DICOM users can provide radiology
services within facilities and across geographic
regions, gain maximum benefit from existing
resources, and keep costs down through compatibility
of new equipment and systems. For example, workstations,
CT scanners, MR imagers, film digitizers, shared
archives, laser printers, and host computers
and mainframes made by multiple vendors and
located at one site or many sites can "talk
to one another" by means of DICOM across
an "open-system" network. As a result,
medical images can be captured and communicated
more quickly, physicians can make diagnoses
sooner, and treatment deci- sions can be made
sooner.
The DICOM 3.0 standard evolved from versions
1.0 (1985) and 2.0 (1988) of a standard developed
by the American College of Radiology (ACR) and
National Electrical Manufacturers Association
(NEMA). To support the implementation and demonstration
of DICOM 3.0, the RSNA Electronic Communications
Committee began to work with the ACR-NEMA MedPacs
ad hoc section in 1992. This committee, chaired
by Robert Hindel, PhD, established the concept
of the central test node (CTN), a central exchange
point that obviated the need for vendors to
make pre- arrangements in order to exchange
images directly with one another. At the RSNA
annual meeting and scientific assembly, held
at McCormick Place in Chicago, images compliant
with DICOM 3.0 reside on the CTN and remain
available to all partici- pants on the network,
including those on the technical exhibit floors.
With funds from RSNA, the Electronic Radiology
Laboratory (ERL) at the Mallinckrodt Institute
of Radiology developed software that was the
first of its kind to implement the written technical
specification of the DICOM standard. The software
was installed on the CTN for demonstrating the
standard over a local area network in the infoRAD
section of RSNA '92. Mallinckrodt produced more
sophisticated software, which was demonstrated
across a wide area network at RSNA '93. In January
1994, an access to the source code and documentation
would provide users and developers a model for
understanding the standard and for design considerations
and a set of utilities that would be useful
for initial testing in developers' laboratories.
The following organizations have been involved
in support of the DICOM effort:
American College of Radiology
Mallinckrodt Institute of Radiology
National Electrical Manufacturers Association
Radiological Society of North America. |
4 |
Telemedicine and
E-Health
http://www.americantelemed.org/news/newres.htm
E-health is a very broad term that encompasses
many different activities related to the use
of the Internet for healthcare. Many of these
activities have focused on administrative functions
such as claims processing or records storage.
However, there is an increasing use of e-health
related to patient and clinical care. With this
development, the world of e-health and telemedicine
began to merge and ATA started to address clinical
and patient care issues related to e-health.
Information provided here focuses on clinical
care and patient education aspects of e-health
and is targeted to the health provider.
A Guide to E-Health for the Healthcare Professional
An Introduction (http://www.americantelemed.org/ehealth/guide.htm)
What Your Patients Should Know (http://www.americantelemed.org/ehealth/whattotell.htm). |
5 |
NEW BOOK
Telemedicine and Telehealth: Principles, Policies,
Performance and Pitfalls
Adam William Drakins and Margaret Ann
Cary
(http://link.spinger.de/ol/medol/Index.htm)
Excerpt from book review from TELEMEDICINE
JOURNAL ANSD e-HEALTH, Volume 7 Number 2, 2001
by Norman E. Alessi, M.D. as reviewer
"...This book is well written and should
be read by administrators, physicians, allied
health professionals, and policy makers involved
with the delivery of healthcare... ". |
|
TELEMEDICINE JOURNALS |
|
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News
1 |
Perhaps not everyone knows
that...
Ann Oncol 2001;12:1337.
The CD155 gene, which
encodes a transmembrane protein facil- itating
poliovirus entry to the cell, is overexpressed
in colorectal carcinoma. Moreover, overexpression
begins at an early stage in tumorigenesis and
continues to late stages. Previous studies in
rat have shown that the Tage4 gene (tumor associated
glycoprotein E4), which exhibits 40% identity
with human CD155, is overexpressed in colon
tumour cells. Consequently, researchers at Nantes
University Hospital have now used reverse transcription-polymerasr
chain reaction and immunohistochemical analyses
to examine CD155 expression in human colorectal
carcinoma. CD155 mRNA levels were increased
in six of six colorectal cancer tissues compared
with the tumour free colon mucosa, while immunohistochemical
analysis revealed an increased level of CD155
protein in 12 of 12 samples. The relative expression
of different CD155 variant transcripts was similar
in the various normal and cancer samples tested,
indicating that this overexpression is not associated
with a particular mRNA variant. |
2 |
Changed trends of cancer
mortality in the elderly
Levi F, Lucchini
F, Negri, Boyle P, La Vecchia C.
Ann Oncol 2001;12:1467-177.
Between the
late 1980s and the late 1990s total cancer mortality
at age 65 to 84 has been declining in the European
Union (UE) (-5.5% in males, -4.5% in females),
in United States (US) males (-2.3%), but not
females (+4.4%), and in Japanese females (-5.6%),
but not males (+6.3%). Cancer mortality in the
elderly rose for both sexes in eastern Europe.
Gastric cancer mortality declined in all the
areas. Lung cancer rates declined over the last
decade by 8.5% in males in the EU, and by 0.9%
in the US. Rates were still increasing in eastern
Europe, in Japanese males and females in all
areas. Pancreatic mortality rates were increasing
in both sexes in the EU and Japan up to the
late 1980s, and in eastern Europe up to the
1990s, whereas rates for US males have been
declining certification may have played a role
in these trends. Mortality from leukemia in
the elderly increased in eastern Europe and
Japan, but was stable in the US and the EU. |
3 |
Radon: A likely carcinogen
at all exposures
Darby S, Hill D,
Doll R.
Ann Oncol 2001;12:1341-51.
Estimates are
uncertain, but residential radon is probably
responsible for about 2000 lung cancer deaths
per year in the United Kingdom, or around 6%
of the total, making it the second biggest cause
after smoking. Over 80% of the deaths are estimated
to occur at ages less than 75 and over 80% in
smokers or ex-smokers. Around 90% of radon-induced
deaths in the United Kingdom probably occur
as a result of exposures to radon concentrations
below the currently recommended action level
of 200 Bq mexp-3 . Further work is needed to
obtain more reliable estimates of the risk of
lung cancer associated with residential radon
and on the cost-effectiveness of various intervention
strategies before the most appropriate policies
can be developed for managing exposure to this
natural carcinogen. |
Book Review
Book Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 4 |
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Coverpage
Medical and Scientific Meetings
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Volume 8 |
Issue 1 |
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News
1 |
Hydroxyurea is an usually
well-tolerated antitumor agent, but its side
effects include cutaneous lesions that appear
mainly during long-term continuous therapy.
The reported rate of such adverse reactions
varies from 2 to 35%. A patient is described
with chronic myeloproliferative disease in a
form of myelofibrosis who developed lichenoid
skin changes after several years of treatment
with hydroxyurea. The changes consisted of:
xerosis, scalling, hyperpigmentation, atrophy,
erythema of the face and hands and ungual atrophy.
The histological changes were similar to those
seen in lichen planus. |
2 |
The goals of health
policy in Serbia until the year 2010 The general
goals of health policy Contemporary concept
of health protection starts from the commonly
accepted value that the most important goal
of the development of a society is the improvement
of quality of life of people, and that health
is the basic component of quality of life. Therefore,
the protection and the improvement of health
get the central position in all developing strategies.
On the other hand, the fact that the capability
for the development of a society depends on
health of the population is accepted. Therefore,
health and healthy environment become the integral
part of the total developing policy of a society.
In accordance with these principles, and according
to the performed analyses and studies, the following
General goals of health policy in Serbia until
the year 2010 were stated:
1. Preservation and improvement of the biological
integrity of the nation;
2. Prolongation of a life-time of population;
3. Improvement of quality of life of people;
4. Improvement of health condition of population;
5. Provision of equality in achieving health
protection;
6. Raising of quality and efficiency of health
protection;
7. Improvement of material position of health
facilities and health workers;
8. Greater influence of users of health protection
in making and realizing decisions considering
health protection. |
3 |
In the November 15 issue
of the journal Blood, a team of scientists from
the National Cancer Institute reports that four
out of four patients with hairy cell leukemia,
an uncommon cancer of immune B cells, had "major
responses" to a recombinant immunotoxin
called LMB-2. All of the patients previously
had not responded to standard treatments for
the cancer, including chemotherapy and removal
of the spleen. Robert Kreitman, M.D., lead author
on the study, said one patient in this early
stage clinical trial had a complete remission
after treatment with the immunotoxin and has
not relapsed 16 months later. For the three
other patients, Kreitman and colleagues observed
partial responses, detecting a 98% to 99.8%
reduction in malignant circulating cells. All
of the side effects were reversible and usually
lasted less than a week. These included fever,
nausea, vomiting, and rush. |
4 |
Matched urine and serum
DNA samples were obtained before surgery from
30 patients with clinically organ-confined solid
renal masses (25 with malignant tumors and five
with tumors of low malignant potential) and
were subjected to microsatellite analysis. Nineteen
(76%) of the 25 patients with malignant tumors
were found to have one or more microsatellite
DNA alterations in their urine specimen, and
15 were found to have alterations in their serum
DNA by microsatellite analysis. In every case,
the microsatellite changes in urine or serum
were identical to those found in the primary
tumor. Three of five patients with tumors of
low malignant potential were found to have DNA
alterations in their urine, but none displayed
alterations in their serum. Microsatellite alterations
were not identified in either the urine or the
serum samples from normal control subjects.
These data suggest that microsatellite DNA analysis
of urine specimens provides a potentially valuable
tool for the early detection of resectable kidney
cancer. Furthermore, microsatellite analysis
of serum samples reveals evidence of circulating
tumor-specific DNA in approximately half of
these patients and may reflect the propensity
of these tumors to spread to distant sites at
an early stage. |
5 |
17-allylamino,17-demethoxygeldanamycin
(17AAG) is the first inhibitor of heat shock
protein 90 (Hsp90) to enter a phase I clinical
trial in cancer. Inhibition of Hsp90, leads
to depletion of important oncogenic proteins,
including Raf-1 and mutant p53. In two independent
in vitro human tumor cell panels, authors observed
a positive relationship between DT-diaphorase
expression level and growth inhibition by 17AAG.
Stable, high-level expression of the active
NQO1 gene transfected into the DT-diaphorase-deficient
(by NQO1 mutation) BE human colon carcinoma
cell line resulted in a 32-fold increase in
17AAG growth-inhibition activity. Increased
sensitivity to 17AAG in the transfected cell
line was also confirmed in xenografts. The extent
of depletion of Raf-1 and mutant p53 protein
confirmed that the Hsp90 inhibition mechanism
was maintained in cells with high and low levels
of DT-diaphorase. 17AAG was shown to be a substrate
for purified human DT-diaphorase. |
6 |
The study confirms that
excessive body weight increases breast cancer
risk in postmenopausal women. On the contrary,
in premenopausal women, excessive body weight
may be protective among women who have a lower-body
type of fat accumulation (low WHR). An upper-body
fat accumulation (high WHR) is a predictor of
breast cancer risk in premenopausal women, and
this effect is especially pronounced among subjects
who are overweight. |
7 |
Prostate cancer is the
most commonly diagnosed malignancy and the second
leading cause of cancer-related deaths in the
Western male population. Despite the tremendous
efforts that have been made to improve the early
detection of this disease and to design new
treatment modalities, there is still an urgent
need for new markers and therapeutic targets
for the management of prostate cancer patients.
Using differential display analysis to compare
the mRNA expression patterns of normal versus
tumor tissue of the human prostate, we identified
a cDNA, DD3, which is highly overexpressed in
53 of 56 prostatic tumors in comparison to nonneoplastic
prostatic tissue of the same patients. Reverse
transcription-PCR analysis using DD3-specific
primers indicated that the expression of DD3
is very prostate specific because no product
could be amplified in 18 different normal human
tissues studied. Also, in a sampling of other
tumor types and a large number of cell lines,
no expression of DD3 could be detected. Molecular
characterization of the DD3 transcription unit
revealed that alternative splicing and alternative
polyadenylation occur. The fact that no extensive
open reading frame could be found suggests that
DD3 may function as a noncoding RNA. The DD3
gene was mapped to chromosome 9q21-22, and no
homology of DD3 to any gene present in the computer
databases was found. This data indicate that
DD3 is one of the most prostate cancer-specific
genes yet described, and this makes DD3 a promising
marker for the early diagnosis of prostate cancer
and provides a powerful tool for the development
of new treatment strategies for prostate cancer
patients. |
8 |
Parathyroid hormone-related
protein (PHTrP) is produced by prostate carcinoma
cells and tumors, but little is known of its
role in prostate carcinogenesis. The goal of
this study was to evaluate PTHrP expression
in the regulation of prostate carcinoma growth
using human and animal models. PTHrP expression
was assessed in prostate cancer cell lines in
vitro. Seven of nine cell lines produced PTHrP,
and increased expression was seen during cell
proliferation. The MatLyLu rat prostate carcinoma
model was used to determine the effects of PTHrP
overexpression on prostate tumor growth. PTHrP
overexpression did not alter proliferation of
the cells in vitro. However, when PTHrP overexpression
cells were injected into rat hind limbs, primary
tumor growth and tumor size were significantly
enhanced as compared with control cells. To
evaluate PTHrP in human prostate carcinoma patients,
immunohistochemistry was performed on metastatic
bone lesions. Immunolocalization of PTHrP protein
was found in the cytoplasm and nucleus of cancer
cells in the bone microenvironment. Because
nuclear localization of PTHrP has been associated
with an inhibition of apoptosis, the ability
of full-length PTHrP to protect prostate cancer
cells from apoptotic stimuli was examined. Cells
transfected with full-length PTHrP showed significantly
increased cell survival after exposure to apoptotic
agents as compared with cells producing no PTHrP
(plasmid control) or cells transfected with
PTHrP lacking its nuclear localization signal.
To determine the mechanism of action of PTHrP
in prostate cancer cells, the parathyroid hormone
PTHrP receptor status of the cells was determined.
These cell lines did not demonstrate parathyroid
hormone PTHrP receptor-mediated binding of iodinated
PTHrP or steady-state receptor message by Northern
blot analysis, but they did have a detectable
receptor message by reverse transcription-PCR
analysis. In summary, PTHrP is expressed in
many prostate cancer cell lines in vitro and
in metastatic bone lesions in vivo. PTHrP expression
positively influences primary tumor size in
vivo and protects cells from apoptotic stimuli.
These data suggest that PTHrP plays an important
role in the promotion of prostate tumor establishment
and/or progression. |
9 |
Patients at advanced
stage of colorectal cancer with liver metastases
have been treated with deep hyperthermia alone
or in combination with chemotherapy (5-FU+FA+MMC).
Hyperthermia was achieved by arrangements of
capacitive electrodes with a radiofrequency
field of 13.56 MHz (RF-DHT). This prospective
open single-arm clinical study with 80 patients
suffering from liver metastases from colorectal
cancer gives some first hints, that deep RF-hyperthermia
alone may have a substantial beneficial effect
on overall survival time of patients with liver
metastases from colorectal cancer. Long lasting
no-change, partial and even some complete remissions
could be observed. The overall median survival
time from progression of metastases or relapse
was 24.5 months and survival rates at 1,2 or
3 years from first diagnosis of metastases or
progression were twice as high as expected from
patients treated with chemotherapy. |
10 |
The association between
drug-resistance and three markers for invasive
capacity: cathepsin D (Cath D), urokinase type
plasminogen activator (uPA) and inhibitor of
plasminogen activator type 1 (PAI-1) was examined
in nine cervical and laryngeal carcinoma cell
lines resistant to different cytostatics. All
drug resistant cell lines had increased concentration
of cathepsin D. uPA levels were similar in parental
and drug resistant cervical carcinoma cells,
but significantly higher in all examined drug
resistant laryngeal carcinoma cells. In cervical
carcinoma cells, PAI-1 concentrations were similar
in parental and cisplatin resistant, but significantly
higher in doxorubicin resistant cells. In laryngeal
carcinoma cells, no increase in concentrations
of PAI-1 was determined in the three from five
resistant cell lines. There was no uPA in conditioned
medium of parental or drug resistant cells.
PAI-1 was detected in conditioned medium. Its
levels were significantly increased in the medium
of two cervical and three laryngeal drug resistant
carcinoma cells. |
11 |
Myo-Inositol is one
of a relatively few compounds that has an inhibitory
effect on carcinogenesis of the lung in experimental
animals when administered during the post-initiation
period. It prevents pulmonary adenoma formation
in A/J mice when fed in the diet subsequent
to administrations of benzo(a)pyrene or the
tobacco specific carcinogen 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) to the mice. A second compound, dexamethasone,
also prevents pulmonary neoplasia under the
same conditions. Experiments in which both myo-inositol
and dexamethasone were administered together
in the diet showed an additive inhibitory effect. |
12 |
Extracts from European
mistletoe (Viscum album L., VAL) are used for
complementary cancer treatment. Viscotoxins
(VT) and whole plant extracts with high amounts
of the VT have been shown to stimulate functional
activity of granulocytes. Authors stimulated
neutrophils from healthy donors in vitro with
aqueous VT-free VAL extracts and mistletoe lectins
(ML) in the presence of E.coli and studied phagocytosis
and respiratory burst by flow cytometry. The
VT-free VAL extract significantly stimulated
granulocyte activity, and this effect correlated
with the content of the ML, although the ML
exerted no influence at relevant concentrations.
Co-incubation of the cells with VAL in the presence
of VT further increased granulocyte response.
From these data it is suggested that (1) a non-VT
non-ML component of the VAL extracts activated
granulocytes and (2) different activation pathways
may be involved in the stimulation by the whole
plant extract and the VT. |
13 |
This report demonstrates
the potential efficacy of allogeneic hematopoietic
transplantation for mantle-cell lymphoma (MCL)
and provides the first evidence suggestive of
graft-versus-malignancy in MCL. Data supportive
of this concept include 1) achievement of remission
concomitant with GVHD, 2) the conversion from
a positive PCR status early after transplant
to negative PCR status over time and 3) that
the only relapse was in a patient who failed
to engraft. |
14 |
Testing stool for occult
blood at the time of digital rectal examination
(DRE) does not increase the number of false-positive
test results or the cost per cancer detected
in asymptomatic patients at average risk for
colorectal cancer. These are the conclusions
of a study of medical records of consecutive
asymptomatic patients at average risk for colorectal
cancer who were referred for colonscopy to evaluate
a positive faecal occult blood test result obtained
by DRE or spontaneously passed stool samples. |
15 |
The new strategies are
dependent on the techniques of molecular biology,
which are able both to identify potential target
tumor antigens at the gene level, and to help
to unravel the complexities of immune mechanisms
required. Vaccine delivery systems can also
be genetic, with DNA vaccines able to act as
viral mimics and enter several antigen processing
pathways. One difficulty faced by tumor antigens
is that they may be weak, and therefore fail
to engage the immune system. Attaching genes
encoding alert signals appears to solve this
problem. Author have focused initially on idiotypic
determinants of B-cell tumors, where the encoding
variable region genes can induce protective
anti-idiotypic immunity if delivered as a fusion
protein with a fragment of Tetanus toxin. This
model may have relevance for alternative tumor
antigens. |
16 |
In low-risk patients
with cancer who have fever and granulocytopenia,
oral therapy with ciprofloxacin plus amoxicillin-clavulanate
is as effective as intravenous therapy. These
are the conclusion of a prospective multicenter
trial, in which 353 febrile patients with cancer
who had granulocytopenia. Treatment was successful
in 86% of the patients in the oral-therapy group
and 84% of those in the intravenous-therapy
group. |
17 |
Authors investigated
the occurrence of malignant tumors affecting
bone tissue in a population of mummeries and
skeletons, which had been excavated from the
large necropolis of Thebes-West, Upper Egypt.
This study material comprised a series of at
least 415 individuals dating from approx. 1500-500
B.C. They identified at least 4 cases showing
malignant tumors affecting the skeleton. In
two cases, multiple mixed osteolytic-osteoblastic
lesions suggested multiple metastases from carcinomas.
Two further individuals presented with multiple
osteolyses most suggestive of multiple myeloma. |
18 |
Inositol hexaphosphate
(IP6) is abundant in cereals and legumes, particularly
in the bran part of mature seeds. Experimental
studies using 7,12-dimethylbenz(alpha)anthracene
(DMBA) and N-methylnitrosourea (NMU) in rats
and mice in vivo, as well as human cell lines
in vitro demonstrate a reproducible and striking
anti-cancer action of IP6. This data shows that
pure IP6 is definitively more effective than
a high fiber diet in preventing experimental
mammary tumors. Thus, for cancer prevention,
prophylactic intake of IP6 may be not only more
effective, but also more practcial than gorging
on large quantities of fiber. |
19 |
The combination of lumpectomy,
radiation therapy, and tamoxifen was effective
in the prevention of invasive cancer for patients
with ductal carcinoma in situ (DCIS). These
are the results of a randomized trial on 1804
women with the disease who were assigned lumpectomy,
radiation therapy (50 Gy), and placebo or lumpectomy,
radiation therapy, and tamoxifen. Women in the
tamoxifen group had fewer breast cancer events
at five years than did those on placebo. |
20 |
Lymphoproliferative
diseases that occur in immunocompromised patients
are frequently associated with herpesviruses.
These patients often fare poorly after treatment
with conventional chemotherapy. Authors reported
previously that patients with AIDS-related Burkitt's
lymphoma (BL) responded to parenteral azidothymidine
(AZT) and IFN-sigma. They found that EBV-positive
lymphoma cells derived from these patients cultured
with AZT express CD95 and undergo apoptosis.
AZT-mediated apoptosis was caspase dependent
and occurred despite Fas receptor blockade.
In contrast, EBV-negative lymphomas were resistant
to AZT-induced apoptosis, as were EBV-positive
lymphomas that expressed high levels of bcl-2.
Primary effusion lymphoma (PEL) cell lines infected
with human heperpesvirus type 8 required IFN-alpha
to potentiate AZT-induced apoptosis. INF-alpha
did not up-regulate CD95 in BL or PEL but did
induce expression of the death receptor ligand,
CD95 ligand. AZT-sensitive lymphomas also accumulated
significantly higher intracellular AZT monophospate
than did resistant lymphomas. This data demonstrated
distinct apoptotic responses to AZT and IFN-alpha
in herpesvirus-associated lymphomas. EBV-positive
BL cells that expressed low BCL-2 levels were
sensitive to AZT alone; PEL cells required the
addition of IFN-alpha to enhance apoptosis,
and EBV-negative lymphomas were insensitive
to both agents. AZT-sensitive BL cells transfected
with BCL-2 became resistant. Susceptibility
to antivirus-mediated apoptosis may be exploited
to improve the therapy of certain herpesvirus-associated
lymphomas. |
21 |
The use of three courses
of neoadjuvant chemotherapy with cisplatin,
methotrexate, and vinblastine before cystectomy
or radiotherapy does not yield the 10% improvement
in three-year survival that was judged to be
necessary for its introduction into routine
use. These are the conclusions of a large trial
with 976 patients with T2, G3, T3, T4a, No-Nx,
or M0 transitional-cell carcinoma of the bladder
undergoing curative cystectomy or radiotherapy.
Median survival in the chemotherapy group was
44 months compared with 37.5 months for the
no-chemotherapy group. |
22 |
To assess the levels
of prostaglandin (PG)E2 in plasma and unstimulated
saliva of patients with advanced soft tissue
sarcoma receiving high-dose epirubicin. PGE2
levels were determined in plasma and unstimulated
salive of 10 healthy controls, and of 10 patients
with advanced soft tissue sarcoma treated with
high-dose epirubicin (180 mg/m2). Plasma from
patients free of epirubicin-related stomatitis
was taken prior to treatment and on day 7 of
the chemotherapy cycle. Unstimulated saliva
was used for PGE2 determination to avoid parotid
gland contribution to the whole salivary volume,
and patients without evidence of stomatitis
were selected to avoid false salivary levels
of PGE2 which could be caused by plasma leakage
into the oral cavity. The determination of PGE2
was performed with the ELISA technique. Controls
had a median PGE2 plasma level of 151 pg/ml
(range 47-227.5) and salivary level of 111 pg/ml
(range 59.5-245.5). Patients with soft tissue
sarcoma presented levels which were not statistically
different: median plasma level 125 pg/ml (range
47-220) , median salivary level 134 pg/ml (range
63-196). On day 7, the plasma levels were significantly
higher (median 218 pg/ml, range 103-950, p=0.031)
and the salivary levels were significantly lower
(median 49 pg/ml, range 13-245, p=0.021). The
results of study are in accordance with the
relevant literature data in rats. Increase of
PGE2 plasma levels and decrease of its salivary
levels is possibly related to two independent
mechanisms of action of anthracyclines. Decrease
of salivary PGE2 levels following epirubicin
can only speculatively be related to the development
of stomatitis, as none of the patients with
low salivary PGE2 following epirubicin administration
developed any signs of stomatitis during the
observation period. |
23 |
Cytologic examination
of fluid accumulated in a serous cavity is of
paramount importance, because the presence of
cancer cells in such a specimen denotes that
the patient has cancer that is not only advanced,
but also almost always inoperable and thus incurable.
The purpose of study by Yerci et al. was to
define the role of diagnosing malignancy in
effusions of serous cavities, and to report
the current number and positivity rates of pleural,
pericardial and peritoneal effusions submitted
to their pathology department. This retrospective
study included 2058 fluid specimens (1094 pleural,
908 peritoneal, and 56 pericardial) belonging
to 1000 male and 1058 female patients, and which
were evaluated in the pathology department during
the period between January 1994 and March 1998.
Specimens were reviewed, calssified, and evaluated
statistically. 1645 cases were diagnosed as
benign, 188 cases as malignant, 12 cases as
suspicious, and 213 as unsatisfactory material.
The malignant cases represented 9% of all cases,
and most of them were diagnosed as adenocarcinoma.
Adenocarcinomas are most common tumors found
in a serous cavity effusion. In most cases of
a malignant effusion, a previously documented
tumor exists. Nonmalignant effusions exceed
malignant ones, and they are usually lymphocytic. |
24 |
The cleaved confirmation
of antithrombin has potent antiangiogenic and
antitumor activity in mouse models. Antithrombin,
a member of the serpin family, functions as
an inhibitor of thrombin and other enyzmes.
Cleavage of the carboxyl-terminal loop of antithrombin
induaes a conformational change in the molecule.
The latent form of intact antithrombin, which
is similar in confirmation to the cleaved molecule,
also inhibited angiogenesis and tumor growth.
These data provide further evidence that the
clotting and fibrinolytic pathways are directly
involved in the regulation of angiogenesis and
it might be speculated that interventions on
these pathways might interfere with tumor progression. |
25 |
Most of the human immunodeficiency
virus 1 (HIV-1) protease inhibitors antiretrovirals
are also potent inhibitors (and occasionally
inducers) of hepatic and intestinal cytochrome
P450 systems and, therefore, have the potential
to alter the elimination of any substance that
utilises these metabolic pathways. The authors
describe a patient infected with HIV-1 who was
treated with ritonavir and saquinavir and then
experienced a prolonged effect from a small
dose of methylenedioxymetanphetamine (MDMA or
ecstasy) and a nearly fatal reaction from a
small dose of gamma-hydroxybutyrate (GHB). The
metabolism of benzodiazepines and opiates typically
involves P450. |
26 |
Cervical cancer emerges
from cervical intraepitheial neoplasia (CIN)
induced by high-risk HPV (HR-HPV) infections.
Howerever, the vast majority of CIN lesions
regresses spontaneously, and only a few lewsions
persist or progress to invasive carcinoma. On
the basis of morphological criteria, it is not
possible to differentiate high-grade lesioins
that will progress to invsive cancers. In most
cervical carcinomas, human papilomavirus (HPV)
genomes are integrated into host cell chromosomes
and transcrobed into mRNAs encompassing viral
and cellular sequences. In contrast, in early
preneoplastic lesions, HPV genomes persist as
episomes, and derived transcripts contain excusively
viral sequendec. Thus, detection of HPV transcripts
derived from integrated HPV genomes may specifically
indicate both CIN lesions at high risk for progression
as well as invasive cervical cancers. Here,
authores established a protocol for the amplificaton
of papillomavirus oncogene transcripts (APOT)
from cervical specimens taht allowsus to distinguish
episome-from integrate-derived HPV mRNAs. Cervical
swab and biopsy samples from 549 patients attending
outpatient clinics for cervical dysplasia were
screened for the presence of HPV DNA, and 155
samples taht were positive for either HPVtype
16 (n=143) or 18(n=12) were subjected to the
APOT assay. In samples derived from normal cervical
epithelia (n=19) or low-grade cervical lesions
(CIN I, n=10), no integrate-derived HPV transcripts
were found. In contrast, in 1 (5%) of 22 samples
derived from CIN II lesions, and 10 (16%) of
64 samples from patients with cervical cancer,
integrate-derived HPV transcripts were detected.
Thus, detection of integrate-derived HPV transcripts
in cervical swabs or biopsy specimens by the
APOT assay points to advanced dysplasia or invasive
cervical cancer. |
27 |
SEREX (serological analysis
of recombinant tumor cDNA expression libraries)
has been applied to several different tumor
types and has led to the identification of a
wide range of tumor antigens. In this study,
a breast cancer library and a normal testicular
library were analyzed using autologusand allogeneic
breast cancer sera. Thirty genes were isolated,
including 27 known genes and 3 previously unknow
genes. Among the known genes, two cancer-tstis
(CT) antigens, NY-ESO-1 and SSX2, previously
defined by SEREX analysis, were found. In addition,
ING1, a cadidate breast cancer suppressor gene,
was isolated. This ING1 gene product was also
recognized by 2 or 14 allogeneic sera from breast
cancer patients but not 12 normal adult sera.
Comparison of ING1 cDNA from normal and tumor
tissues showed no mutation in the index breast
cancer case and revealed the presence of at
last three different mRNA trascriptors with
variable transcription initiation sites and
exon usage. Tissue-specific expression of these
transcriptors was found in normal tissues and
tumor cell line mRNAs. Furthermore, a novel
gene, designated as ING2, sharing 76% nucleotide
homology with ING1 was identified in the breast
cancer cDNA library. The basis of the immunogenicity
of ING1 and the biological role of ING1 and
ING2 need further exploration. |
28 |
It is generally considered
that MHC class I restriced antigens are recognized
by CD8+ T cells, whereas MHC class II-restricted
antigens are recognized by CD4+T cells. In the
present study, authors report an MHC class I-restricted
CD4+T cell isolated from the tumor infiltrating
lymphocytes (TILs) of a patient with metastatic
melanoma. TIL 1383 I recognized by TIL 1383
I was tyrosinase, and the epitope was the 398-376
peptide. Antibody blocking assays confirmed
that TIL 1383 I was HC class I restridted, and
the CD4 and CD8 coreceptors did not contribute
significantly to antigen recognition. TIL 1383
I was weakly cytolytic and secreted cytokines
in a pattern consistent with it being a Th1
cell. The avidity of TIL 1383 I for peptide
pulsed targets is 10-100-fold lower than most
melanoma-reactive CD8+T cell clones. These CD4+T
cells may represent a relatively rare population
of T cells that express a T-cell receptor capable
of cross-reating with an MHC class I/peptide
complex with sufficient affinity to allow triggering
in the absence of the CD4 corecptor. |
29 |
The signaling pathways
critical for cell survival are mediated in part
by the composition and integrity of the extracellular
matrix and the action of its component on specific
cell adhesion receptors. With-drawal of anchorage-dependent
epithelial cells from their association with
ECM result in apoptotic cell death. Consistently,
the matrix metalloproteinases (MMPs) or their
inhibitors (TIMPs) have been suggested to regulate
apoptosis. In this report, authors investigated
whether bcl-2 inhibiton of apoptosis involves
regulation of TIMP expression. Authors have
found that bcl.-2 overexpression induces TIMP-1
expression in breast epithelial cell lines (MCF10A,
MCF10AneoT.TG3B, and MCF-7), whereas it has
no effect on TIMP-2 expression. They demonstrated
that TIMP-1 inhibits cell death induced by hydrogen
peroxide, Adriamycin, or X-ray irradiation.
In addition, TIMP-1 overexpression inhibits
apoptosis after the loss of cell adhesion (anoikis)
in MCF10A cells, sugesting that the antiapoptotic
activity of TIMP-1 does not depend on its ablity
to stabilize cell-matrix intgeractions. Authors
also showed that TIMP-1 overexpression is associated
with constitutive activation of focal adhesion
kinase, a signaling molecule known to be critical
for the cell survival pathway. |
30 |
The one-hybrid system
with an inverted CCAAT box as the DNA target
sequence was used to identify proteins acting
on key DNA sequences of the promoter of the
topoisomerase IIa gene. Screening of cDNA libraries
from the leukemia Jurket cell line and from
the adult human thymus relulted in the isolation
of a novel protein of 793 amino acids (89, 758
Da). This protein has in vitro CCAAT binding
properties and has been called ICBBP90. Adult
thzmus, fetal thymus, fetal liver, and bone
marrow, known as active tissues in terms of
cell proliferation, are the tisuses richest
in ICBP90 mRNA. In contrast, highly diferentiated
tissues and cells such as the central nervous
system and peripheral leukocytes are freee of
ICBP90 mRNA. Western blotting experiment s showed
a simultaneous epxression of topoisomerase IIa
and ICB90 in proliferating human lung fibroblats.
Simultaneous epxression of both proteins has
also been observed inHeLa cells, but in both
proliferating and confluent cells. Overexpression
of ICBP90 in COS-1-transfected cells induced
an enhanced expression of endogenous topoisomerase
IIa. Immunohistochemistry experiments showed
that topoisomerase IIa and ICBP90 were coexpressed
in proliferating areas of paraffin-embedded
human appendix tissues and high-grade breast
carcinoma tissues. Authors have identified ICBP90,
which is a novel CCAAT binding protein, and
their results suggest that it may be involved
in topoisomerase IIa expression. ICBP90 may
also be useful as a new proliferation marker
for cancer tissues. |
|
MISCELLANEUS |
1 |
Lukatela and Turvey
(September 1998) have nicely studied the reading
process using written Serbo-Croatian language
in its Cyrillic and Roman forms. I would like
to suggest that the authors include a third
alphabet in their investigations. In 1985, I
devised a combined alphabet, Slavica, to be
used instead of the two existing alphabets.
My intention was to bring about a closer association
among the four nationalities in the Yugoslav
area, "who speak practically one language,
but write in two different alphabets" (Igic,
1987). The basis for the Slavica alphabet is
the Roman alphabet, which provides 17 of 30
letters or 30 phonemes. Eight Cyrillic letters
are used in those cases where the Roman alphabet
uses diacritic signs and combined letters:
. These letters are rendered by their Cyrillic
equivalents. Five common letters - a, e, o,
j, k - are also included in the new alphabet.
Thus, the Slavica alphabet follows the principle
of one grapheme for one sound, a principle also
carried out in the Cyrillic alphabet. In 1988
and 1989, the new alphabet was tested by students
of the primary school in Buje, Republic of Croatia
(see Figure), and it was especially attractive
to the people of Bosnia, Vojvodina, and Istria
(Igic, 1997b). Despite the positive response
of Yugoslav and other reviewers of the Slavica
alphabet (Milivojevic, 1991), with strong opposition
only in the Croatian media, its wider acceptance
was prevented by the civil war in Yugoslavia.
Serbs, Croats, Montenegrins, and Bosnian Muslims
are one ethnos, and they speak the same language,
Serbo-Croatian. Whereas Croats now use only
the Roman alphabet, Serbs and Montenegrins mainly
use the Cyrillic alphabet. The language itself
is being progressively modified to make it reflect
three separate traditions by the introduction
of new words and the legal suppression of others
(Lewison & Igic, 1999). Bosnian Muslims
speak Serbo-Croatian but are adding new words
and calling it Bosniak. Before the civil war
they were using both the Roman and Cyrillic
alphabets; now they are using the Roman alphabet
only. However, the latest experiences of the
Bosnian Muslims, Serbs, and Croats, especially
in Bosnia and Herzegovina (Igic, 1997a), might
soon bring them to be in favor of needed alphabetical
reform. Practically all readers of Serbo-Croatian
who know both Cyrillic and Roman alphabets can
easily read the Slavica alphabet. Therefore,
it would also be interesting to test the decoding
process for the three alphabets of the same
language.

Figure. Poster against tobacco smoking prepared
by Ivana Batop, a sixth grade student at the
primary school in Buje, Istria, Republic of
Croatia. Text of the poster , which
means "smoking is dangerous to your health",
is written in the Slavica alphabet. Medical
students printed and distributed 40.000 copies
of this poster and three similar posters throughout
Yugoslavia from 1989 to 1992, always several
weeks before January 31, which is known as "A
Day Without a Cigarette". |
2 |
Prim. Dr. Vladimir Ljikar,
the chief of Sector for hygiene and protection
of the environment at the Institute for health
protection in Novi Sad, beside many other recognitions
for his professional and scientific activities,
was awarded the Medal for his merits in the
field of defence and the first level security.
During the NATO bombing, Dr. Ljikar successfully
organized the work on the examination of the
formed contamination in the air, drinkable water,
food, above-ground waters, and after the bombing
he and his associates participated in the work
of the UN Commission considering the examination
of the previous contaminations. |
3 |
Formal reception on
the occasion on awarding the annual rewards
of Serbian Medical Society- Society of Doctors
of Vojvodina: After considering the suggestions
of Branches and Specialized Assemblies of the
Socitey, the jury chosen for awarding the annual
rewards of SMS-SDU decided to give the following
rewards:
1. For life-work achievement - Prof.dr Boris
Nedvide, Novi Sad
2. For scientific research work - Prof. dr Stevan
Popovic, Novi Sad
3. For protection of health of the population
- Prim. dr Zorica Bopkov-Jagodic, Zrenjanin
4. For many years of successful work in the
primary health protection - (was not awarded)
5. For the best grades during the Meical studies
- dr Jovan Obradovic
6. For the best grades during the Medical studies
- dr Branislav Markov
7. For the best student work - Natasa Prvulovic
8. The members of the families of the deceased
were given the memorials:
- Prof.dr Miladin Mirilov (1931-1998)
- Dr Dragic Isakov (1952-1998) |
4 |
On the occasion of the
Day of the Institute, the following rewards
were awarded:
a) For scientific - research work
1. Dr sci med Jasna Mihailovic - for doctoral
dissertation and entire scientific - research
activity
2. Prof.dr Marica Miladinov-Mikov - for her
geat contribution in scientific - medical journalism
and the highest competence index at the Institute.
3. Ass.dr Dusko Kozic - for hist important presented
and published scientific - research work and
high competence index.
4. Dubravka Devaja, BSEE and Svetozar Zdravkovic,
BSEE - for creating a programme Registries of
malignant neoplasms.
b) For supreme results in diagnostisc and tretmant
1. Ass.dr Andrija Golubovic - for introduction
of localization of sentinel lymphoid nods methodology
as an important improvement in efficient breast
cancer therapy.
2. Dr ing. Zlatko Selir - for an important improovement
of protection during the application of high
therapeutic dosec of radioactive isotopes
3. Ass.dr Roberst Semnic - for supreme diagnostic
competence verified by taking the first place
at the competition at the European Congress
of Radiologists
c) For the most humane deed
1. The surgical team led by doc.dr Milan Breberina
- for the operation performed during the bombing
near by the Institute.
2. Djordje Elez - for extreme involvement in
maintaining the appliances of the Imaging Diagnostics
Centre, so that they managed to function successfully
during the whole time of the NATO aggression
on our contry. |
Books Review
Meetings and Congress Reports
Medical and Scientific Meetings
|
|
|
Issue 2 |
|
|
News
1 |
In vivo masurement of myocardial
oxidative metabolism and blood flow does not
show changes in cancer patients undergoing doxorubicin
therapy
Nony P, Guastalla
JP, Rebattu P, Landais P, Lievre M, Bontemps
L, et al. Cancer Chemother Pharmacol 2000;45:375-80.
The aim was to investigate
in patients receiving doxorubicin whether any
alteration in myocardial oxidative metabolism
or blood flow as assessed by positron emission
tomography (PET) could be observed either after
the first dose of the drug, or during its chronic
administration. Using PET for both acute and
chronic toxicity evaluations, no significant
effect of doxorubicin was observed either one
the flux through the tricarboxylic acid (TCA)
cycle or on myocardial blood flow. However,
systolic left ventricular function showed a
small but significant impairment after the administration
of 300 mg/m2 of doxorubicin.. |
2 |
The role of p53 in gemcitabine-mediated
cytotoxicity and radiosensitization
Chen M, Hough AM,
Lawrence TS. Cancer Chemother Pharmacol 2000;45:369-74.
The results suggest that
p53 status may influence dFdCyd-mediated apoptosis,
cytotoxicity, and cell cycle progression but
do not support an importante role for p53 in
radiosensitization. |
3 |
Increase in tumor GADD153
mRNA level following treatment correlates with
response to paclitaxel
De las Alas MM,
Christen RD, Gately DP, Weiner DE, Khalid B,
Kirmani S, et al. Cancer Chemother Pharmacol
2000;45:381-8.
An increase in GADD153
mRNA level reflects chemotherapy-induced damage
sufficient to be manifest as a clinically detectable
reduction in tumor volume. Measurement of the
change in GADD153 mRNA level successfully indentified
patients destined to respond as early as 24
h posttreatment. |
4 |
Modulation of plasma uridine
concentration by 5-(phenylselenenyl) acyclouridine,
an inhibitor of uridine phosphorylase: relevance
to chemotherapy
Ashour OM, Al Safarjalani
ON, Naguib FNM, Goudgaon NM, Schinazi RF, Kouni
MH, et al. Cancer Chemother Pharmacol 2000;45:351-61.
PSAU (5-(phenylselenenyl)-acyclouridine)
is a new potent adn specific inhibitor of uridine
phosphorylase (UrdPase, EC 2. 4. 2. 3), the
enzyme responsible for uridine catabolism. The
effectivens of the PSAU plus uridine combination
in elevating and sustaining high plasma uridine
concentration may be useful to rescue or portect
from host toxicity of various chemotherapeutic
pyrimidline analogs as well as in the management
of medical disorders that are remedied by administration
of uridine. |
5 |
Magnetic resonance imaging
of prostatic cancer: Does detection vary between
high and low Gleason score tumors?
Ikonen S, Karkkainen
P, Kivisaari L, Salo JO, Taari K, Vehmas T,
et al. Prostate 2000;43:43-8.
Endorectal MRI detects
poorly differentiated prostate cancer lesions
more accurately than clinically insignificant
tumors. |
6 |
Role of virtual computed
tomographic colonography in patients with colorectal
cancer and obstructing colorectal lesions
Morrin MM, Farrell
RJ, Raptopoulos V, McGee JB, Bleday R, Kruskal
JB. Dis Colon Rectum 2000;43:303-11.
Computed tomographic colongraphy
has an overall staging accuracy of 81 percent
for colorectal cancer and is superior to barium
enema in visualizing colonic segments proximal
to obstructing colorectal lesions. |
7 |
Expression of tumor suppressor
gene p16INK4 products in primary gastric cancer
Tsujie M. Yamamoto
H, Tomita N, Sugita Y, Ohne M. Sakita I, et
al. Oncology 2000;58:126-36.
Recent studies have shown
that the cyclin-dependent kinase (CDK) inhibitor
p27Kip1 represents an indicator for patients'
outcome in several human malignancies including
gastric cancer. However, the clinicopathologic
value of another class of CDK inhibitor, p16INK4,
has not been determined. In a retrospective
study, authors examined the expression of p16INK4
by immunohistochemical assay of 80 samples of
primary gastric cancers and their adjacent nonneoplastic
mucosas. Less than 10% of non-tumor gastric
mucosal cells were p16INK4 positive, whereas
the expression of p16INK4 in gastric cancer
cells varied widely from 0 to 100% (mean, 24.5%).
The expression of p16INK4 was not seen in 11.3%
(9/80) of the cancer cases, but in 65% (52/80)
this protein was even overexpressed when compared
with the nonneoplastic mucosa. A clinocopathologic
survey indicated that a low or no expression
of p16INK4 was associated with poorly differentiated
carcinoma (p=0.0133), but the level of expression
did not correlate with other parameters including
patients' prognosis or with the expression of
the pRb protein. In an effort to explore the
underlying mechanism for the p16INK4-negative
cases, a prospective study was also performed
on 20 cases of gastric cancer to compare the
level of the p16INK4 protein with the methylation
status of the p16INK4 promoter. Gastric cancer
tissues with methylation expressed significantly
lower levels of the p16INK4 protein (p=0.0013)
and two of them lacked p16INK4 expression altogether,
whereas all the cancer tissues without methylation
expressed it. These findings suggest that the
p16INK4 protein may be associated with differentiation
of gastric cancer tissues and that methylation
of the p16INK4 promoter may, in part account
for the loss of p16INK4 expressions. |
8 |
DNA repair protein Ku80
suppresses chromosomal aberrations and malignant
transformation
Difilippantonio
MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC,
Max EE, et al. Nature 2000;404:510-4.
Cancer susceptibility
genes have been classified into two groups:
gatekeepers and caretakers. Gatekeepers are
genes that control cell proliferation and death,
whereas caretakers are DNA repair genes whose
inactivation leads to genetic instability. Tumors
results from a specific set of chromosomal translocations
and gene amplifications involving Igh and c-Myc,
reminiscent of Burkitt´s lymphoma. Authors conclude
that Ku80 is a caretaker gene that maintains
the integrity of the genome by a mechanism involving
the suppression chromosomal rearrangemets. |
9 |
BRCA1 and BRCA2 have a
limited role in familial prostate cancer
Sinclair CS, Berry
R, Schaid D, Thibodeau SN, Couch FJ. Cancer
Res 2000;60:1371-5.
Thus, BRCA1 and BRCA2
appear to have a limited role in familial prostate
cancer, and families with both prostate and
breast cancer may result from mutations in other
predisposition genes. |
10 |
Quality of life in survivors
of colorectal carcinoma
Ramsey SD, Andersen
MR, Etzioni R, Moinpour C, Peacock S, Potosky
A, et al. Cancer 2000;88:1294-303.
Colon carcinoma is a common
malignancy that accounts for a substantial share
of all cancer-related morbidity and mortality.
However, little is known with regard to general
and disease specific quality of life in survivors
of colorectal carcinoma, particularly from community-based
samples of cases across stage and survival times
from diagnosis. Subjects with colorectal carcinoma
were recruited from the National Cancer Institute's
Ssurveillance, Epidemiology, and End Results
cancer registry. Subjects completed two self-administered
surveys: the Functional Assessment of Cancer
Therapy Scales for Colorectal Cancer (FACT-C)
and the Health Utilities Index (HUI) Mark III.
One hundred seventy-three respondents (average
age: 70.4 years, 71.4% female) completed the
survey. In the first 3 years after diagnosis,
quality of life was lower and varied substantially
among respondents. After 3 years, respondents
in all TNM stages of disease except Stage IV
reported a relatively uniform and high quality
of life. Pain, functional well-being, and social
well-being were affected most substantially
across all stages and times from diagnosis.
Low income status was associated with worse
outcomes for pain, ambulation, and social and
emotional well-being. Only emotional well-being
scores improved significantly over time in both
surveys. Those individuals who achieve a long
term remission from colorectal carcinoma may
experience a relatively high quality of life,
although deficits remain for several areas,
particularly in those of low socioeconomic status.
Sampling design may have excluded the most severely
ill patients. |
11 |
Selective augmentations
of intratumoral 5-fluorouracil concentration
by local immunotherapy with OK-432 and fibrinogen
Amano M, Sekimoto
M, Monden T, Tomita N. Ohue M, Haba A, et al.
Dis Colon Rectum 2000;43:402-7.
In patients with colorectal
cancer, selective high 5-fluorouracil concentration
in the cancer tissue could be achieved by a
combination of 5'-deoxy-5-fluorouridine and
local immunotherapy with a mixture of OK-432
and fibrinogen. |
12 |
Antiangiogenic and antitumor
activities of cyclooxygenase-2 inhibitors
Masferred JL, Leahy
KM, Koki AT, Zweifel BS, Settle SL, Woerner
BM, et al. Cancer Res 2000;60:1306-11.
Authors provide evidence
that cyclooxygenase (COX)-2-derived prostaglandins
contribute to tumor growth by inducing newly
formed blood vessels (neoangiogenesis) that
sustain tumor cell viability and growth. COX-2
is expressed within human tumor neovasculature
as well as in neoplastic cells present in human
colon, breast, prostate, and lung cancer biopsy
tissue. COX-1 is broadly distributed in normal,
as well as in neoplastic, tissues. The contribution
of COX-2 to human tumor growth was indicated
by the ability of celecoxib, an agent that inhibits
the COX-2 enzyme, to suppress growth of lung
and colon tumors implanted into recipient mice.
Mechanistically, celecoxib demonstrated a potent
antiangiogenic activity. In a rat model of angiogenesis,
authors observe that corneal blood vessel formation
is suppressed by celecoxib, but not by a COX-1
inhibitor. These and other data indicate that
COX-2 and COX-2 derived prostaglandins may play
a major role in development of cancer through
numerous biochemical mechanisms, including stimulation
of tumor cell growth and neovascularization.
The ability of celecoxib to block angiogenesis
and suppress tumor growth suggests a novel application
of this anti-inflammatory drug in the treatment
of human cancer. |
13 |
Tumor necrosis factor-alpha
and fas activate complementary fas-associated
death domain-dependent pathways that enhance
apoptosis induced by gamma-irradiation
Kimura K, Gelmann
EP. Biol Chem 2000;275:8610-7.
Activation
of either tumor necrosis factor receptor 1 or
Fas induces a low level of programmed cell death
in LNCaP human prostate cancer cells. Authors
have shown that LNCap cells are entirely resistant
to gama-radiation-induced apoptosis, but can
be sensitized to irradiation by TNF-alpha. Fas
activation also sensitized LNCap cells to irradiation,
causing nearly 40% cell death 72 h after irradiation.
Caspase-8 was cleaved and activated after exposure
to tumor necrosis factor (TNF)-alpha. However,
after exposure to anti-Fas antibody caspase-8
cleavage occurred only between the 26-kDa N-terminal
prodomain and the 28-kDa C-terminal region that
contains the protease components. Although anti-Fas
antibody plus irradiation induced apoptosis
that could be blocked by the pancaspase inhibitor
zVAD, there was no meassurable caspase-8 activity
after exposure to anti-Fas antibody. The effector
caspases-6 and -7, and to a lesser extent caspase-3,
were activated by TNF-alpha, but not by anti-Fas
antibody. Anti-Fas antibody, like TNF-alpha
also activated serine proteases that contributed
to cell death. Exposure of LNCaP cells simultaneously
to TNF-alpha and anti-Fas antibody CH-11 resulted
in marked enhancement of apoptosis that occurred
very rapidly and was still furher augmented
by irradiation. Rapid apoptosis that ensued
from combined treatment with TNF-alpha, anti-Fas
antibody, and irradiation was completely blocked
either by zVAD or expression of dominant negative
Fas-associated death domain. Their data shows
that there are qualitative differences in caspase
activation resulting from either TNF receptor
1 or Fas. Simultaneous activation of these receptors
was synergistic and caused rapid epithelial
cell apoptosis mediated by the caspase cascade. |
14 |
Human papillomavirus vaccines
Breitburd F, Coursaget
P. Sem Cancer Biol 1999;9:431-4.
Genital human papillomavirus
(HPV) infections are the viral sexually transmitted
diseases most frequently diagnosed that include
anogenital condylomas and squamous intra-epithelial
lesions, among which the precursors of invasive
carcinomas of the uterine cervix. In animal
PV models, vaccination against L1 and/or L2
viral capsid proteins provides an efficient
protection against infection, involving virus
type-specific neutralizing antibodies. Vaccination
against non-structural E1, E2, E6 of E7 viral
proteins does not prevent infection, unless
administered altogether, but tends to stimulate
regression, warranting the design of therapeutic
vaccines. Prophylactic vaccines based on the
use of virus-like particles (VLPs) obtained
by auto-assembly of L1 or L1 and L2 proteins
produced by recombinant DNA technology are under
phase I/II clinical trials for HPV 6/11 associated
with condylomas and for HPV16, the most frequent
oncogenic genotype. Second generation vaccines
are chimeric proteins or VLPs incorporating
one of the structural proteins (L1 or L2) fused
to a non-structural protein (E6, E7 or E2),
which should induce both humoral and cellular
immunity. Vaccine valency (number of genotypes),
route of administration (humoral versus local
immunity), vaccines (children, young adults,
gender) and forms of vaccines (recombinant $Lsalmonella
typhimurium*I$L, edible plants expressing L1
and L2 proteins, DNA vaccines, synthetic antigenic
peptides) are under study. End points to evaluate
vaccine efficacy in phase III trials should
include viral DNA detection and typing, and
screening for low or high grade intraepithelial
lesions. Therapeutic vaccines based on recombinant
HPV E6 and/or E7 vaccinia virus, L2-E7 fusion
proteins or E7 peptides corresponding to cytotoxic
T cell epitopes are currently tested (phase
I/II trials) in patients with cervical carcinomas
of advanced clinical stages or high grade intraepithelial
lesions. Animal studies, phase I/II clinical
trials and implementation of the community support
that HPV vaccines will constitute an efficient
means to prevent carcinoma of the uterine cervix. |
15 |
Overexpression of the heat
shock protein HSP70 family and p53 protein and
prognosis for patients with gastric cancer
Maehara Y, Oki
E, Abi T, Tokunaga E, Shibahara K, Kakeji Y,
et al. Oncology 2000;58:144-51.
Authors findings show
that the expresion of HSP70 is not associated
with tumor advance-related characteristics or
with the prognosis of gastric cancer. Measurements
of HSP70 expression do not appear to be a useful
prognostic marker. |
16 |
Phase I trial of interleukin-2
and high-dose arginine butyrate in metastatic
colorectal cancer
Douillard JY, Bennouna
J, Vavasseur F, Deporte-Fety R, Thomare P, Giacalone
F, et al. Cancer Immunol Immunother 2000;49:56-61.
Interleukin-2 (IL-2) and
sodium butyrate allow rats to be cured of peritoneal
carcinomatosis from colon cancer. Authors performed
a phase I trial of IL-2 and high-dose arginine
butyrate (ArgB) in patients with advanced metastatic
colorectal cancer. From April to July 1997,
six patients were included in the trail; they
had a median age of 52 years, four had a performance
status of 0, two had a performance status of
1 with normal biological functions. All patients
had received at least two prior lines of chemotherapy.
A fixed dose of 18 MIU/m2 IL-2, was administered
by subcutaneous injection and ArgB was delivered
via continuos intravenous infusion on days 1-6
with escalating doses starting at 2 g kg-1 day-1.
The planned dose escalation was not possible
because of toxicities. A daily ArgB dose of
2 g/kg was delivered for nine cycles. Level
2 (4 g/kg) could not be delivered in three of
the six patients because of liver toxicity.
The dose-limiting toxicities were fatigue and
liver function disturbances. The maximum tolerated
dose for ArgB was 3 g kg-1 day-1, in combination
with IL-2 at 12 MIU m2 day-1. No clinical response
was seen. Pharmacokinetic analysis showed large
intra- and interindiviual variations. This schedule
with a high dose of ArgB proved to be highly
toxic with liver insufficiency. Authors will
be running another trial with lower doses of
ArgB calculated from the schedule used in the
experimental model, starting at a dose of 20
mg kg-1 day-1 for ArgB and 200 000 UI kg-1 day-1
IL-2, every 8 h. |
17 |
Differential modulation
of chemosensitivity to alkylating agents and
platinum compounds by DNA repair modulators
in human lung cancer cell lines
Heim MM, Eberharot
W, Seeber S, Mçller MR J Cancer Res Clin Oncol
2000;126:198-204.
Modulation of DNA repair
represents one strategy to overcome cellular
drug resistance to alkylating agents and platinum
compounds. The effects of different known DNA
repair modulators such as O6-benzylguanine (6
mg/ml), fludarabine (25 ng/ml), aphidicolin
(8.5 ng/ml), pentoxifylline (1.4 mg/ml) and
methoxamine (12.4 mg/ml) on the cytotoxicity
of mafosfamide, chlorambucil, 1,3-bis-(2-chloroethyl)-1-nitrosourea
(BCNU), cisplatin and carboplatin were tested
in human lung cancer cell lines. Chemosensitivity
of the human adenocarcinoma cell line MOR/P
and the cisplatin-resistant subline MOR/CPR
as well as the large-cell lung cancer cell line
L23/P and its cisplatin-resistant counterpart
L23/CRP were evaluated by the MTT colorimetric
assay. O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA
alkyltransferase, significantly sensitised MOR/P
and MOR/CPR cells to the cytotoxic effect of
BCNU. Fludarabine, methoxamine and aphidicolin
did not change the chemosensitivity of the parental
and cisplatin-resistant cell lines to any cytotoxic
drug tested. Interestingly, O6-benzylguanine
enhanced the chemoresistance of parental and
cisplatin-resistant cell lines to platinum compounds.
Also, pentoxifylline increased resistance of
the MOR cell lines to mafosfamide. Modulation
of DNA repair elicits not only chemosensitisation
but may also enhance cellular resistance to
DNA-affine drugs. |
18 |
An unaffected individual
from a breast/ovarian cancer family with germline
mutations in both BRCA1 and BRCA2
Moslehi R, Russo
D, Phelan C, Jack E, Antman K, Narod S. Clin
Genet 2000;57:70-3.
Currently many centers
offer testing for three specific mutations,
185delAG, 5382 insC, and 617delT, in the BRCA1
and BRCA2 genes to Ashkenazi Jewish individuals
at high risk for breast and ovarian cancer.
Authors recently tested members of a family
with multiple cases of breast and ovarian cancer
(Family R014). The proband in this family tested
positive for the 185delAG mutation. The unaffected
sister of the proband tested positive for both
the 185delAG and the 6174delT mutations. Further
testing and review of the family history suggest
that both mutations may have come from a maternal
grandfather and passed down for two generations.
Counseling of the unaffected double heterozygote
individual in this family is complicated by
lack of information on the risk of breast, ovarian,
and other cancers in such individuals. A better
understanding of these risk will depende on
the indentification and study of more individuals
carrying mutations in both the BRCA1 and BRCA2
genes. Their study empahasizes the importance
of testing Ashkenazi Jewish individuals from
high-risk breast and ovarian cancer families
for all three common BRCA1 and BRCA2 mutations
indentified in this ethnic group. |
19 |
p53 status in breast carcinomas
revealed by FASAY correlates well with p53 protein
accumulation determined by immunohistochemistry
Smardova J, Vagunda
V, Jandakova E, Vagundova M, Koukalova H, Kovarik
J et al. Neoplasmat 1999;46:384-9.
The prognostic and predictive
value of p53 mutation in breast cancer is still
conflicting. The choice of the p53 status detection
method may account for some discrepancies. In
this pilot study authors compared two differently-based
methods for detection of p53 alteration in 32
breast carcinoma samples: the immunohistochemical
method using Bp53,DO1 and DO11 monclonal antibodies
for analysis of the p53 protein accumulation
in cell nuclei and the functional mthod FASAY.
FASAY - functional analysis of the separated
alleles in yeast - tests the capability of the
human p53 to transactivate a reporter with a
p53 binding site RGC driving the ADE2 gene in
yeast. In their group the percentage of breast
cancers with accumulated p53 protein was 50%,
as well as percentage of mutant p53 scored by
FASAY was 50%. Although the agreement of both
methods, when comparing the results of individual
patients was high (94%), their results show
that immunohistochemistry does not reflect the
p53 status quite exactly. |
20 |
Targeting therapy using
a monoclonal antibhody against tumor vascular
endothelium
Tsunoda S, Tsutsumi
Y, Nakagawa S, Mayumi T Yakugaku Zasshi 2000;120:256-64.
Recent studies have revealed
that the targeting therapy using monoclonal
antibody against tumor associated antigens did
not have a clinically satisfactory effect due
to various physiological characters of tumor.
Authors propose a novel approach targeting tumor
vascular endothelium to solve the inefficiency
of common tumor missile therapy. In this study,
the tissue distribution of anti-tumor vascular
endothelium monoclonal antibody (TES-23) produced
by immunizing with plasma membrane vesicles
obtained from isolated rat tumor-derived endothelial
cells (TECs) was assessed in various tumor-bearing
animals. Radiolabeled TES-23 dramatically accumulated
in KMT-17 fibrosarcoma, a source of isolated
TECs after intravenous injection. In Meth-A
fibrosarcoma, Colon-26 adenocarcinoma in BALB/c
mice and HT - 1080 human tumor tissue in nude
mice, radioactivites of 1251-TES-23 were also
up to fifty times higher than those of control
antibody with little distribution to normal
tissues. Furthermore, immunostaining of human
tissue sections showed specific binding of TES-23
on endothelium in esophagus and colon cancers.
These results indicate that tumor vascular endothelial
cells express a common antigen in different
tumor types of various animal species. In order
to clarify the eficacy of TES-23 as a drug carrier,
and immunoconjugate, composed of TES-23 and
neocarzinostatin, was tested for its antitumor
effect in vivo. The immunoconjugate (TES-23-NCS)
caused a marked regression of the tumor, KMT-17
in rats and Meth-A in mice. Thaus, from a clinical
view, TES-23 would be a novel drug carrier because
of its high specificity to tumor vascular endothelium
and its application to many types of cancer. |
21 |
Mismatch repair proteins
and microsatellites hit clinical practice
Adv Anat Pathol
2000;7:85-93. Stahl J. Adv Anat Pathol 2000;7:85-93.
Hereditary nonpolyposis
colon cancer (HNPCC) is one of the most common
familial cancers with characteristic molecular
changes that are different from those found
in familial adenomatous polyposis (FAP) coli.
Genetic mutations in the germline and somatic
cells lead to loss of expression of one of the
two most commonly involved mismatch repair genes,
hMSH2 or hMLH1, and consequently, to expansion
of certain repetitive DNA sequences (microsatellite
instability (MSI)). The paper describes a distinct
subtype of "HNPCC-like" sporadic colonis
carcinoma that can easily be identified by immunohistochemistry.
Recognition of this subtype of colonic cancer
is important because it occurs in the younger
age group and is associated with better survival,
but also a five-fold chance of developing a
second colorectal carcinoma compared to "conventional"
colorectal carcinomas. |
22 |
The duration of antigen
receptor signalling determines CD4+ versus CD8+T-cell
lineage fate
Yasutomo K, Doyle
C, Miele L, Germain RN. Nature 2000;404:506-10.
Signals elicited by binding
of the T-cell antigen receptor and the CD4/C8
co-receptor to major histocompatibility complex
(MHC) molecules control the generation of CD4+
(helper) or CD8+ (cytotoxic) T cells from thymic
precursors that initially express both co-receptor
proteins. These precursors have unique, clonally
distributed T-cell receptors with unpreddictable
specificity for the self-MHC molecules involved
in this differentiation process. However, the
mature T cells that emerge express only the
CD4 (MHC class II-binding) or CD8 (MHC class
I-binding) co-receptor that complements the
MHC class-specificity of the T-cell receptor.
How this matching of co-receptor-defined lineage
and T-cell-receptor specificity is achieved
remains unknown, as does whether signalling
by the T-cell receptors, co-receptors and/or
general cell-fate regulators such as Notch-1
contributes to initial lineage choice, to subsequent
differentiation processes or to both. Here authors
show that the CD4 versus CD8 lineage fate of
immature thymocytes is controlled by the co-receptor-influenced
duration of initial T-cell receptor-dependent
signalling. Nothc-1 does not appear to be essential
for this fate determination, but it is selectively
required for CD8+ T-cell maturation after commitment
directed by T-cell receptors. This indicates
that the signals constraining CD4 versus CD8
lineage decisions are distinct from those that
support subsequent differentiation events such
as silencing of co-receptor loci. |
23 |
Erythropoietin in radiation
oncology - a review
Henke M, Guttenberger
R. Oncology 2000;58:175-82.
The therapeutic potential
of erythropoietin gains increasing attention
among radiation oncologists because the prognosis
is better for patients with high blood hemoglobin
levels following radiotherapy. Further, the
means to manipulate the hemoglobin level, their
indication and administration need to be clarified.
Available experimental and clinical data on
hypoxia, anemia and on their treatment with
erythropoietin have been extensively disscussed
at an international conference in Freiburg,
Germany, in June 1999. |
24 |
Janssen-Cilag receives
expanded approval for the marketing EPREX®/ERYPO®
Janssen-Cilag Press
Release
Beerse, Belgium, March 31, 2000 - Janssen-Cilag
announced today that it has received an expanded
indication in Europe via the manual recognition
procedure to market EPREX®/ERYPO® (epoetin alfa)
for the "tretment of anemia and reduction
of transfusion requirements in adult patients
receiving chemotherapy for solid tumors, malignant
lymphoma or multiple myeloma at risk of transfusion
as assessed by the patient's general status
(eg cardiovascular status, pre-existing anemia
at the start of chemotherapy)".
Previously, the use of EPREX/ERYPO in Europe
was restricted to cancer patients receiving
platinum-containing chemotherapy. The European
Member States reached the decision to aprove
the extended indication on February 10, 2000.
Janssen-Cilag is now awaiting implementation
of the approval at the national level by the
competent authorities.
Approval for the expanded indication was based
on two large multi-center, placebo-controlled
trials of 520 cancer chemotherapy patients in
Europe. Published results from one of the trials
determined that "epoetin alfa is highly
effective in increasing hemoglobin, reducing
transfusion requirements, reducing fatigue and
increasing energy, acitivity levels and overall
quality of life in cancer patients receiving
non-platinum chemotherapy1".
EPREX/ERYPO is a genetically engineered version
of erythropoietin, a naturally occurring hormone
produced by the kidney that stimulates bone
marrow to produce red blood cells. The main
function of red blood cells is to carry oxygen
needed for energy throughout the body. Anemia
is an abnormally low level of red blood cells,
and is assessed primarily through measurements
of hemoglobin and hematocrit values.
In addition to cancer chemotherapy, EPREX/ERYPO
is approved in Europe for the treatment of anemias
associated with adjunctive therapy in autologous
blood pre-deposit programs and reduction of
allogeneic blood exposure in orthopedic surgery.
EPREX/ERYPO is widely used for patients with
chronic renal failure.
Epoetin alfa has been used to treat more than
three million patients worldwide. It has proven
to be effectie with a good safety profile when
administered according to the prescrubing information.
Janssen-Cilag is a member of the Jonhson &
Jonhson family of companies.
1 Littlewood TJ, et al. Proc ASCO 1999; 18:574a.
|
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 3 |
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News
1 |
Syk gene may be a tumor
suppressor in breast cancers
Reuters Medical
News
http://oncology.medscape.com/reuters
WESTPORT, Aug 17 (Reuters Health)
The Syk tyrosine kinase
is lost in aggressive breast cancers and is
a potential tumor suppressor, researchers report
in the August 17th issue of Nature. Dr. Susette
C.Mueller, of Georgetown University Medical
School, in Washington, DC, and colleagues examined
Syk expression in cultured human breast cells
and tissues ranging from normal to progressively
more invasive cancers. They found that Syk was
found in normal breast in the cells lining the
ducts, benign breast lesions, and less aggressive
cancers, while invasive breast cancers lacked
the protein. "That started ringing a lot
of bells", Dr Mueller told Reuters Health.
Next, they introduced the Syk gene into Syk-negative
breast cancer cells and found that this significantly
inhibited tumor growth and metastasis in immunodeficient
mice. Conversely, introducing a form of the
Syk gene that inhibits the function of the normal
gene into a Syk-positive breast cancer increased
its ability to form tumors. Dr. Mueller noted
that most tyrosine kinases are thought to promote
cancer, not suppress it. "Lots of tyrosine
kinases, when they are not regulated correctly,
actually cause cancer", she said. "This
is kind of unusual. It seems to block excessive
growth and excessive invasion". In examining
tumors with a normal Syk gene that were growth-inhibited,
they found that the tumors had trouble with
cell division. "It looked like they were
trying to divide. They had multiple nuclei that
were stuck together, but something was abnormal
about it", she said. "The chromosomes
were not separating properly, they kept being
stuck together". She noted that one of
the proteins Syk is known to modify is tubulin,
which makes up the mitotic spindle. Why the
Syk gene is not expressed in invasive breast
cancers is not clear, according to Dr. Mueller.
The gene appears to be present, but could be
mutated. In the future, she suggested that this
work could potentially be useful in treating
breast cancers through the introduction of the
Syk gene. |
2 |
Telomere shortening in
gastric carcinoma with aging despite telomerase
activation
Furugori E, Hirayama
R, Nakamura KI, Kammori M, Esaki Y, Takubo K.
J Cancer Res Clin Oncol 2000;126:481-5.
In this study, authors
analyzed both telomere length and telomerase
activity in surgical and autopsy samples of
non-neoplastic mucosa and carcinomas of the
stomach. Telomere length, determined by Southern
blot analysis, demonstrated progressive shortening
with age in non-neoplastic gastric mucosal specimens
from 38 human subjects aged between 0 and 99
years, with an average annual loss rate of 46
base pairs (bp). The mean (±SD) telomere length
in 21 gastric carcinomas was 7.0±1.6 x 10 base
pairs (1.6 kbp). In 20 (95%) of the 21 subjects,
the values were smaller than those in the non-neoplastic
gastric mucosa (mean shortehning 1.8kbp), although
a strong correlation was observed for the paired
data (r=0.69, P=0.0004). Similarly, telomere
lengths in carcinomas were shorter than those
for intestinal metaplasia (a mean difference
of 1.1 kbp). Telomerase activity, estimated
using the telomeric repeat amplification protocol
assay, was positive in 18 (86%) of the 21 gastric
carcinomas, without significant differences
among the three histological types (well, moderately,
and poorly differentiated adenocarcinomas) or
with sex or age. The resul suggest that telomere
length and possibly shortening rates vary with
the individual, and that examination of both
non-beoplastic mucosa and tumoris is necessary
to improve our understanding of the significance
of telomerase in neoplasia. |
3 |
Apoptotic cell death: its
implications for imaging in the next millennium
Blankenberg FG,
Tait JF, Strauss HW. Eur J Nucl Med 2000;27:359-67.
Apoptosis, also known
as programmed cell death, is an indispensable
component of normal human growth and development,
immunoregulation and homeostasis. Apoptosis
is nature's primary opponent of cell proliferation
and growth. Strict coordination of these two
phenomena is essential not only in normal physiology
and regulation but in the prevention of disease.
Programmed cell death causes susceptible cells
to undergo a series of stereotypical enzymatic
and morphologic changes governed by ubiquitous
endogenous biologic machinery encoded by the
human genome. Many of these changes can be readily
exploited to create macroscopic images using
existing technologies such as lipid proton magnetic
resonance (MR) spectroscopy, diffusion-weighted
MR imaging and radionuclide receptor imaging
with radiolabeled annexin V. In this review
the cellular phenomenon of apoptotic cell death
and the imaging methods which can detect the
process in vitro and in vivo are first discussed.
Thereafter an outline is provided of the role
of apoptosis in the pathophysiology of clinical
disorders including stroke, neurodegenerative
diseases, pulmonary inflammatory diseases, myocardial
ischemia and inflammation, myelodysplastic disorders,
organ transplantation, and oncology, in which
imaging may play a critical role in diagnosis
and patient management. Objective imaging markers
of apoptosis may soon become measures of therapeutic
success or failure in both current and future
treatment paradigms. Since apoptosis is a major
factor in many diseases, quantification and
monitoring the process could become important
in clinical decision making. |
4 |
Development of a new vaccine
formulation that enhances the immunogenicity
of tumor-associated antigen CaMBr
Perico ME, Mezzanzanica
D, Luison E, Alberti P, Panza L, Russo G, Canevari
S. Cancer Immunol Immunother 2000;49:296-304.
Aberrant glycosylation
is one of the most constant traits of malignant
cells. The CaMBr1 hexasaccharide antigen, originally
defined on the human breast carcinoma cell line
MCF7, is expressed on some normal tissues but
overexpressed in a high percentage of human
breast ovary, prostate and lung carcinomas.
CaMBr1 overexpression is associated with poor
prognosis. The epitope consists of the tetrasaccharide
Fuc(alpha~1-2)Gal(`beta~1-3)GalNAc(`beta~1-3(Gal`alpha~-0-spacer,
which has recently become available as a synthetic
oligosaccharide. Here authors report the CaMBr1
tetrasaccharide conjugation to two different
carrier proteins (CRM197 and KLH) and the evaluation
of conjugate immunogenicity in mice following
their administration in various vaccine formulations
with two adjuvants (MPL-SE and Detox-PC). Radioimmunoassay
to determine the level and isotype of anti-tetrasaccharide
antibodies in mouse sera, and cytofluorimetric
analysis and 51Cr-release assay on human tumor
cells, to evaluate specificity of binding and
complement-dependent lysis respectively, indentified
CaMBr1-CRM197, in association with the MPL-SE
adjuvant, as the best vaccine formulation. This
combination induced (1) production of tetrasaccharide-specific
antibodies, with negligible side-effects; (2)
antibodies with complement-mediated cytotoxic
activity on human CaMBr1-positive cells and
(3) a high titer of IgG1 detected in sera obtained
3 months after the first injection, indicating
that the anti-tetrasaccharide antibody response
was mediated by T cell activation. The availability
of CaMBr1-glycoconjugate in the minimal and
functional antigenic structure and the identification
of an efficacious vaccine formulation opens
the way to exploring the activity of this glycoconjugate
in a clinical setting. |
5 |
Sequential administration
of interferon`gamma~and interleukin-2 in metastatic
renal cell carcinoma: results of a phase II
trial
Schmidinger M,
Steger GG, Wenzel C, Locker GJ, Brodowicz T,
Budinsky AC et al. Cancer Immunol Immunother
2000;49:395-400.
Because of the known efficacy
of several cytokines in the treatment of advanced
renal cell cancer (RCC), authors have conducted
a phase II trial of the efficacy and toxicity
of subcutaneous interferon <Gamma>(IFN<Gamma>)
and interleukin-2 (IL-2). 63 patients with progressive
metastatic RCC were treated with 100 mg recombinant
IFN<Gamma>1b administered three times
weekly during weeks 1 and with 4.5 MU recombinant
IL-2 administered on 4 consecutive days during
weeks 3 and 4, every 6 weeks. 11% of patients
had on objective response (CR: 3%, PR 8%), 33%
had SD. Toxicity was generally mild. The median
duration of remissions (CR+PR) was 9.6 months;
the median duration of SD 8 months. A significant
survival benefit was evident at a median observation
time of 51 months for patients (44%) responding
to therapy (P<0.0001). Authors conclude that
sequential treatment with IFN<Gamma>and
IL-2 may prolong survival in patients with metastatic
RCC responding to therapy. |
6 |
The impact of FDG positron
emission tomography imaging on the management
of lymphomas
Shah N, Hoskin
P, McMillan A, Gibson P, Lowe J, Wong WL. Br
J Radiol 2000;73:482-7.
The role of 2-(F-18)-fluoro-2-deoxy-D-glucose
positron emission tomography (FDG-PET) imaging
in the management of patients with lymphoma
has been evaluated. 29 patients (12 Hodgkin's
disease, 17 non Hodgkin's lymphoma (NHL)) who
underwent FDG-PET imaging during their lymphoma
treatment programme were reviewed retrospectively.
Correlation between FDG-PET and CT was evaluated,
together with the impact upon clinical management
of the findings on FDG-PET imaging. FDG-PET
added extra information to the findings on clinical
examination and CT in 12 patients (41%). This
was seen both in patients with negative and
positive CT scan. Two false positive FDG-PET
scans were seen, reflecting FDG uptake in extranodal
sites. Information from FDG-PET imaging resulted
in a change in clinical management in 10 patients
(34%); in two, initial management was altered,
and in eight consolidation therapy after completion
of initial chemotherapy was influenced. These
changes in clinical management occurred in six
patients with high grade NHL, two with low grade
NHL and two with Hodgkin's disease. No specific
subgroup was identified in whom FDG-PET was
particularly discriminant. |
7 |
Transperineal magnetic
resonance image guided prostate biopsy
D'Amico AV, Tempany
CM, Cormack R, Hata N, Jinzaki M, Tuncali K,
Weinstein M, Richie JP. J Urol 2000;164:385-7.
Authors report the findings
of a transperineal magnetic resonance image
(MRI) guided biopsy of the prostate in a man
with increasing prostate specific antigen who
was not a candidate for a transrectal ultrasound
guided biopsy. Using an open configuration 0.5
Tesla MRI scanner and pelvic coil, a random
sextant sample was obtained under real time
MRI guidancefrom the peripheral zone of the
prostate gland as well as a single core from
each MRI defined lesion. The patient had previously
undergone proctocolectomy for ulcerative colitis
and, therefore, was not a candidate for transrectal
ultrasound guided biopsy. Prior attempts to
make the diagnosis of prostate cancer using
a transurethral approach were unsuccessful.
The random sextant samples contained benign
prostatic hyperplasia, whereas Gleason grade
3 + 3 = 6 adenocarcinoma was confirmed in 15%
and 25% of the 2 cores obtained from the MRI
targeted specimens of 2 defined lesions. The
procedure was well tolerated by the patient.
Transperineal MRI guided biopsy is a new technique
that may be useful in detecting prostate cancer
in men with increasing prostate specific antigen
who are not candidates for transrectal ultrasound
guided biopsy. |
8 |
Sentinel node analysis
increases detection of GI cancer micrometastasis
Reuters Medical
News
http://oncology.medscape.com/reuter.
WESTPORT, Aug 15 (Reuters Health)
In patients with gastrointestinal
neoplasms, lymphatic mapping and sentinel lymphadenectomy
are feasible, accurately predict the tumor status
of regional lymph nodes, and identify abnormal
lymphatic drainage, researchers report in the
August issue of the Archives of Surgery. Noting
that intraoperative lymphatic mapping and sentinel
lymphadenoctomy have already been shown to be
useful for melanoma, Dr. Anton J. Bilchik and
colleagues from the John's Health Center, in
Santa Monica, California, prospectively tested
these techniques in 65 patients with gastrointestinal
cancers.
Using isosulfan blue dye, the researchers found
at least one sentinel lymph node in 95% of patients.
The mapping only added about 10 minutes to the
surgery, they noted.
Using hematoxylin-eosin staining, multiple sectioning
and cytokeratin immunohistochemistry, they identified
36 cases of nodal metastases, of which 89% had
at least one posivite sentinel node. Fifteen
of these cases (42%) had metastases only to
the sentinel node. "Based on the sentinel
node focused analysis, 23% of the neoplasms
were upstaged," they write. The report
also noted that in 8% of cases, "lymphatic
mapping identified aberrant lymphatic drainage
that altered the extent of the lymphadenectomy".
In addition, the sentinel node was the only
positive node in all T1 stage cancers and 70%
of T2 stage cancers, implying that "sentinel
node analysis may be particularly relevant in
identifying micrometastatic spread from T1-T2
neoplasms".
"The preliminary findings of this feasibility
study suggest that lymphatic mapping with focused
examination of the sentinel nodes improves the
staging of gastrointestinal neoplasms and may
affect the selection of patients for adjuvant
therapy", Dr. Bilchik and colleagues write.
A prospective phase II trial is now ongoing
to investigate these possibilities, they note. |
9 |
D3 lymph node dissection
in gastric cancer: evaluation of postoperative
mortality and complications
Gunther K, Horbach
T, Merkel S, Meyer M, Schnell U, Klein P, Hohenberger
W. Surgery Today 2000;30:700-5.
Since November 1995 authors
have been performing a D3 lymph node dissection
in patients undergoing an operation for gastric
cancer with a curative intent. The aim of the
their study was to evaluate whether this procedure
results in an increased postoperative mortality
of complication rate in a Western population.
Between November 1995 and August 1997 the postoperative
courses of 76 patients were retrospecively assessed
(45.3 lymph nodes per patient, lymph node ratio:
0.16). The patient outcome was compared with
data from a historic control group of patients
(n=383) in whom the newly established D2 dissection
was studied in our department. Regarding the
demographic, clinical, and tumor-pathologic
data, and the choice of resection and reconstructive
procedures, the two groups differed only slightly.
The postoperative mortality of 1% was lower
(vs 6.8%) while the overall complication rate
of 34% (vs 32.1%) was identical. in particular,
no anastomotic leakage (vs 9.4%) and fewer nonsurgical
complications (17.1% vs 27.9%) occurred. The
reoperation rate was 1% vs 9.7%. However, in
6% of the patients drainage tubes had to be
inserted under computed tomographic guidance.
The average hospital stay remained unchanged
(21.9 vs 20.7 days). A D3 dissection was shown
to be feasible while demonstrating no disadvantages
in the patients when compared with the D2 procedure. |
10 |
Brachytherapy yields excellent
long-term results in prostate carcinoma
Reuters Medical
News
http://oncology.medscape.com/reuters
WESTPORT, Jun 30 (Reuters Health)
Prostate brachyterapy,
the implantation of small, radioactive metal
seeds within the prostate gland, provides excelent
long-term, disease-free survival, according
to a report in the July 1st issue of Cancer.
Dr. Haakon Ragde of the Northwest Prostate Institute,
in Seattle, Washington, and colleagues studied
the effects of brachytherapy in 229 prostate
cancer patients, 147 of whom were low-risk for
extracapsular spread and 82 of whom faced a
higher risk. The overall median follow-up was
93 months, and half the surviving patients were
followed for at least 122 months, the authors
report. Only four patients died from prostate
cancer, yielding a disease-specific 10-year
survival rate of 98%. By the 10-year evaluation
point, 70% of the patients had shown no evidence
of prostate cancer by clinical examination or
by measurement of prostate-specific antigen
(PSA) levels, the report indicates. In fact,
the mean PSA level of this group was only 0.16
ng/mL. Results differed somewhat in the two
risk groups, the investigators observe. The
low-risk group. which received only brachytherapy,
had a 66% control rate at 10 years. The high-risk
group, which received brachyterapy plus external
beam radiation therapy, showed a 79% control
rate. Most disease recurrences occurred within
the first 5 years of treatment, the researchers
note. After 5 years, the failure rate averaged
only 1.5% per year, and there were no treatment
failures after 115 months (in 109 men). "The
addition of 77 more patients to our ongoing
analysis of prostate brachytherapy with up to
12 years of follow-up confirms the previously
documented excellent results for men with localized
prostate carcinoma", the authors conclude.
"The apparent benefit of adding external
beam radiation to brachytherapy in selected
high-risk patients is demonstrated by the excellent
results achieved in this group", the researchers
write. "However", they add, "we
do not yet feel that the data support the addition
of external beam radiation to every brachytherapy
patient". |
11 |
Accelerated hyperfractionated
radiotherapy in supratentorial malignant astrocytomas
Genc M, Zorlu AF,
Atahan IL. Radiother Oncol 2000;56:233-8.
To determine the safety
and effectiveness of accelerated hyperfractionated
radiotherapy in the treatment of supratentorial
malignant astrocytomas. Between June 1995-July
1997, 75 patients were enrolled to a prospective
phase II study. A total dose of 60 Gy was delivered
in 2 Gy b.i.d. fractions with an interval of
6-8 h, 5 days per week, in an overall time of
3 weeks. The treatment protocol was planned
to give 40 Gy to a treatment volume covering
the contrast-enhancing lesion and oedema (+
3-cm margin) and additional 20 Gy to the volume
encompassing the contrast-enhancing lesion alone
with a 1-cm margin based on preoperative magnetic
resonance imaging and/or CT findings. The patients
had a median age of 46 years and a median Karnofsky
performance status score of 80. Histology consisted
of anaplastic astrocytoma (AA) in 16 (21%) and
glioblastoma multiforme (GBM) in 59 (79%) patients.
Median survival was 11 months for all patients;
10 months for GBM patients and 40 months for
AA patients. Survival rates at 1 and 3 years
were 41%, 11% for all patients; 62, 37% for
AA patients and 35, 6% for GBM patients, respectively.
Multivariate analysis revealed significant impact
of age, histology and neurological functional
class on survival. The incidence of grade 3
or worse late neurological toxicity was 5.3%.
Although accelerated hyperfractionated radiotherapy
showed no significant advantage on survival,
it shortened the treatment period from 6 to
3 weeks. Radiotherapy was well tolerated and
the incidence of late toxicity is acceptable. |
12 |
An integrated service digital
network (ISDN)-based international telecommunication
between Samsung Medical Center and Hokkaido
University using telecommunication helped radiotherapy
planning and information system (THERAPIS)
Huh SJ, Shirato
H, Hashimoto S, Shimizu S, Kim DY, Ahn YC et
al. Radiother Oncol 2000;56:121-3.
This study introduces
the integrated service digital network (ISDN)-based
international teleradiotherapy system (THERAPIS)
in radiation oncology between hospitals in Seoul,
South Korea and in Sapporo, Japan. THERAPIS
has the following functions: (1) exchange of
patient's image data, (2) real-time teleconference,
and (3) communication of the treatment planning,
dose calculation and distribution, and of portal
verification images between the remote hospitals.
Authors preliminary results of applications
on eight patients demonstrated that the international
telecommunication using THERAPIS was clinically
useful and satisfactory with sufficient bandwidth
for the transfer of patient data for clinical
use in radiation oncology. |
13 |
15-LOX-1: a novel molecular
target of nonsteroidal anti-inflammatory drug-induced
apoptosis in colorectal cancer cells
Shureigi I, Dongning
C, Lee JJ, Peiying Y, Newman RA, Brenner DE
et al. J Natl Cancer Inst 1999;92:1136-42.
Nonsteroidal anti-inflammatory
drugs (NSAIDs) appear to act via induction of
apoptosis-programmed cell death- as potential
colorectal cancer chemopreventive agents. NSAIDs
can alter the production of different metabolites
of polyunsaturated fatty acids (linoleic and
arachidonic acids) through effects on lipoxygenases
(LOXs) and cyclooxygeneses. 15-LOX-1 is the
main enzyme for metabolizing colonic linoleic
acid to 13-S- hydroxyoctadecadienoic acid (13-S-HODE),
which induces apoptosis. In human colorectal
cancers, the expression of this enzyme is reduced.
NSAIDs can increase 15-LOX enzymatic activity
in normal leukocytes, but their effects on 15-
LOX in neoplastic cells have been unknown. Authors
tested the hypothesis that NSAIDs induce apoptosis
in colorectal cancer cells by increasing the
protein sxpression and enzymatic activity of
15-LOX-1. Authors assessed 15-LOX-1 protein
expression and enzymatic activity, 13-S-HODE
levels, and 15-LOX-1 inhibition in association
with cellular growth inhibition and apoptosis
induced by NSAIDs (primarily sulindac and NS-398)
in two colorectal cancer cell lines (RKO and
HT-29). All values are two-sided. Sulindac and
NS-398 progressively increased 15-LOX-1 protein
expression in RKO cells (at 24, 48, and 72 hours)
in association with subseguent growth inhibition
and apoptosis. Increased 13-S-HODE levels and
the formation of 15-hydroxyeicosatetraenoic
acid on incubation of the cells with the substrate
arachidonic acid confirmed the enzymatic activity
of 15-LOX-1. Inhibition of 15-LOX-1 in RKO cells
by treatment with caffeic acid blocked NS-398-induced
13-S-HODE production, cellular growth inhibition,
and apoptosis (P=.007, P<.001, and P<.0001,
respectively); growth inhibition and apoptosis
were restored by adding exogenous 13-S-HODE
(P<.0001 for each) but not its parent compound,
linoleic acid (P=1.0 for each). Similar results
occurred with other NSAIDs and in HT-29 cells.
These data identify 15-LOX-1 as a novel molecular
target of NSAIDs for inducing apoptosis in colorectal
carcinogenesis. |
14 |
"Gene shaving"
as a method for identifying distinct sets of
genes with similar expression patterns
Hastie T, Tibshirani
R, Eisen MB, Alizadeh A, Levy R, Staudt L et
al. Genome Biology 2000;1(2).
Large gene expression
studies, such as those conducted using DNA arrays,
often provide millions of different pieces of
data. To address the problem of analyzing such
data, authors describe a statistical method,
which they have called "gene shaving".
The method identifies subsets of genes with
coherent expression patterns and large variation
across conditions. Gene shaving differs from
hierarchical clustering and other widely used
methods for analyzing gene expression studies
in that genes may belong to more than one cluster,
and the clustering may be supervised by an autocome
measure. The technique can be "unsupervised",
that is, the genes and samples are treated as
unlabeled, or partially or fully supervised
by using known properties of the genes or samples
to assist in finding meaningful groupings. Authors
illustrate the use of the gene shaving method
to analyze gene expression measurements made
on samples from patients with diffuse large
B-cell lymphoma. The method identifies a small
cluster of genes whose expression is highly
predictive of survival. The gene shaving method
is a potentially useful tool for exploration
of gene expression data and identification of
interesting clusters of genes worth further
investigation. |
15 |
...but data release remains
an open question
Nature 2000;406
http://www.nature.com
On of the question marks
hanging over cooperation in structural genomics
is how and when the structures of proteins and
other macromolecules should be made public.
At a meeting in Cambridge in April, organized
by the Wellcome Trust, scientists from public
agencies in nine countries agreed that there
should be timely release of all data. But a
loophole remains in that, for the next couple
of years, the decision of when a structure is
complete and ready for a database is left to
researchers themselves. This is because there
is no agreement or way of defining when a protein
structure is accurate and complete - is largely
a matter of personal judgement. Arriving at
an automatic cutoff point based on "numerical
criteria" of quality is "now key goal",
says John Norvell, head of the US Protein Structure
Initiative based at the National Institute of
General Medical Sciences. This would allow for
clear rules on the timing of data release. An
early agreement between researchers on data
access is also critical to facilitating collaboration
with industry. As several delegates at a meeting
organized by the Organisation for Economic Cooperation
and Development in Florence in June pointed
out, researchers may be reluctant to put valuable
structural data into the public domian. The
Cambridge meeting agreed that data released
should be accompanied by a short research paper,
published simultaneously on the Internet. |
16 |
Genome website set up to
help with sequence analysis
Nature 2000;406.
http://www.nature.com
London. After PubMed Central
and Biomed Central comes 'Human Genome Central'
- a 'master website' being set up by the International
Human Genome Seguencing Consortium to provide
access to tools for analysing the sequence data
being produced by its members. The consortium
says that although the raw sequence data are
already available in three public databases
- Genbank, the European Molecular Biology Laboratory
Database and the DNA Database of Japan - analysing
this data is a daunting and time-consuming task.
The new website has therefore been designed
to give users "comprehensive and comprehensible"
ancillary information and tools. These should
provide visitors to the site with a picture
of the genome that is continually updated. The
information available will include the overlaps
between clones, the location of each clone,
an integrated sequence that merges the individual
clones, and annotation of gene content.
http://www.ncbi.nim.nih.gov/genome/central
http://www.ensembl.org/genome/central |
17 |
Improving therapy of colorectal
cancer with new agents - Next steps in colorectal
cancer
Cassidy J.
http://oncology.medscape.com/
The data presented at
the meeting and reviewed in this activity indicate
that we may be entering a new era in the therapy
colorectal cancer. 5-FU has been mainstay of
therapy of this disease for over 40 years. It
seems likely that fluoropyrimidines will still
be an integral part of therapy - but 5-FU will
be replaced by more convenient, less toxic,
and possibly more active oral fluoropyrimidines.
Capecitabine has the added advantage over UFT
that it produces tumor-specific activation of
5-FU in the cancer site. It is for these reasons
that, on current evidence, I would favor this
agent as the optimal way of giving fluoropyrimidine
in the future. The next major steps forward
in this disease are, however, likely to be achieved
by novel combinations of the active drugs that
have been reviewed so far. Phase III trials
of irinotecan in combination with 5-FU demonstrated
that efficacy, including survival, can be enhanced
by combining irinotecan with fluoropyrimidines.
Similarly, the combination of oxaliplatin with
5-FU/LV has also been shown to produce dramatic
improvements in response rate. A logical step
in our attempts to further improve efficacy
is to use highly active fluoropyrimidine agents
such as capecitabine, which achieves superior
response rates compared with a standard bolus
5-FU/LV schedule (Mayo Clinic regimen). A number
of phase I trials exploring oral fluoropyrimidines
in combination with irinotecan or oxaliplatin
have been conducted and recommended doses for
more extensive clinical development have been
established. The next few years should see these
combinations enter large-scale comparative studies.
In addition, as radiotherapy has been shown
to upregulate TP activity, the combination of
capecitabine with radiotherapy is being explored
and the updated results presented by Dr. Tanner
are encouraging. The results of phase II trials
for all of these combination regimens are eagerly
awaited. It is also worth noting that these
new agents are not necessarily restricted to
colorectal cancer. The promising efficacy and
safety shown by capecitabine has also been demonstrated
in small scale pilot trials that have been performed
in pancreatic, hepatocellular, gall bladder
cancer patients, and a host of other solid tumor
types. Recently presented phase II results of
capecitabine monotherapy and phase I results
of capecitabine/gemcitabine combination therapy
in metastatic pancreatic cancer are encouraging,
and phase II and III trials of capecitabine/gemcitabine
combination therapy are planned following demonstration
of a favorable safety profile and high antitumor
activity. In conclusion, the future of therapy
in colorectal cancer is likely to involve the
use of combinations and/or sequences of all
of the new agents discussed above. The adjuvant
use of such active combinations is being actively
pursued and it seems likely that we will be
able to cure a higher proportion of our patients
in the near future by the judicious application
of these new therapies. |
18 |
Improved efficiency of
gene transfer to the transplanted lung by retrograde
vascular gene delivery
Jeppsson A, Pellegrini
C, Lee R, O'Brien T, Miller VM, Tazelaar HD
et al. Transplant International 2000;13:241-6.
Experiments were designed
to evaluate the efficiency of antegrade compared
to retrograde vascular gene transfection of
donor lungs used for transplantation. Rat donor
lungs (n=5/group) were transduced with an adenoviral
vector encoding for - galactosidase (AdGal),
either antegrade in the pulmonary artery (Group
A, 3x108 pfu, Group B, 3x109 pfu) or retrograde
into the pulmonary vein (Group C, 3x108 pfu),
immediately after pneumoplegia. After storage
a 4!C for 1 h, the transduced lungs were transplanted
orthotopically in syngeneic animals. The lungs
ere assessed for transgene expression by ELISA
and X-Gal-staining at day 7 after operation.
Inflammation was graded based on the extent
of inflammatory cell infiltration. Transgene
expression was similar between Groups A (1.7±0.7
ng/mg protein) and B (2.1±1.0 ng/mg protein).
With retrograde delivery, there was a four-fold
(8.3±2.6 ng/mg protein) increase (P`0.05) in
transgene expression compared to either group
A or B. In all groups, pneumocytes were transduced
most frequently. The degree of inflammation
correlated positively with the extent of transgene
expression (r=0.75, P<0.01). The efficiency
of vascular gene delivery to transplanted lungs
can be improved by retrograde delivery of the
vector via the pulmonary vein. Transgene expression
predominates in pneumocytes following both antegrade
and retrograde delivery The severity of inflammation
in the transplanted lung appears to correlate
with the extent of transgene expression. |
19 |
Medicine can prevent war
Igic R. Pak Armed
Forces Med J 1999;49:80.
Like a cancer, war destroys
the normal functions of society, spreads rapidly
leaving destruction in its wake, and is the
most serious threat to millions of lives. because
war is medical problem, medical doctors have
a special opportunity and obligation to fight
for peace. In September 1998 author suggested
to the British Medical Journal, several International
Medical Journals and the World Association of
Medical Editors (WAME) that an international
meeting be organized on medicine's role in thepromotion
of peace and prevention of war. That is a good
first step. However, his idea is to gather medical
professionals from varioud countries to give
their opinion on this important topic - the
prevention of war and other war-related major
threats to the health of global society. This
could be the basis for the permanent preventive
activities of our profession. The begining of
a new millenium is a perfect time for a big
convocation of the healthcare force to present
the medical, social and political solutions
that may influence public opinion in all countries
and save countless lives from the most serious
disease that destroys humanity. |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
|
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Issue 4 |
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News
1 |
AT - cell-selective interleukin
2 mutein exhibits potent antitumor activity
and is well tolerated in vivo
Shanafelt AB, Lin
Y, Shanafelt M-C, Forte CP, Dubois-Stringfellow
N, Carter C et al.
Nature Biotechnology 2000;18:1197-202.
Human interleukin 2 (IL-2;
Proleukin) is an approved therapeutic for advanced-stage
metastatic cancer; however, its use is restricted
because of severe systemic toxicity. Its function
as a central mediator of T-cell activation may
contribute to its efficacy for cancer therapy.
However, activation of natural killer (NK) cells
by therapeutically administered IL-2 may mediate
toxicity. Here we have used targeted mutagenesis
of human IL-2 to generate a mutein with 3,000-fold
in vitro selectivity for T cells over NK cells
relative to wild-type IL-2. We compared the
variant, termed BAY 50-4798, with human IL-2
(Proleukin) in a therapeutic dosing regimen
in chimpanzees and found that although the T-cell
mobilization and activation properties of BAY
50-4798 were comparable to human IL-2, BAY 50-4798
was better tolerated in the chimpanzee. BAY
50-4798 was also shown to inhibit metastasis
in a mouse tumor model. These results indicate
that BAY 50-4798 may exhibit a greater therapeutic
index than IL-2 in humans in the treatment of
cancer and AIDS. |
2 |
Declaration of Helsinki
revised, holds researchers responsible after
trials
Reuters Medical
News http://oncology.medscape.com/reuters/prof/2000/10/10.10/200011009plcy001.html
(November 17)
LONDON (Reuters Health)
Oct 10 - Revisions to the Declaration of Helsinki
newly adopted by World Medical Association (WMA)
hold researchers to the standard of "the
best current prophylactic, diagnostic, and therapeutic
methods" for research and follow-up treatment.
On Saturday, the 52nd General Assembly of the
WMA, held in Edinburgh, Scotland, unanimously
voted to strengthen protections for individual
research subjects and for the populations of
host countries. "No population in any country
should be used as a guinea pig without benefiting
from the results of the research", Dr.
Anders Milton of Sweden, chairman of the World
Medical Association, told Reuters Health. As
an example, he said "When human research
is carried out in a country, there should be
a reasonable chance of the drug being used there".
Dr. Milton added, "We also say that for
individuals participating in a study, either
the control group or the test group, that at
the conclusion of the study should have access
to the best proven treatment for the disease
state in question". Long considered the
"cornerstone of research ethics",
the Declaration of Helsinki calls for "absolute
transparency regarding economic incentives involved
in research", said Dr. Delon Human, Secretary
General of the WMA. Not only must subjects be
adequately informed regarding risks and benefits
in language they can understand, but institutional
affiliations and possible conflicts of interest
must be clarified to subjects, ethical review
committees and publishers. The WMA is an independent
confederation of professional national associations
from approximately 70 countries and represents
8 million doctors. This is the fifth time that
the Helsinki document has been revised since
its adoption in 1964. The full text of the revised
declaration is available on the WMA Web site
at www.wma.net. |
3 |
Early oophorectomy protects
against breast cancer in BRCA1/2 mutation carriers
Reuters Medical
News http://oncology.medscape.com/reuters/prof/2000/10/10.10/20001009clin015.html
(November 17)
PHILADELPHIA (Reuters
Health) Oct 10- Findings presented at the annual
meeting of the American Society of Human Genetics
further substantiate the benefit of bilateral
prophylactic oophorectomy in significantly reducing
the risk of breast cancer in women who carry
mutations of the BRCA1 or BRCA2 genes. In a
multicenter case-control study Dr. Andrea Eisen
of the University of Pennsylvania School of
Medicine and colleagues compared data on 415
matched pairs of mutation carriers to estimate
the magnitude of the risk reduction conferred
by oophorectomy. All the cases had breast cancer,
while the controls were apparently free of breast
cancer. The researchers found the overall odds
ratio for breast cancer with bilateral oophorectomy
to be 0.42. The greatest reductions in breast
cancer risk was attained when oophorectomy was
performed before age 40 (odds ratio 0.24). "The
effect is lost if (the surgery) is at age 50
or later", Dr. Eisen said. "Although
these data support the case for prophylactic
oophorectomy, there are adverse events to consider",
Dr. Eisen noted. These include quailty of life
effects owing to premature menopause and an
increased risk of osteoporosis and coronary
heart disease. Commentators agreed that early
prophylactic surgery provides optimal protection.
"We consider 35 possibly to be the optimum
age of surgery for breast cancer prevention,
"Dr. Steven A. Narod, a co-moderator of
the session, said. "It's better to have
prophylactic oophorectomy with hormone replacement
therapy than no prophylactic oophorectomy at
all, " added Dr. Narod, who is at the Center
for Research in Women's Health in Toronto, Canada.
"We try to titrate the estrogen to treat
the acute symptoms, and then wean them off of
it after a few years". |
4 |
Ultrasonography effectively
measures tamoxifen's effect on endometrium
Reuters Medical
News http://oncology.medscape.com/reuters/prof/2000/10/10.12/20001011clin016.html
(November 17)
WESTPORT, CT (Reuters
Health) Oct 12-Researchers in Israel, who followed
58 postmenopausal women after termination of
tamoxifen treatment for breast cancer, found
that transvaginal ultrasonography is a valuable
tool in assessing tamoxifen's effects on the
endometrium. Dr. Ilan Cohen, of Sapir Medical
Centre, in Kfar-Saba, and associates in this
prospective study, observed a significant decrease
in median thickness of the endometrium, from
7.75 mm just before tamoxifen discontinuation,
to 5.2 mm 6 months later. When performed about
every 6-months over the next 30 months, ultrasonography
showed that the endometrial thickness remained
"constantly low". The investigators
note in the September issue of the British Journal
of Obstetrics and Gynaecology that previous
studies found transvaginal ultrasonography to
be of limited value in evaluating women taking
tamoxifen. In these studies, ultrasonography
yielded many false-positives and disparities
with sonographic and histologic results. The
authors believe their "findings are extremely
important when using ultrasonography to assess
the endometrium in postmenopausal breast cancer
patients following discontinuation of tamoxifen
treatment".
Dr. Cohen's group concludes that tamoxifen causes
thickening of the endometrium of the subendometrial
tissue or both. An endometrial thickness greater
than that observed before stopping tamoxifen
therapy or an increase in thickness "should
alert the clinician to the possible existence
of endometrial pathology". |
5 |
High-dose chemo plus stem
cell support promising for primary refractory
NHL
Reuters Medical
News http://oncology.medscape.com/reuters/prof/2000/10/10.10/20001009clin012.html
(November 17)
WESTPORT, CT (Reuters
Health) Oct 10- High-dose chemoradiotherapy
(HDT) followed by autologous stem cell transplantation
(ASCT) should be used for certain patients with
primary refractory aggressive non-Hodgkin's
lymphoma (NHL), according to a report in the
October 1st issue of Blood. While HDT/ASCT is
the treatment of choice for patients with relapsed
NHL, its role in primary refractory aggressive
NHL has not been demonstrated, the authors explain.
Tarun Kewalramani and colleagues from Memorial
Sloan-Kettering Cancer Center in New York reviewed
the outcomes of 90 consecutive patients with
primary refractory aggressive NHL who were eligible
for HDT/ASCT based on disease sensitivity to
chemotherapy. Half the patients had partial
remissions with induction chemotherapy, and
half failed induction therapy. Forty-three patients
(50.6%) experienced complete or partial remissions
with second-line chemotherapy (ICE-ifosfamide,
carboplatin, and etoposide), the authors report,
and 42 patients (38 ICE-sensitive and 4 in whom
ICE failed) underwent HDT/ASCT. There were no
transplant-related deaths, the investigators
observe, although 4 patients died within 100
days after stem-cell reinfusion, all from lymphoma
or its complications. Overall 3-year survival
for the entire group was 25%, the report indicates,
whereas survival in the HDT/ASCT subgroup was
52.5%. Event-free survival rates were 22% and
44.2%, respectively. "Our data strongly
suggest that patients with primary refractory
aggressive NHL should be treated with second-line
chemotherapy with the intent of performing HDT/ASCT
for those patients with chemosensitive disease",
the authors conclude. |
6 |
Hereditary nonpolyposis
colorectal cancer: screening can impact cancer
mortality
Isselbacher JK.
http://oncology.medscape.com/HOL/articles/2000/07/hol08/hol08.html
(November 17)
Hereditary nonpolyposis
colorectal cancer (HNPCC) is a disease characterized
by the early onset of colorectal cancer (CRC)
and by other non-GI malignancies such as endometrial
and renal cell carcinomas. HNPCC is a disease
due to a germline mutation in one of the five
DNA mismatch repair genes and is inherited as
an autosomal dominant trait. Individuals who
inherit HNPCC have an 80 percent lifetime risk
of developing CRC. Therefore, efforts are aimed
at identifying individuals at risk by genetic
testing and early endoscopic screening. Järvinen
and colleagues (2000) report the results of
a 15-year endoscopic screening for CRC in HNPCC.
They followed up 252 asymptomatic individuals
from 22 families with HNPCC, all at 50 percent
risk of being a carrier of one of the five possible
mismatch repair gene mutations. Of this total
number, 133 individuals chose to undergo colonoscopic
screening at 3-year intervals while 119 chose
to avoid screening despite prior counseling.
When genetic testing became available in 1996,
it was offered to 205 individuals; 193 accepted-namely,
116 in the study group and 77 in the control
group. Mutations in a mismatch repair gene were
found in 44 and 46 individuals in the study
and control groups, respectively. CRC developed
in 6 percent of the screened group and 16 percent
of the control group with screening thereby
reducing the rate of CRC by 62 percent in the
screened group. In those who tested positive
for a mutation, CRC rates were 18 percent in
the screened group vs. 41 percent in the control
group. Most importantly, CRC detected in the
screened group consisted of local disease not
associated with death. The authors conclude
that colonoscopic screening for individuals
at risk for HNPCC can reduce their risk of CRC
by 50 percent, prevent death associated with
CRC, and decrease mortality by up to 65 percent.
It remains to be determined if colonoscopic
surveillance programs every 3 years will be
the optimal frequency or if shorter intervals
will further improve both morbidity and mortality. |
7 |
Genome expression reveals
origin of Reed-Sternberg cell
http://oncology.medscape.com/Medscape/f.../Lymphoma/public/RC-index-lymphoma.html
(November 17)
Using advanced genomic
techniques, researchers from Georgetown University,
Human Genome Sciences Inc, and the National
Cancer Institute have demonstrated that the
Reed-Sternberg (R-S) cell the pathognomonic
feature of Hodgkin's disease, has a B-cell origin.
The article is published in the July 15 issue
of Blood. Evidence collected over the past several
years has suggested a B-cell origin for the
Reed-Sternberg cell, primarily the finding of
rearranged immunoglobulin genes among R-S cells.
However, the R-S cell is very scarce in Hodgkin's
tumors, hindering attempts to characterize R-S
cell function and to define its origins. In
the Blood study, researches prepared distinct
cDNA expression libraries from Hodgkin's derived
cell lines, germinal center B-cells, dendritic
cells, and R-S cells. For the R-S cells, cDNA
was prepared from single viable cells, isolated
by using advanced optical and isolation devices.
The cDNA libraries were sequenced using automated
seguencing techniques. The first result was
the identification of more than 27,000 ESTs
(expressed sequence tags, or single gene identifier
sequences) from Hodgkin's disease sources. Of
these ESTs, 2666 represented genes already present
in genome databases. Previously, only 100 named
genes had been identified as expressed in Hodgkin's
disease. In general, the researchers found that
preparations from single R-S cells had gene
expression panels very similar to those identified
through pooled Hodgkin's disease lines and sources,
suggesting that their microdissection method
gave valid representations of expressed genes
in Hodgkin's disease. By comparing the expression
of panels of known genes from a variety of different
sources, the researchers could infer the cell
origin of the R-S cells. As expected for cells
derived of B-cell origin, R-S cells express
the immunoglobulin genes as well as other B-cell
lineage-specific surface proteins, including
BL34, B7, CD20, CD80 and NF-B. By way of comparison,
there was minimal overlap with genes normally
expressed by dendritic cells, including Mac1,
CD68, and a variety of chemoattractants such
as MCP-4. The technological power of such genomic
screens could, in principal, be applied to any
malignant cell population or other cell source.
As clinicians and pathologists attempt to come
to terms with dozens of different surface antigens,
and possibly scores of known oncogenes, the
prospect of understanding disease using thousands
of different genes is at once tantalizing and
daunting. |
8 |
Computed tomography/magnetic
resonance based volume changes of the primary
tumour in patients with prostate cancer with
or without androgen deprivation
Lilleby W, Fosa
SD, Knutsen BH, Abildgaard A, Skovlund E, Lien
H.
Radiother Oncol 2000;57:195-200.
To evaluate changes of
the volume of the cancerous prostatic gland
during androgen deprivation (AD) started immediately
after diagnosis (IAD). Hypothetically, these
data would assist the radiotherapist to determine
the appropriate duration of pre-radiotherapy
downsizing neoadjuvant luteinizing hormone releasing
hormone (LHRH) treatment. A second aim was to
assess any increase of the prostatic volume
during the 1st year of diagnosis in patients
who were allocated to a deferred treatment policy
(DAD) group, all with T1-3pN1-2M0 prostate cancer,
had regular computed tomography/magnetic resonance
(CT/MR) examinations during the 1st year after
randomization within the EORTC-GU trial 30846.
Pre-treatment prostate specific antigen (PSA)
values were available in only 12 patients. In
the IAD group the prostate gland decreased with
significant difference as compared with the
DAD patients (P=0.033). As compared with the
pre-treatment situation the prostate gland in
the IAD group was reduced in size by 18, 35,
and 46% at 1,6, and 12 months, respectively.
In four of six evaluable IAD patients the prostatic
volume continued to shrink after achievement
of the nadir PSA level (at 3 months). In three
of the 13 DAD patients the prostate volume increased
by ~25% during the 1st 3 months after randomization.
If neoadjuvant androgen deprivation is applied
before local treatment to downsize the volume
of the cancerous prostate gland, our limited
data suggest that such treatment should last
at least 6 months in order to achieve a maximal
effect in the majority of patients. In about
1/4 of untreated patients an increase in the
prostate volume by~25% may occur within 3 months
of diagnosis. If no AD is given, radiotherapy
should start within this period. |
9 |
An IL6 promoter polymorphism
is associated with a lifetime risk of development
of kaposi sarcoma in men infected with human
immunodeficiency virus
Foster CB, Lehrnbecher
T, Samuels S, Stein S, Mol F, Metcalf JA et
al.
Blood 2000;96:2562-7.
Kaposi sarcoma (KS) is
an angioproliferative inflammatory condition
that occurs commonly in patients infected with
human immunodeficiency virus (HIV). Inflammatory
cytokines and growth factors promote the development
of KS. Because physiologically important cytokine
polymorphisms modulate host inflammatory responses,
we investigated the association between KS and
common regulatory polymorphisms in 5 proinflammatory
cytokine genes encoding interleukin (IL) IL-1alpha,
IL-1beta, tumor necrosis factor (TNF) alpha,
TNF-beta, and IL-6 and in the IL-1 receptor
antagonist (IL1RN). Authors also examined the
contribution of stromal-derived factor 1 and
chemokine receptor 5 (Delta32) polymorphisms
to KS development. The population consisted
of 115 HIV-infected men with KS and 126 deceased
HIV-infected men without KS. The only strong
association was observed between an IL6 promoter
polymorphism (G-174C) and susceptibility to
KS in HIV-infected men (P=.0035). Homozygotes
for IL6 allele G, associated with increased
IL6 production, were overrepresented among patients
with KS (P=.0046), whereas allele C homozygotes
were underrepresented (P=.0062). Substantial
in vitro evidence indicates that IL-6 contributes
to the pathogenesis of KS. Our results show
that IL6 promoter genotypes associated with
altered gene expression are risk factors for
development of KS. Identification of a genetic
risk factor for development of KS has important
clinical implications for prevention and therapy. |
10 |
Measurement of breast skin
viscoelasticity and a pilot study on the potential
radioprotective effect of a zinc-based cream
Gorodetsky R, Andriessen
A, Polyansky I, Vexler A.
J Wound Care 1999;8:514-8.
Radiation-induced late
skin effects were studied in patients with breast
cancer in relation to different protocols of
fractionated radiotherapy in three different
medical centres, in Israel, the UK and the USA.
The mechanical properties of skin were evaluated
in breasts of healthy volunteers, and non-irradiated
and irradiated breasts of patients, using a
newly developed viscoelasticity skin analyser
(VESA). The increase of the dose of radiation
per fraction was found to have more impact on
the development of radiation-induced late skin
effects than the elevation of the total dose
given. In addition, a pilot sutdy on the possible
radioprotective effect of external application
of a cream containing zinc oxide on radiation-induced
early skin changes in patients with breast cancer
was initiated. Non-invasive measurement of trace
elements and zinc pharmacokinetics in the skin
of healthy controls following the application
of the zinc oxide cream were performed by unique
diagnostic X-ray spectrometry (DXS). Application
of the cream, followed by thorough skin cleansing,
significantly increased the amount of residual
zinc in the skin, but continuous daily treatment
did not cause further build-up of the dermal
zinc level. The radioprotective effect of the
zinc oxide cream on the skin is now being studied. |
11 |
CT-targeted irradiation
of the breast and internal mammary lymph nodes
using a 5-field technique
Scrimger RA, Connors
SG, Halls SB, Starreveld AA.
Int J Radiat Oncol Biol Phys 2000;48:983-9.
The purpose was to develop
an effective and resource-efficient radiotherapy
technique to treat the breast and regional nodes,
including the ipsilateral internal mammary nodes.
Eighty female patients who underwent MRI scans
for a variety of indications had coronal, T1-weighted
images of the chest performed to determine the
position of the internal mammary chain (IMC).
Based on these results, a 5-field treatment
technique was developed that would include the
breast, supraclavicular fossa, and ipsilateral
IMC, while maintaining a low dose to the heart,
lungs, and contralateral breast. This technique
was implemented in a cohort of 13 patients.
The lateral position of the right and left IMC
were measured in three cephalo-caudad positions:
at the clavicular heads, upper manubrium, and
midsternum (at the 2nd/3rd rib interspace).
The mean lateral separation between the right
and left IMC chains at each level (and 95% confidence
interval) at each level were 5.8 cm (4.67-7.00),
5.6 cm (4.49-6.73), and 5.9 cm (4.66-7.19),
respectively. Treatment was delivered to 13
patients using a 5-field technique, with tangential
photon fields for the breast, anterior and posterior
supraclavicular/axillary field, and a matching
anterior electron field. Three-dimensional treatment
planning of a representative case confirmed
adequate coverage of the planning target volume
(PTV). The median dose to the whole heart was
10 Gy, and 20% of the ipsilateral lung received
more than 20Gy. Seven of the 13 patients treated
experienced moist desquamation at the junction
of the electron field and breast tangents, and
1 patient had persistent ulceration at 3 months´
follow-up. The 5-field technique described in
this paper provides good coverage to the breast
and regional nodes with acceptable toxicy, and
without requiring three-dimensional treatment
planning or intensity-modulated radiotherapy
techniques. |
12 |
Preliminary analysis of
a randomized clinical trial of adjuvant postoperative
RT vs. postoperative RT plus 5-FU and levamisole
in patients with TNM stage II-III resectable
rectal cancer
Cafiero F, Gipponi
M, Peressini A, Bertoglio S, Lionetto R.
J Surg Oncol 2000;75:80-8.
Two-hundred eighteen patients
with TNM stage II-III resectable rectal cancer,
enrolled into a randomized clinical trial, were
assessed for efficacy and toxicity of adjuvant
postoperative radiation therapy (RT) vs. those
of combined RT and chemotherapy (CT), with 5-fluorouracil
(5-FU) plus levamisole. End points were overall
survival, disease-free survival, the rate of
loco-regional recurrence, and treatment-related
toxicity. Patients in arm I underwent RT (50Gy)
in daily fractions of 2 Gy, 5 days/week for
5 weeks. Patients in arm II began with 5-FU
(450 mg/m(2)/day intravenous bolus, days 1-5)
plus levamisole (150 mg/day orally, days 1-3);
postoperative RT was delivered during week 2
at the same dosage and schedule as in arm I.
The other five cycles of CT (5-FU every 28 days
and levamisole every 15 days for the length
of 5-FU administration) continued after the
end of RT if clinical and hemato-biochemical
parameters were normal. RT was completed or
modified in 170 (90%) of 189 evaluable patients
undergoing RT (both treatment groups). Only
44 (59%) of 75 evaluable patients of arm II
completed or had an adjustment of the CT schedule;
the remaining 31 patients (41%) had to stop
or never started the CT regimen. Patients undergoing
combined RT and CT had more severe toxicity
(enteritis, P=0.03). There was one CT-related
death (gastrointestinal bleeding) in this subset.
No significant difference was observed in outcome
of patients in the two study groups, nor for
pattern of recurrence (heterogeneity chi (2)=4.82;
d.f.=2; P=0.08). These preliminary findings
suggest a similar efficacy, coupled with less
morbidity, of postoperative RT alone compared
with a combined regimen of postoperative RT
and CT in patients undergoing radical surgery
for stage II-III rectal cancer. |
13 |
A common variant in BRCA2
is associated with both breast cancer risk and
prenatal viability
Healey SC, Dunning
AM, Teare MD, Chase D, Parker L, Burn J et al.
Nature Genetics 2000;26:362-4.
Inherited mutations in
the gene BRCA2 predispose carriers to early
onset breast cancer, but such mutations account
for fewer than 2% of all cases in East Anglia.
It is likely that low penetrance alleles explain
the greater part of inherited susceptibility
to breast cancer; polymorphic variants in strongly
predisposing genes, such as BRCA2, are candidates
for this role. BRCA2 is thought to be involved
in DNA double strand break-repair 1,2. Few mice
in which Brca2 is truncated survive to birth;
of those that do, most are male, smaller than
their normal littermates and have high cancer
incidence 3,4. Here we show that a common human
polymorphism (N372H) in exon 10 of BRCA2 confers
an increased risk of breast cancer: the HH homozygotes
have a 1.31-fold (95% Cl, 1.07-1.61) greater
risk than the NN group. Moreover, in normal
female controls of all ages there is a significant
deficiency of homozygotes compared with that
expected from Hardy-Weinberg equlibrium, whereas
in males there is an excess of homozygotes:
the HH group has an estimated fitness of 0.82
in females and 1.38 in males. Therefore, this
variant of BRCA2 appears also to affect fetal
survival in a sex-dependent manner. |
14 |
Obesity and hypertension
independently linked to risk of kidney cancer
in men
Reuters Medical
News http://oncology.medscape.com/reuters/prof/2000/11/11.02/20001101epid004.html
(November 17)
WESTPORT, CT (Reuters
Health) Nov 2 - A new prospective study confirms
that high body-mass index and elevated blood
pressure independently increase the long-term
risk of renal-cell cancer in men, according
to a report in the November 2nd issue of the
New England Journal of Medicine. "Previous
studies have shown that obesity and hypertension
may increase the risk of renal-cell cancer",
Dr. Wong-Ho Chow from the National Cancer Institute,
Bethesda, Maryland, told Reuters Health. The
advantage of this study, she said, is that they
had actual measurements of hypertension and
higher body weight, so they could look at the
dose-response relationship in a more precise
manner. Dr. Chow noted the prospective design
of their study, which included baseline measurements
of body-weight and blood pressure. They also
followed the subjects for cancer incidence,
not cancer mortality, for an average of 16 years.
"As opposed to other studies, in this study,
subject self-reporting does not bias the information",
she added. Dr. Chow and an international team
collected data on 363,992 Swedish men who underwent
physical examination from 1971 to 1992. These
subjects were followed until the end of 1995
or death. Using the Swedish Cancer Registry,
the researcher identified 759 cases of renal-cell
cancer and 136 cases of renal-pelvis cancer
in this cohort. After adjusting the data for
other risk factors, the investigators found
that "compared with men in the lowest three
eighths of the cohort for body-mass index, men
in the middle three eighths had a 30% to 60%
greater risk of renal-cell cancer, and men in
the highest two eighths had nearly double the
risk". In addition, they found "a
direct association between higher blood pressures
and a higher risk of renal-cell cancer".
However, thy did not observe any association
between blood pressure or obesity and renal-pelvis
cancer. Dr Chow told Reuters Health that it
seems that regardless of the level of blood
pressure or body-weight at baseline, if blood
pressure goes up, the risk of renal-cell cancer
goes up, or if weight increases, the risk increases.
"We also have a suggestion that if a patient's
blood pressure is reduced, it may reduce the
risk of renal-cell cancer". Dr. Chow noted
that no one really knows exactly what the mechanism
for this association is, "but hypertension
is so insidious it can cause all kinds of damage
to the kidney and it could make the kidney more
susceptible to other carcinogens", she
explained. In terms of obesity, Dr. Chow said,
obese patients have higher levels of growth
factors, which may be related to an increased
risk of cancer. "We have pretty much confirmed
the relationship between obesity and hypertension
and the risk of renal-cell cancer, which were
not widely known before", Dr Chow concluded.
"I think physicians should advise their
patients that reducing the risk of renal-cell
cancer is one more benefit of controlling weight
and blood pressure", she added. |
15 |
The farnesyl protein transferase
inhibitor SCH66336 synergizes with taxanes in
vitro and enhances their antitumor activity
in vivo
Shi B, Yaremko
B, Hjian G, Terracina G, Bishop WR, Liu M et
al.
Cancer Chemother Pharmacol 2000;46:387-93.
SCH66336 is an orally
active, farnesyl protein transferase inhibitor.
SCH66336 inhibits ras farnesylation in tumor
cells and suppresses tumor growth in human xenograft
and transgenic mouse cancer models in vivo.
The taxanes, paclitaxel (Taxol) and docetaxel
(Taxotere) block cell mitosis by enhancing polymerization
of tubulin monomers into stabilized microtubule
bundles, resulting in apoptosis. We hypothesized
that anticancer combination therapy with SCH66336
and taxanes would be more efficacious than single
drug therapy. We tested the efficacy of SCH66336
and taxanes when used in combination against
tumor cell proliferation in vitro, against NCI-H460
human lung tumor xenografts in nude mice, and
against mammary tumors in wap-ras transgenic
mice. SCH66336 synergized with paclitaxel in
10 out of 11 tumor cells lines originating from
breast, colon, lung, ovary, prostate, and pancreas.
SCH66336 also synergized with docetaxel in four
out of five cell lines tested. In the NCI-H460
lung cancer xenograft model, oral SCH66336 (20
mg/kg twice daily for 14 days) and intraperitoneal
paclitaxel (5 mg/kg once daily for 4 days) caused
a tumor growth inhibition of 56% by day 7 and
65% by day 14 compared to paclitaxel alone.
Male transgenic mice of the wap-ras/F substrain»FVB/N-TgN(WapHRAS)69LlnYSJL1
spontaneously develop mammary tumors at 6-9
weeks of age which have been previously shown
to be resistant to paclitaxel. Paclitaxel resistance
was confirmed in the present study, while SCH66336
inhibited growth of these tumors. Most importantly,
SCH66336 was able to sensitize wap-ras/F mammary
tumors to paclitaxel chemotherapy. Clinical
investigation of combination therapy using SCH66336
and taxanes in cancer patients is warranted.
Further, SCH66336 may be useful for sensitizing
paclitaxel-resistant tumors to taxane treatment. |
16 |
Placebo-controlled trials
needed for interferon alpha treatment of cutaneous
melanoma
Reuters Medical
News http://oncology.medscape.com/reuters/prof/2000/10/10.26/20001025clin003.html
(November 17)
WESTPORT, CT (Reuters
Health) Oct 26 - Because of significant toxicities
and financial costs of interferon therapy, New
York-based researchers do not endorse interferon
alpha as the standard of care for melanomas,
at least "until the results of randomized,
placebo-controlled trials evaluating the survival
advantages of interferon alpha for melanoma
become available". In a report in the October
issue of the Journal of the American Academy
of Dermatology, Drs. Arash Kimyai-Asadi and
Adil Usman of The New York University School
of Medicine, summarized the findings of randomized
trials of interferons for melanoma. None of
the trials reviewed included a placebo group,
the investigators report. Four of the studies
failed to show any statistically significant
overall survival benefit in patients receiving
interferon compared with those receiving only
observation. One study, the researchers note,
found no survival benefit of interferon alpha.
There was, however, a statistically increased
disease-free survival in patients with melanoma
thicker than 1.5 mm who were randomized to interferon
alpha or to observation alone. Another study
comparing patients who received interferon alpha
with those who were only observed showed a decreased
rate of metastases in patients who received
interferon alpha, they add. A study published
in 1996 was the first and only trial to show
a statistically significant survival benefit
in subjects receiving interferon alpha. Among
patients with "melanomas either deeper
than 4 mm or with clinically or histologically
evident lymph node metastases", statistically
significant 0.7-year and 1-year increases in
disease-free survival and overall survival,
respectively, were observed. "In summary,
the randomized trials of interferons for melanoma
fail to show an overall survival benefit",
they conclude. "Any prolongation in disease-free
survival can be explained by the placebo effect,
and any such prolongation without a concomitant
prolongation in life expectancy is of questionable
value in light of the significant toxicities
of interferon therapy". |
17 |
Phase I clinical trial
of a recombinant canarypoxvirus (ALVAC) vaccine
expressing human carcinoembryonic antigen and
the B7.1 co-stimulatory molecule
Cassidy J.
http://oncology.medscape.com
The generation of cytotoxic
effector T cells requires delivery of two signals,
one derived from a specific antigenic epitope
and one from a costimulatory molecule. A phase
I clinical trial was conducted with a non-replicating
canarypoxvirus (ALVAC) constructed to express
both human carcinoembryonic antigen (CEA) and
the B7.1 costimulatory molecule. This was the
first study in cancer patients to determine
if the delivery of costimulation with a tumor
vaccine was feasible and improved immune responses.
Three cohorts of six patients, each with advanced
CEA-expressing adenocarcinomas, were treated
with increasing doses of an ALVAC-CEA-B7.1 vaccine
(4.5x106, 4.5x107, and 4.5x108 plaque-forming
units, PFU). Patients were vaccinated by intramuscular
injection every 4 weeks for 3 months and monitored
for side-effects, tumor growth and anti-CEA
immune responses. ALVAC-CEA-B7.1 at doses up
to 4.5x108 PFU was given without evidence of
significant toxicity or autoimmune reactions.
Three patients experienced clinically stable
disease that correlated with increasing CEA-specific
precursor T cells, as shown by in vitro interferon-<Gamma>enzyme-linked
immunoassay spot tests (ELISPOT). These three
patients underwent repeated vaccination resulting
in augmented CEA-specific T cell responses.
This study represents the first use of costimulation
to enhance antitumor vaccines in cancer patients.
This approach resulted in CEA-specific immunity
associated with stable diseases in three patients.
This study also demonstrated that CEA-specific
T cell responses could be sustained by repeated
vaccinations. Although the number of patients
was small, the addition of B7.1 to virus-based
vaccines may improve immunological and stable
diseases to vaccination against tumor-associated
antigens with tolerable toxicity. |
18 |
... (from Yugoslavia)
Glas osiguranika
2000;(21):1-2.
The newly elected Serbian
Minister of Health, Dr Nada Kostic, has been
working at the Clinical Hospital Center "Dr
Dragisa Misovic" since 1984. She specialized
in endocrinology. She says that she sees her
life, first of all filled with her work with
patients but also with giving lectures to
students of the Faculty of Medicine. She is
supposed to change her title of a docent into
the title of a professor, soon, according
to the regulations of law.
|
19 |
... (from Yugoslavia)
Glas osiguranika
2000;(21):1-2.
According to the words
of Nebojsa Janovski, who is the coordinator
for health within the G17 Plus, which is the
non-governmental expert organization, whose
members are chosen according to the criteria
of expertise and ethical behaviour, this organization
and the Independent syndicate of doctors and
pharmacists of Serbia have joined their mutual
efforts for doing the some job. During the first
phase, the situation in the health system was
analyzed, the second phase implies a search
for the urgent solutions, which would lead to
the improvement of the current situation in
the health system, while the third phase is
characterized by the long-term projects. Among
others, the urgent solutions consider the acceptance
of the humanitarian aid. The problem are also
the medications, which, as was emphasized by
Janovski, come at the end of the medical procedure,
as well as the importance of the diagnostic
processes. The diagnosing is a specific problem
- many health facilities are short on the equipment:
the chemicals or the key apparatuses, which
causes the enormous crowds in the health care
centers, insisting in the hospitalized treatment,
which is, again, very expensive, etc.
G17 Plus, tries to point out the basic problems,
and as we are facing the limited material possibilities,
the need for saving and economical use of goods
was emphasized.
The qualitative health protection can be expected
only after the process of "healing"
of the health system itself. |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Volume 7 |
Issue 1 |
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News
1 |
Hepatocellular carcinoma
(HCC) is a common tumor world-wide with extremely
poor prognosis. Recent studies have shown that
inositol hexaphosphate (IP6), a naturally occurring
carbohydrate, has novel anti-cancer function
in various in vitro and in vivo models. The
aim of this study was to assess whether IP6
could inhibit the growth of human hepatocellular
carcinoma. We treated HepG2, a human liver cancer
cell line in vitro with IP6 and evaluated its
effect on growth and differentiation. IP6 treatment
of HepG2 cells caused a dosedependent growth
inhibition. Compared to other cancer cell lines,
HepG2 cells were quite sensitive to IP6 IC50
(50% inhibition of cell growth) of IP6 being
<1.0 mM (0.338 mM). Treatment with IP6 decreased
the ability of HepG2 cells to form colonies,
as assessed in the plating efficiency assay.
Morhpological changes induced by IP6 drastically
decreased the rate of production of a-fetoprotein
(AFP), a tumor marker of HCC, indicating also
that IP6 treatment leads to differentiation
of malignant liver cells. Further, IP6 treatment
caused a decreased expression of mutant p53
protein in HepG2 cells, with no significant
change in the expression of wild-type p53. The
expression of p21 WAF1 protein was increased
by 1.5 fold, as determined by immunocytochemical
staining and ELISA assay. These data demonstrate
that IP6 inhibits the growth, and induces differentiation,
and a less agressive phenotype of HepG2 cells,
suggesting a role of IP6 in the treatment of
HCC. |
2 |
99mTc-MIBI retention
index quantified from its early and delayed
sintigraphy is a good indicator to predict the
chemosensitivity of anthracyclines in unterated
breast cancer. |
3 |
Metallothionein (MT),
acting as an antioxidant and zinc binding protein,
may play an important role in regulation of
apoptosis. Its differential expression has been
documented in various human tumours.The incidence
of APC in HCC was markedly higher than that
in control liver of adjancent cirrhotic liver.
The negative correlation of numbers of APC with
MT expression was statistically significant.This
investigation is important in understanding
the mechanisms of the drug resistance of tumour
cells, and may help to design better treatment
strategies. |
4 |
Results of the experiments
indicate that oltipraz has a dose-dependent
inhibitory effect on HBV replication and specifically
blocks HBV transcription in 2.2.15 cells. In
addition, oltipraz induces endogenous wild-type
p53 protein in a dose- and time-course-dependent
manner. Taken together, we speculate that the
effects of olitpraz against replication of HBV
and specific blocking of HBV transcription may
be through the induction of p53-mediated pathway
in 2.2.15 cells. In addition to its known chemopreventive
action on aflatoxin B1 hepatocarcinogenesis,
oltipraz was shown here to inhibit HBV replication.
These dual effects put oltipraz as the excellent
candidate for the chemopreventive agent of human
hepatocellular carcinoma. |
5 |
Cyclooxygenease-2 has
been reported to play an important role in colorectal
carcinogenesis. The effects of meloxicam (a
COX-2 inhibitor) on the growth of two colon
cancer cell lines that express COX-2 (HCA-7
and Moser-S) and a COX-2 negative cell line
(HCT-116) were evaluated. The growth rate of
these cells eas measured folowing treatment
with meloxicam. HCA-7 and Moser-S colony size
were siginificantly reduced following treatment
with meloxicam; however, there was no significant
change in CHT-116 colony size with treatment.
In vivo studies were performed to evaluate the
effect of meloxicam on the growth of HCA-7 cells
when xenografted into nude mice. We observed
a 51% reduction in tumor size after 4 weeks
of treatment. Analzsis of COX-1 and COX-2 protein
levels in HCA-7 tumor lysates revealed a slight
decrease in COX-2 expression levels in tumors
taken from mice treated with meloxicam and no
detectable COX-1 expression. Here we report
that meloxicam significantly inhibited HCA-7
colony and tumor growth but had no effect on
the growth of the COX-2 negative HCT-116 cells. |
6 |
The p16 protein is an
inhibitor of cyclin-dependent kinase 4 (Cdk4)
and is encoded by the multiple tumor-supressor
1 gene, called also MTS1, CDKN2, or p16INK4agene
. The tissues were microdetected to enrich tumor
cell content of the samples and the isolated
genomic DNAs were amplified for CDKN2 gene,
exon 1 and 2, resulting into analyzable products
of 156 bp, 245 bp and 190 bp. The exon 2 amplification
products of 245 bp were screened for point mutations
using PCR-SSCP. All samples harvested the studied
regions of exon 1 and 2 of the gene and hence
no deletions were detected. No mutations in
the analyzed 210 bp gene region were observed
in the particular patient specimens. These results
suggest that mechanisms other than genetic alterations
(by transcriptional or post-transcriptional
mechanisms)might be important for inactivation
of the p16 gene product in late stage metastatic
melanoma. |
7 |
The characterization
of the genes encoding melanoma-associatioed
antigens MART-1 or gp 100, recognized by T cells,
has opened new possibilities for the development
of immunization strategies for patients with
metastatic melanoma. With the use of recombinant
adenoviruses expressing either MART-1 or gp100
to immunize patients with metastatic melanoma,
we evaluated the safety, immunologic, and potential
therapeutic aspects of these immunizations.
Recombinant adenoviruses expressing MART-1 or
gp100 were safely administred. One of 16 patients
with metastatic melanoma receiving the recombinant
adenovirus MART-1 alone experienced a complete
response. Other patients achieved objective
responses, but they had received IL-2 along
with an adenovirus, and their responses could
be attributed to the cytokine. Immunologic assays
showed no consistent immuniyation to the MART-1
or gp100 transgenes expressed by the recombinant
adenoviruses. High levels of neturalizing antibody
were found in the pretreatment sera of the patients.
High doses of recombinant adenoviruses could
be safely administered to cancer patients. High
levels of neutralizing antibody present in patients´
sera prior to treatment may have impaired the
ability of these viruses to immunize patients
against melanoma antigens. |
8 |
The relationship between
cutaneous malignant melanoma and sunlamp use
was examined in a Caucasian population in Connecticut.Study
subjects consisted of 624 newly diagnosed cases
of first primary invasive cutaneous malignant
melanoma and 512 controls.141 (23%) cases and
95 (19%) controls reported ever having used
sunlamps. Those who used more than one type
of sunlamp had a threefold higher risk for melanoma
compared to never users. Subgroup analyses showed
that sunlamp use was associated with a greater
increase in risk for melanoma among those who
used sunlamps at home and those who were first
exposed to sunlamps prior to 1971. The first
use of sunlamps before the age of 25 showed
somewhat higher risk for melanoma compared to
first use later in life. |
9 |
A case-control study
was performed with 129 cases of colorectal carcinoma
in situ and 258 matched controls, in Tokyo from
January 1991 to March 1993.
There was a significant, positive association
between serum total cholesterol levels and the
risk of colorectal carcinoma in situ after adjustment
for age, sex, body mass index, smoking status
and alcohol consumption.
A modest increase of colorectal carcinoma in
situ risk was observed in the highest category
(>=116 mg/dl) of fasting plasma glucose levels.
The strong association with serum triglyceride
levels and the weak association with fasting
plasma glucose levels support the hypothesis
that hyperinsulinaemia may play an important
role in colorectal carcinogenesis. |
10 |
This study explored
the ecologic relationship between pancreatic
cancer incidence and measures of cigarette smoking,
income, and solid waste collection for Florida‘s
67 counties.
County-specific incidence rates for pancreatic
cancer ranged from 0 to 9.1 per 100 000 per
year and were significantly correlated with
income (r = 0.35), cigarette smoking (r = 0.47).
The correlation between pancreatic cancer and
solid waste was largely attributable to one
sub-component of solid waste, yard trash (grass
clippings, and tree and shrub trimming) (r =
0.42).
These data suggest that some factor associated
with grass and tree trimmings, e.g. insecticides
and herbicides, may increase the risk for pancreatic
cancer. |
11 |
The case group comprised
105 patients with newly diagnosed papillary
thyroid carcinoma. Of the 2 control groups the
first one was recruited among patients with
injuries, and the other was composed of patients
with polznodose nontoxic goiter. When cases
were compared with the first control group,
the following factors were significatly related
to papillary thyroid cancer: residence at an
endemic goiter area, goiter, diagnostic X-rays,
other malignant tumors in personal history and
malignant tumors in first and second degree
relatives. When cases were compared with the
second control group, papillary thyroid cancer
was related with other primary tumors in personal
history and malignant tumors in family members. |
12 |
The discordance rate
between clinical and autopsy doagnoses of malignant
neoplasms is large. This conclusion is based
upon a study of a review of 1105 cases (654
male and 451 female) with a mean age of about
48 years. Four hundred thirty-three neoplasms
were detected, 250 of which were malignant.
One hundred eleven malignant neoplasms in 100
patients had been either undiagnosed or misdiagnosed.
In 57 patients the malignant neoplasm was defined
as the direct cause of death. The discordance
between clinical and autopsy diagnoses of malignant
neoplasms in the study was of 44%. Respiratory
and gastrointestinal tract were the most frequently
missed or misdiagnosed. |
13 |
These are the results
of a large randomized, confirmatory trial which
included 1387 patients with metastatic prostate
cancer. All had bilateral orchidectomy, 700
were randomly assigned to receive flutamide
and 687 received placebo. The use of flutamide
did not significantly improve prognosis overall
or in a subgroup of patients with minimal disease. |
14 |
In retrospective, non-radnomized
study were analyzed 45 patients with local recurrences
of rectal carcinoma treated by combined external
beam radiotherapy (EBRT) and "High dose
rate (HDR) remote afterloading" brachytherapy
in the period from January 1st, 1988 to May
1st, 1988. Depending on the localization of
the local recurrent disease, 20 patients were
with vaginal relapase, 13 with vaginal and presacral,
9 with perineal and 3 with presacral and rectal.
Combined radiotherapy was applied as follows:
33 patients (73.3%) had EBRT with endovaginal
brachytherapy, 3(6.7%) EBRT plus intraluminal
brachytherapy and 9 (20%) patients EBRT plus
interstitial brachytherapy. Techniques with
3 and 4 field for EBRT were used and doses ranged
45-65 Gy with conveniet fractionation were applied,
combined with the doses ranged 15-35 Gy for
brachytherapy. Radiotherapy was planned according
to the computer tomography cross image on simulator
with computer planning. Complete regression
of the tumor was observed in 19 patients (42.2%),
and partial in 23 patients (51.1%). Median followup
period was 34 months (8-72). Acute radiation
adverse effects were registered in 32 patients,
and late sequels in 6 (13.3%). Overall 3-year
survival rate was 54% and desease-free survival
rate was 34% in the same period. |
15 |
Currently there are
at leas 22 countries world-wide where national,
regional or pilot population-based breast cancer
screening programes have been established. The
1990 survey was sent to ten contries in the
IBSN-international breast cancer screening Net-Word
and was completed by nine countries. The 1995
survey was sent to and completed by the 13 countries
in the organization at that time and ad additional
nine countries in the European Network. The
programmes vary in how they have been organized
and have changed from 1990 to 1995.
The most notable change is the increase in the
number of countries that have implemented or
plan to implement an organized breast cancer
screening programme. a second major change is
in guidelines with age 50 being the lower age
limit recommended for initiation of mammography
screening in about two-thirds of countries.
The screening interval for women over 50 years
of age is 2 years in most contries.
There is much greater variation among countries
in the upper age limit for screening, with age
69 set by about half the contries.
Mammography is the dominant detection method;
clinical examination of the breast is performed
in addition to mammograpy on only eight countries
and breast self-examination is added as a third
method in four countries. |
|
MISCELLANEUS |
1 |
The Society of Physicians
of Vojvodina has made a decision to start an
informative journal "VOX MEDICORUM".
Being a physician, you can fully perceive health
problems and problems of our profession, so
you are kindly asked to write your opinions,
attitudes and viewpoints in regard to them in
our informative journal. In this way you have
an opportunity to turn to the auditorium of
5000 physicians in Vojvodina who will most certainly
welcome your ideas, wellintentioned suggestions
and useful advice. Please be so kind to write
your suggestions considering the profile of
our journal as well as possibility of your financial
support. Expecting your letters, thank you in
advance.
Vox Medicorum 1999;1:3. |
2 |
Platform of the Assembly
of the Medical Society of Serbia E Society of
Physicians of Vojvodina
The Assembly of the MSS-SPV. The Platform consists
of items as follows:
1. It is necessary to solve the material status
of the health care system as well as the position
of health workers.
2. The Medical Society of Serbia has to be an
influential and relevant partner to Ministry
of Health in creating strategy and realization
of vital measures in providing health care for
all.
3. It is necessary to derogate the present bylaw
and other acts which regulate activities of
the Medical Association of Serbia and pass the
law on Medical Association according to suggestions
of MSS, whereas till the beginning of work of
Medical Association or in case it stops working,
MSS is obliged to take its activities in accordance
with the law.
4. Respect only professional and scientific
competence when selecting persons for managerial
positions in health institutions.
5. Obtain full publicity of activities, principles
and ways of acquiring health insurance money
and of financial distribution.
6. Absolute respect of ethical and moral principles
in medicine and condemnation of all who have
violated them recently.
7. Respect for the autonomy of the University
and request for full democratization of the
society.
8. MSS-SPV has not been fully informed by MSS
and it has not respected requests of MSS-SPV,
so in the future we expect members of MSS-SPV
to be regularly, timely and adequately informed
on activities and events in MSS and gain timely
responses on their requests.
Vox Medicorum 1999;1:5. |
3 |
Vice-president of the
Executive Council of Vojvodina, Prof. Dr. Pavle
Budakov and Provincial Secretary of Health,
Prof. Dr. Dragoljub Zoricic made an official
visit to the Institute of Oncology, that is
Center of Diagnostic Imaging, on January 21,
1999. On this occasion they were introduced
with the new diagnostic equipment: Computerized
Tomograph (CT) and a new ultrasonography apparatus
and had a conversation with the director of
the Institute and manager of the Center of Diagnostic
Imaging. The guests were informed about the
4-year achievements of the magnetic resonance
imaging, as well as with the first results achieved
after purchasing a new scanner. It has been
stated that our patients are mostly from Vojvodina,
especially from Novi Sad where these highly
specialized institutions are localized, and
that problems the Center of Diagnostic Imaging
faces are mostly financial due to irregular
payments of their services. The esteemed guests
were pleased that such an outstanding diagnostic
center was founded in Vojvodina and on this
occasion promised support in further development
of th is Center, as well as improvement of entire
health care system in Vojvodina.
Mladen Prvulovic |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 2 |
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News
1 |
The study group comprised
170 patients with colorectal carcinoma who had
been opereted in Bydgoszcz (Poland) between
1994 and 1997. Prior to surgical intervention,
all patients submitted a through history concerning
familial colorectal cancer or other neoplasms.
Group I - families with HNPCC features (heredetary
non-polyposis colorectal cancer; group II -
HNPCC suspicion in the family; group III - sporadic
colorectal cancer cases - singular colorectal
cancer cases in the family. Authors noted 4
families complying with ICG-HNPCC criteria (2.4%)
and 21 families with suspicion of HNPCC (12.3%).
The remaining 145 patients (85.3%) presented
with sporadic colorectal cancer cases. The results
demonstrate, that nearly 15% of colorectal cancer
patients operated upon in our clinic are of
familial origin. The percentage of families
with HNPCC amounts 2.4%. |
2 |
Agw-adjusted liver cancer
mortality rates have been increasing for both
men and women in Japan since 1970: however,
increases in mortality rates in men are much
greater than those in women. Alcohol consumption
is more important than hepatitis C virus infections
as a major cause of liver cancer deaths in Japanese
men. |
3 |
In surveys done by International
Psycho-Oncology Society a decade apart in 1986
and 1996, the frequency of revealing the diagnosis
of cancer to the patients varies from less than
25% in several countries, and up to 90% in countries
such as the US. However, orrespective of cultural
factors, oncologists must often give bad news
and do it in the most kind and sensitive way.
It is more important how bad news is given than
the words that are actually used. |
4 |
Authors examined the
influence of tumor stage on the circulating
levels of Vascular Endothelial Growth Factor
(VEGF) in sera from breast cancer patients.
Thirty women with breast cancer who were studied
did not receive any prior therapy. In patients
with stage IV breast cancer there was a significant
increase in VEGF levels compared to stage II
disease. The study suggests that large tumor
burden was associated with significantly increased
serum levels of VEGF. |
5 |
Changes over time of
mortality rates from cutaneous malignant melanoma
(CMM) in Belgium were analysed, based on people
(n=3695) aged 25-84 years, who died of CMM from
1954 to 1992. The age-adjusted mortality rates
(per 10 5 ) for the age sroup 25-84 years old
increased from 0.5 in 1954 to 3.0 in 1992 in
men, and from 0.8 in 1954 to 2.2 in 1992 in
women. The average annual percentage change
in men (-0.003%) was stable over the period
1973-1982, and increased to 4.4% over the period
1983-1992. In women, the average annual increase
was 4.6% over the period 1973-1982, and continued
to increase to 6.8% over the period 1983-1992. |
6 |
Three cases of women
with chronic liver inflammation caused by hepatitis
B (two) and C (one) viral infections, were followed
up to twelve years after diagnosis. As conventional
therapy was ineffective and the patients progressed
into decompensated liver disease, they superinfected
with massive doses of an attenuated variant
(MTH-68/B) of the apathogenic avian Bursal Disease
virus. Clinical symptoms and biochemical abnormalities
were resolved in two patients. Cirrhosis was
stabilized and significant clinical improvement
was achieved in the third patient - who before
the virus therapy was moribund. |
7 |
The angiogenic factors
Platelet Derived Endothelial Cell Growth Factor
(PD-ECGF), basic Fibroblast Growth Factor (bFGF)
and Vascular Endothelial Growth Factor (VEGF)
were determined immunohistochemically in 168
non-small cell lung carcinomas to investigate
whether the expression of these parameters is
correlated with lymph node metastasis of patients.
Only 43% of the patients had lymph node involvement
when all factors were negative whereas 77% showed
metastasis when all factors were positive (one
factor positive: 53%, two factors positive:
68). |
8 |
Growth factor-stimulated
phospholipase D (PLD) catalyzes the hydrolysis
of phosphatidycholine generating phosphaditic
acid which may act as a second messenger during
cell proliferation. Authors measured PLD activity
in human gastric carcinoma to evaluate its role
in gastric carcinogenesis. The mean ratio of
PLD activity in gastric carcinoma and adjacent
noncancerous mucosa was 1.63. This ratio was
significantly higher in patients with larger
tumors (>=5cm). |
9 |
Sixty nine patients
with urogenital cancers (renal, bladder and
prostate cancer) were studied to determine whether
the serum concentrations of Vascular Endothelial
Growth Factor (VEGF) and basic Fibroblast Growth
Factor (b-FGF) reflected the status of the patients
and/or the prognosis of the disease. Renal cell
carcinoma patients expressed the highest levels
of VEGF indicating that these tumors are more
VEGF dependent. The values of b-FGF could be
considered normal in all three malignancies.
No correlation was observed between the expression
of VEGF and b-FGF, nor between VEGF and b-FGF
and patients survival. |
10 |
New drugs registrations
adopted up to June 30, 1998. List of drugs with
the permition for usage of the Federal Ministry
for Work, health and Social Welfare up to June
30, 1998:
- cytostatic antibiotics: Daunorubicin-Hlorid
and Darubicin;
- other drugs for neoplasm therapy: Irinotekan. |
11 |
Besides anatomically-based
radiodiagnostics, functional imaging may be
used for characterizing soft tissue sarcomas
(STS). This study evaluates positron emission
tomography (PET) with three different radiotracers
(fluorine-18 deoxyglucose (FDG), carbon-11 aminoisobutyric
acid <sup>a</sup>AIB<sup>o</sup>
and oxygen-15-labeled water <sup>a</sup>015-water<sup>o</sup>)
for imaging STS and the detection of local recurrence.....Besides
FDG, AIB and 015-water were shown to accumulate
in primary and recurrent STS of different histologic
type. A precise differentiation from normal
muscle was found for all tracers. FDG and AIB
differentiated biable tumor from blood vessels.
PET using FDG, AiB and 015-water is suitable
for functional imaging of STS and the detection
of sarcoma recurrence. |
12 |
This study evaluates
the tolerance and efficacy of Intraperitoneal
Chemohyperthermia (IPCH) with Mitomycin C (MMC)
associated with surgery, in peritoneal carcinomatosis
of gastric origin....IPCH appears as a safe
new therapeutic approach in gastric cancers
with peritoneal carcinomatosis with small malignant
granulations (stage 1 and 2) and randomized
trials are now needed to clearly evaluate its
efficacy. |
13 |
Several studies have
evidenced that IGF-I may play a role in the
growth regulation of many cancer cell lines,
and recently GH and IGF-1 have been recognized
as stimulators of lymphopoiesis and immune function.
We investigated whether there are differences
among health-old people and old people suffering
from lung cancer at different stages of disease
in the 24-hour secretory profiles of GH und
iGF-1....Lung cancer is associated with an altered
regulation of GH-IGF-1 system, that might play
a role in the clinical course of neoplastic
disease. |
14 |
Serum concentrations
of tumor necrosis factor-a (TNF-a), interleukin
(IL)-1b, IL-2 and IL-6 were determined by enzyme-linked
immunosorbent assay or chemiluminescent enzyme
immunoassay in 46 Japanese patients with metastatic
breast cancer....These results suggest that
IL-6 levels are elevated and may be an aggressive
parameter in patients with metastatic breast
cancer. Higher IL-6 serum levels are found to
predict a poorer response to chemo-endocrine
therapy, and to represent a poorer prognostic
predictor in metastatic breast cancer. |
15 |
Advanced ovarian carcinoma
is a chemosensitive tumor, but its prognosis
is poor with 20 to 30% 5-year survival using
conventional therapy. increasing doses of chemotherapy
might improve the prognosis because of the doseeffect....Toxicity
of HDC with HSCS is acceptable for poor-prognosis
patients. In the long term, this therapy is
not beneficial for chemotherapy refractory patients,
despite objective response rates better than
the conventional treatment, confirming the dose
effect for alkylating agents in ovarian cancer.
On the other hand, the results seem better than
classical therapy in case of chemosensitive
disease and should be confirmed prospectively
in a larger cohort of patients. |
16 |
In patients with H.
pylori infection and noulcer, of functional,
dyspepsia, treatment with omeprazole and antibiotics
to eradicate the infection is more likely to
resolve symptoms than treatment with omeprazole
alone. These are the results of a randomized,
placebocontrolled trial comparing the efficacy
of treatment for two weeks with 20 mg of omeprazole
orally twice daily, 500 mg of amoxicillin three
times daily (with 500 mg of tetracycline three
times daily substituted for amoxicillin in patients
allergic to penicillin), and 400 mg of metronidazole
three times daily (160 patients) with that of
omeprazole alone (158 patients) for resolving
symptoms of dyspepsia in patients with H. pylori
infection but no evidence of ulcer disease on
upper gastrointestinal endoscopy. One month
after the completion of treatment, 132 of 150
patients (88%) in the group assigned to receive
omeprazole and antibiotics tested negative for
H. pylori as compared with 7 of 152 (5%) in
the omeprazole-alone group. One year later,
dyspepsia had resolved in 33 of 154 patients
(21%) in the omeprazole and antibiotics group,
as compared with 11 of 154 (7%) in the omeprazole-alone
group (95% Cl: 7%-22%; p<0.001).
....preoperative chemotherapy with a combination
of cisplatin and fluorouracil does not improve
overall survival among patients with epidermoid
cancer or adenocarcinoma of the esophagus. |
17 |
The loss of DNA mismatch
repair system was reported in hereditary non-poliposis
colon cancer and in other tumours. The aim of
this study was to detect the protein expression
pattern of hMSH2 and hMLH1 in oral squamous
cell carcinoma (SCC) by immunohistochemistry
in paraffin-embedded tissues.....These data
suggest that examination of hMSH2 and hMLH1
protein expression by immunohistochemistry is
important in oral SCC. The analysis of mismatches
expression in these cases of oral SCC might
suggest that an absent nuclear staining for
both hMSH2 and hML1 could constitute a hallmark
of potential phenotype mutator for this type
of neoplasia. |
18 |
Recent evidence supports
the involvement of integrins in angiogenesis:
blockade of avb5 integrins disrupts angiogenesis
leading to decreased blood vessel formation
and hence decreased tumor growth. We hypothesized
that av antagonistis could inhibit tumor growth
in tumor cells devoid of avb3 integrins. We
evaluated SM256 and SD983, novel small molecules
that are specific av antagonistis in mouse models
of angiogenesis and tumorigenesis, and compared
them with standards....In the mouse xenograft
model, usng human colon carcinoma RKO cells
that do not express avb3 but express avb5, tumor
growth was inhibited by SG 545 (10 mg/kg/day)
and flavopiridol (5 mg/kg/every other day) 40%
and 70%, respectively (p`0.05). Although the
proliferative index (measured by BrdU incorporation)
was not significantly changed with SM 256, SG545
or flavopiridol (29-32%), the apoptotic index
increased significantly (p<0.05) in the SM
256 and SG545-treated groups (2.3-2.7%) compared
with controls (1,1%), suggesting increased cell
death contributed to decreased tumor volumes.
Neovascularization decreased with SM 256 and
SG 545 treatment. The data demonstrate that
potent selective av antagonists can target endothelial
cells, tumor cells, inhibit angiogenesis and
inhibit tumor growth. |
19 |
Topoisomerase I (topo
I) inhibitors are promising anticancer agents
with demonstrated activity against a wide range
of solid tumors. Quantitative information on
topol mRNA levels in tumor bi9psies may predict
response to topo I inhibitors....We conclude
that topol PATTY is a new assay tat quantitates
topol mRNA levels in cell lines and small tumor
samples. |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 3 |
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News
1 |
Twenty four patients
with 38 skin lesions were treated. The patients
were divided in 3 groups: 16 patients with T1N0M0
basal cell carcinoma (group A); 4 patients with
T1N0M0 spin-squamous cell carcinoma (group B);
and 4 patients with disseminated malignant melanoma
(group C). Local injection of lidocaine and
0.5 to 1.5 U bleomycin into the tumor was followed
by application of 3 types of electrical stimuli.
All patients of group A and group B responded
positively to the treatment. Three group C patients
had a positive response with a virtual disappearance
of the metastatic nodules, while in the 4th
patient persistent tumor was histologically
confirmed. |
2 |
Among 417 patients with
DTC treated between 1980-1997, 31 cases (7.5%)
have died from cancer, living 1-10 years (mean
3,3 ±1.8). We compared the main prognostic factors
related to the tumor, host, and treatment modalities
in the lethal group (LG) and the surviving group
(AG) of patients. Age and sex appear to be significant
prognostic factors (p=0.00001). Locally advanced
(68%) and metastatic cases (26%) predominated
in the LG (p=0.007 and p=0.03 respectively).
Thyroidectomy was the surgical treatment of
choice, but in 2/3 of the LG tumor was macroscopically
left behind (p=0.00001). Therefore, more patients
from the LG required aggressive primary radiation
therapy (RT) i.e. external beam (EBRT) and prolonged
131I RT (RIOT) (p=0.007 and p=0.024 respectively).
These patients had mainly G1-G3 papillary tumors.
The vast majority of the LG cases (24/31) showed
perisistent disease. Finally 29 of 31 patients
in the LG developed distant metastases. Although
the difference was not significant, cancer specific
mortality (CSM) was 4% (14 patients) for papillary
cancer, 14% for 12 follicular cancer and 16%
for 5 low differentiated cases. Our study revealed
that persistent disease was the main reason
for death from DTC (78%, p=0.006). We believe
that aggressive primary treatment plays a central
role for the final disease outcome. The percentage
of 7,5% CSM in DTC aligns our results with those
of other investigators. Although the current,
treatment for DTC is efficient, still the "magic
bullet", 131I, misses its target in some
patients. Future research in tumour molecular
biology and patients´ genetics are required
to demarcate those cases bearing lethal potential. |
3 |
Ongoing protocols
1. IELSG 1: Retrospective evaluation of low-grade
MALT lymphoma primarily arising at non-gastric
sites. Registered patients: 267. The accrual
should be completed later 31 May 1999. Chairmen.
Enrico Roggero and Emanuele Zucca.
2. IELSG 3: Randomized trial of observation
vs. chlorambucil after anti-Helicobacter pylori
therapy in low-grade gastric lymphoma. This
UKLG, IELSG and GELA trial is the first randomized
study to assess treatment in this disease. The
recruitment is excellent (180 cases december
1998) and the accrual continues.
3. IELSG 4: Prospective randomized trial of
chemotherapy vs. chemotherapy plus irradiation
in diffuse large-cell gastric lymphoma. Chairmen:
Giovanni Martinelli and Carlo Tondini.
New protocols
1. IELSG 5: Retrospective evaluation of primary
testicular lymphomas. Chairmen: Mary Gospodarowicz,
Tariq Mughal and Umberto Vitolo.
2. IELSG 6: A randomized trial to determine
the effect of consolidation with Rituximab (IDEX
C2B8-Mabthera/Rituxan) in patients with CD 20
+ marginal zone lymphomas who have received
induction therapy. Chairmen: Catherine Thieblemon,
Enrico Roggero.
3. IELSG 7: Retrspective evaluation of Central
Nervous System lymphomas. Chairmen: J. Y. Blay
and Andre´s Ferreri.
4. IELSG 8: retrospective evaluation of intestinal
lymphomas. Chairmen: Sergio Cortelazzo and Carlo
Tondini.
5. IELSG 9: Retrospective evaluation of primary
mediastinal large B-cell lymphomas. Chairmen:
Pier Luigi Zinzani, Maurizio Martelli and Marilena
Bertini.
During the next IELSG meeting that will take
place in Lugano in June 1999 before the Lymphoma
Conference, these protocols will be presented
and discussed. Oncology centers intersted in
these trials can contact the IELSG.
International Extranodal Lymphoma Study group
Trials centre coordination: Oncology Institute
of Southern Switzerland Ospedale San Giovanni
CH-6500 Bellinzona - Switzerland Tel.: +41 91
820 91 11, Fax: +41 91 820 91 82, E-mail: [email protected] |
4 |
Differential polymerase
chain reaction (DPCR) is a sensitive technique
for detecting c-erb-B2 amplification in Mullerian-derived
tumours. Of 25 Mullerian-derived tumours, 17
demonstrated amplified c-erb-B2 by DPCR. The
reexamination of 25 samples by dot blot and
immunohistochemical technique revealed c-erb-B2
amplification and expression of 52.0 and 40.0%,
respectively. The relationship between the amplification
of c-erb-B2 and common prognostic factors such
as grading, stage and survival showed that moderately
and poorly-differentiated tumours of grades
2 and 3, respectively, had a much higher percentage
(68%) of amplified c-erb-B2 gene than well-differentiated
tumours (40%). |
5 |
Preoperative chemotherapy
with a combination of cisplatin and fluorouracil
does not improve overall survival among patients
with epidermoid cancer of adenocarcinoma of
the esophagus. |
6 |
Platinum-based treatment
of ovarian cancer increases the risk of secondary
leukemia. This is the conclusion of a case-control
study of secondary leukemia in a population-based
cohort of 28,971 women in North America and
Europe who had been diagnosed with invasive
ovarian cancer between 1980 and 1993. The relative
risk of leukemia was 4.0 (95% confidence interval
(95%Cl):1.4-11.4). The relative risks for treatment
with carboplatin and for treatment with cisplatin
were 6.5(95%Cl.1.2-36.6) and 3.3 (95%Cl:1.1-9.4),
respectively. The authors found evidence of
a dose-response relation, with relative risks
reaching 7.6 at doses of 1000 mg or more of
platinum (p for trend 0.001). Radiotherapy without
chemotherapy (median dose 18.4 Gy) did not increase
the risk of leukemia. The substantial benefit
that platinum-based treatament offers patients
with advanced disease outweighs the relatively
small excess risk of leukemia, the authors say. |
7 |
The authors conclude
that the familial occurrence in about 6% of
cases of papillary thyroid microcarcinoma is
associated with an unfavourable prognosis, and
suggest a more radical treatment (and careful
follow-up) than for those with no positive family
history. |
8 |
Mycoplasma contamination
of cell cultures is a frequently observed problem.
Authors addressed the question of whether mycoplasma
contamination affects the most frequently used
cytotoxicity assay, the tetrazolium based MTT
assay.They contaminated C6 glioma cells with
mycoplasma and performed MTT assays with doxorubicin,
vincristine, etoposide and cisplatinum under
various conditions. Due to an additional reduction
of tetrazolium by mycoplasmas, contaminated
cells appeared up to 15 fold resistant to doxorubicin,
vincristine and etoposide, but not to cisplatinum.
Differences decreased with decreasing drug doses
and decreasing plated cell count. |
9 |
Data were analysed from
a large case-control study (583 cases, 608 controls)
of malignant melanoma, carried out in southern
Ontario, Canada. Significant risk increases
were identified with several measures of intermittent
exposure, including beach vacations in adolescence
and in the past 5 years, previous sunburn, and
use of sunbeds and sunlamps. Chronic exposure,
indicated by days of outdoor activity during
adolescence and by occupation in recent adult
life, was associated with significantly reduced
risk. Subgroup analyses showed: no major risk
differences by body site of melanoma; stronger
association of lentigo maligna melanoma with
intermittent exposure, more pronounced effects
of beach vacations and sunburn in younger subjects,
and consistently higher risks for intermittent
exposures among subjects with skin more susceptible
to burning. |
10 |
Blood cells of cancer
patients contain greatly elevated amounts of
vascular endothelial growth factor (VEGF), and
this reservoir may have a role in tumor angiogenesis
and metastasis formation. These are the results
of an analysis of VEGF concentrations in serum,
plasma, whole blook, and peripheral blook mononuclear
cells (PBMNCs) and platelets in 56 cancer patients
and 52 healthy controls. The VEGF concentrations
in the lysed whole blook samples were higher
in cancer patients than in healthy controls
(median, 464 vs. 298 pg/ml;P 0.0001). The highest
Blook-VEGF values were found in disseminated
cancer. The cancer patients regularly had higher
Blood -VEGF concentrations than heallty individuals
with comparable leukocyte or platelet counts.
VEGF content of isolated pBMNCs and platelets
was several times higher in cancer patients
than in healthy controls. Very little or no
VEGF was found in the plasma. The authors conclude
that VEGF in the bloodstream is transported
by blook cells, including leukocytes and platelets. |
11 |
There is no convincing
evidence that eradication of H. pylori relieves
the symptoms of functional dyspepsia. This is
the conclusion of a multicentre randomised duoble
blind placebo controlled trial in Australia.278
patients infected with H. pylori who had functional
dyspepsia were randomised to receive omeprazole
20 mg twice daily, amoxicillin 1000 mg twice
daily, and clarithromycin 500 mg twice daily
or placebo for seven days. H. pylori was eradicated
in 113 patients (85%) in the treatment group
and 6 patients (4%) in the placebo group. At
the 12 months follow-up there was no significant
difference betwen patients trated successfully
(by intent to treat) in the eradication arm
(24%, 94% Cl: 17%-32%) and patients treated
successfully in the placebo group (22%, 15%-30%).
Changes in symptom scores and quality of life
did not significantly differ betwen the treatment
and placebo groups. |
12 |
Rituximab is a chimeric
monoclonal antibody directed against the B-cell
CD20 antigen wich has been utilized for therapy
of B-cell non Hodgkin´s lymphoma (NHL). A previous
clinical trial demonstrated that treatment with
four weekly doses of 375 mg/m2 of Rituximab
in patients with relapsed or refractory low-grade
or follicular B-cell non-Hodgkin´s lymphoma
was well tolerated and had significant clinical
activity. The safety profile and efficacy achieved
in this pilot study of extended treatment with
Rituximab compares favorably with those seen
with four weekly doses. Further studies are
warranted to investigate whether this of other
extended Rituximab schedules will result in
increased efficacy in all or in certain subgroups
of patients with low-grade or follicular NHL. |
13 |
Treatment of neuroblastoma
has remained a major challenge in pediatric
oncology because the assessment of the individual
prognosis, particularly in disseminated disease
is still obscure. Previous studies have correlated
clinical outcome with activity levels of telomerase,
a cellular reverse transcriptase which has been
detected in the majority of human malignant
tumors. TA was present in 14 of 69 (20%) samples,
including 3 of 22 stage IVS, 8 of 14 stage IV,
1 of 10 stage III, 1 of 7 stage II and 1 of
14 stage I neuroblastomas and 0 of 2 ganglioneuromas.
We found a strong statistical correlation between
the presence of TA and poor clinical prognosis
with regard to all tumor stages. Multivariate
analysis revealed TA as an independent prognostic
marker.In particular, the analysis of TA in
IVS neuroblastomas distinguished two different
prognostic groups. Our data suggest that TA
is an independent prognostic marker in neuroblastoma
which, in combination with other markers such
as MYCN, may prove useful in assessing the individual
patients´s prognosis. |
14 |
The aim of study was
evaluation of the independence occurence of
CA 15-3 and MCA in serum of women with breast
cancer. Relationship between the concentration
of these antigens and patient age, stage of
the clinical progression, histopathological
grade, presence of metastases to the axillary
lymph nodes and histological type of neoplasm
was evaluated. The studies were carried out
on the serum of 131 women aged 25-81 years (age
average 53 years), treated in the Surgial Department
in the Chair of Oncology at Karol Marcinkowski
Medical University. The MCA concentration was
determined by means of the immunoenzymatic assay
by Roche (Austria) and the contents of CA 15-3
was obtained due to the Abbott immunofluorescent
method (U.S.A) The study showed that CA 15-3
and MCA serum concentrations in healthy women
remained within acceptable values. A slight
percentage of the increased antigen concentrations
was revealed in the serum of women with a benign
breast neoplasm. However, in women with breast
cancer there was the most significant level
of CA 15-3 (40%) and of MCA (31.4%). The higher
clinical stage the higher median of CA 15-3
concentration was noted. There is no such a
correlation as far as MCA is concerned. The
higher the histological grade the lower the
value of CA 15-3. The data analyses indicated
that the biggest percentage of elevated results
was MCA and CA 15-3 in the serum of women with
lobular cancer. The study suggests some valuable
hints how to determine antigens in the serum.
Especially CA 15-3 can put forward information
helpful to establish a diagnosis. It may also
be needed as far as the assessment of the clinical
stage of the disease is concerned. It also has
prognostic value. |
15 |
The epidemiology and
molecular biology of colorectal cancer are reviewed
with a view to understanding their interrelationship.
Risk factors for colorectal neoplasia include
a positive family history, meat consumption,
smoking, and alcohol consumption. Important
inverse associations exist with vegetables,
nonsteroidal anti-inflammatory drugs (NSAIDs),
hormone replacement therapy, and physical activity.
There are several molecular pathways to colorectal
cancer, especially the APC (adenomatous polyposis
coli)-b-catenin-Tcf (T-cell factor; a transcriptional
activator) pathway and the pathway involving
abnormalities of DNA mismatch repair. These
are important, both in inherited syndromes (familial
adenomatous polyposis aFAPo and hereditary nonpolyposis
colorectal cancer aHNPCCo, respectively) and
in sporadic cancers. Other less well defined
pathways exist. Expression of key genes in any
of these pathways may be lost by inherited or
acquired mutation or by hypermethylation. The
roles of several of the environmental exposures
in the molecular pathways either are established
(e.g., inhibition of cyclooxygenase-2 by NSAIDs)
or are suggested (e.g., meat and tobacco smoke
as a source of specific blood-borne carcinogens;
vegetables as a source of folate, antioxidants,
and inducers of detoxifying enzymes). The roles
of other factors (e.g., physical activity) remain
obscure even when the epidemiology is quite
consistent. There is also evidence that some
metabolic pathways, e.g., those involving folate
and heterocyclic amines, may be modified by
polymorphisms in relevant genes, e.g., MTHFR
(methylenetetrahydrofolate reductase) and NAT1
(N-acetyltransferase 1) and NAT2. There is at
least some evidence that the general host metabolic
state can provide a milieu that enhances or
reduces the likelihood of cancer progression.
Understanding the roles of environmental exposures
and host susceptibilities in molecular pathways
has implications for screening, treatment, surveillance,
and prevention. |
16 |
MELANOMA CENTER OPENED
AT THE MEDICAL CENTRE OF BEZANIJSKA KOSA
- The instrument "mole max 2" can
register all pigmentary akin lesions
- The price of the examination is 100 YU dinars
The Medical Centre of Bezanijska Kosa has got
a new centre for the early discovery of skin
cancers - "Melanoma Centre", which
is a single and unique one in the Balkans. Any
pigmentary skin lesion can be examined there
by the instrument "mole max 2" and
highly skilled medical professionals. |
17 |
A gene known as the
fragile histidine triad (FHIT) gene has been
identified as a tumor suppressor gene and shown
to be altered in numerous types of cancer. Eighty
percent of women with breast cancer who have
a defect in the BRCA2 gene also have loss of
heterozygosity in the FHIT gene, compared with
40% of women whose breast cancer is not associated
with an inherited genetic defect (known as sporadic
breast cancer). Based on data presented by Carlo
Croce's group, this suppressor gene seems to
be more ubiquitous. In his award lecture Dr
Croce emphasized that this new suppressor gene
could be a very common finding in many tumors,
probably more so than a mutated p53. |
18 |
Liver involvement is
an important problem in colorectal cancer, which
is present in 40%-70% of patients with metastatic
disease. However, the liver is the sole site
of metastases in only about half of the cases
. Stangl et al. determined the natural history
of colorectal liver metastases in a recent prospective
series on 1099 patients. Thirty-one percent
of the patients underwent liver resection and
complete tumor clearance was achieved in 78%
of those cases. The five-year survival was 32%
after hepatic resection. In contrast, if surgery
was not possible the median survival of patients
receiving chemotherapy or no treatment was 12
and 7.5 months, respectively. It can be concluded
from this and other large series, that unresectable
liver metastases from colorectal cancer are
nearly always fatal within five years. After
liver resection, about 40% of the recurrences
seem again confined to the liver and a three-year
survival of 33% has been reported in this situation.
However, more often relapses occur outside the
liver. This underlines the need for better diagnostic
tools to screen patients for extrahepatic disease
before surgery. Promising options are whole-body
positron emission tomography with (fluorine-18)-2-fluoro-2-deoxy-D-glucose
or the detection of genetic material of micrometastases
by molecular amplification methods. Despite
the fact, that adjuvant chemotherapy has been
proven very successful in primary colorectal
cancer, there is only recent evidence of a benefit
after liver surgery. |
19 |
Angiogenesis, the process
whereby endothelial cells divide and migrate
to form new blood capillaries, has been assessed
in tumours by measuring microvessel density.
High microvessel density is a significant adverse
prognostic factor in breast cancer. The angiogenic
factor, basic fibroblast growth factor (bFGF),
has been associated with tumorigenesis and metastasis
in several human cancers. There are few quantitative
studies of bFGF expression in normal tissues
compared to cancer. Levels of bFGF were more
than 10-fold higher in tumour cytosols compared
to reduction mammoplasty tissue and 3-fold compared
to non neoplastic cytosols from the same breast
as the tumour (P`0.0001). Immunohistochemistry
showed bFGF protein was localised exclusively
in the stroma whereas no bFGF staining was observed
in the epithelial cells. High bFGF levels were
significantly related to high ER (P=0.01). Similarly,
high bFGF levels were significantly related
to low grade (P=0.046), and to small tumour
size (P=0.04). No significant relationship was
obeserved between bFGF and microvessel count,
EGFR or age. In univariate analysis and in a
Cox proportional hazard model bFGF did not reach
significance for overall or relapse free survival.
Their results show that although bFGF is elevated
in breast carcinomas compared to normal breast
tissue it is not related to microvessel density
and it is not an independent predictor of survival
in breast cancer patients. Basic FGF may be
one of multiple factors that synergise with
other growthfactors such as VEGF to enhance
angiogenesis. |
20 |
The principal agent
in the etiology of cervical cancer, i.e., human
papillomavirus (HPV) type 16, encodes three
oncoproteins, E5, E6, and E7. Structural and
mutational studies have identified two potential
zinc-finger domains as critical for E6 protein
function. We investigated several assays to
identify and characterze compounds that interfere
with the binding of zinc to E6. Methods: Thirty-six
compounds vere selected on the basis of their
structure, which would facilitate their participation
in sulfhydryl residue--specific redox reactions,
and were tested for their ability to release
zinc from E6 protein. The zinc-ejecting compounds
were then tested for their ability to inhibit
E6 binding to E6-associated protein (E6AP) and
E6-binding protein (E6BP),two coactivators of
E6-mediated cellular transformation. The binding
of E6 to E6BP and E6AP was measured by use of
surface interactions by measuring changes in
refractive index) and by use of in vitro translation
assays. The compounds were also tested for their
effects on the viability of HPV-containing cell
lines. Nine of the 36 tested compounds ejected
zinc from E6. Two of the nine compounds inhibited
the interaction of E6 with E6AP and E6BP, and
one of these two, 4,4´ - dithiodimorpholine,
selectively inhibited cell viability and induced
higher levels of p53 protein (associated with
the induction of apoptosis (programmed cell
death) in tumorigenic HPV-containing cells.
We have described assay systems to identify
compounds, such as 4,4´- dithiodimorpholine,
that can potentially interfere with the biology
and pathology of HPV. These assay systems may
be useful in the development of drugs against
cervical cancer, genital warts, and asymptomatic
infections by genital HPVs. |
21 |
The incidence of colorectal
cancer in persons under 46 years of age is substantially
higher in Hong Kong than in Scotland and many
other countries. Consequently, we examined whether
there is a hereditary predisposition for colorectal
cancer in this Southern Chinese population.
Authors investigated the incidence of microsatellite
instability (MSI) at 10 DNA sites in 117 colorectal
cancer specimens from Chinese patients of various
ages. Those tumors with new alleles at 405 or
more of the sites investigated were identified
as highly unstable MSI (MSI-H). In young patients,
we also searched for germline mutations in three
mismatch repair genes (hMSH2, h MLH1, and hMSH6).
The incidence of MSI- H varied statistically
significantly vith age, being observed in more
than 60% of those younger than age 31 years
at diagnosis and in fewer than 15% of those
age 46 years or older. In 15 patients (`46 years
old) whose colorectal cancers showed MSI-H,
eight possessed germline mutations in either
hMSH2 or hMLH1. When mutations in hMSH6 were
included, more than 80% of Chinese colorectal
cancer patients younger than 31 years had germline
mutations in mismatch repair genes. We found
a novel germline missense mutation in hMSH6
in a 29-year-old man whose tumor showed no MSI.
Two patients had a 4-base-pair insertion in
exon 10 causing a truncated protein; this insertion
is a common polymorphism with a population allele
frequency in Chinese of 5.6%. Their results
indicate that germline mutations in mismatch
repair genes contribute substantially to the
pathogenesis and high incidence of colorectal
cancer in young Hong Kong Chinese. However,
because young Chinese and Causasians show similar
proportions of colorectal cancers with MSI-H,
despite the higher incidence in the former,
additional factors may underlie the high susceptibility
of young Chinese to colorectal cancer. |
22 |
Although antifolates
are popular agents for use in chemotherapy,
they display minimal toxicity against slow-growing
tumors and are toxic to actively replicating
cells in nomal tissues. These drugs are converted
intracellularly into polyglutamate derivatives
by the enzyme folylpolygutamyl synthetase (FPGS).
Because tumoris with high expression of FPGS
often respond to nontoxic antifolate doses,
we investigated whether augmenting tumoral FPGS
activity by genedelivery would enhance tumoral
antifolate sensitivity. 9L rat gliosarcoma cells
were stably transfected with a human FPGS complementary
DNA (cDNA), producing 9L/FPGS cells. The sensitivity
of these cells to the antifolates methotrexate
and edatrexate was measured in culture and in
subcutaneous tumors, as was their ability to
increase the chemosensitivity of nearby nontransfected
cells, i.e., a bystander effect. The antifolate
sensitivity of nonselected cells transduced
with a hybrid amplicion vector that expressed
FPGS was also ascertained. Results: In comparision
with 9L cells, 9L/FPGS cells displayed enhanced
sensitivity to 4-hour pulses of antifolate.
Subcutaneous 9L/FPGS tumors responded as well
to methotrexate given every third day as 9L
tumors did to daily treatment. A modest bystander
efect was observed with edatrexate treatment
in culture and in vivo. The observed bystander
effect appeared to result from the release of
antifolates by transfected cells after the removal
of extracellular drug. In culture, enhanced
antifolate sensitivity was also seen in other
stably transfected rodent and human glioma cell
lines, including one with high preexisting FPGS
activity, and in canine and human glioblastoma
cell lines transduced with a vector bearing
FPGS cDNA. FPGS gene delivery enhances the antifolate
sensitivity of several glioma cell lines and
merits. |
23 |
The purpose of this
retrospective study was assessment of correlation
between Tc-99 m sesta MIBI uptake and some prognostic
factors of breast cancer. The following prognostic
factors have been included in this study: size
of the tumour, age of the patients, axilla node
invovlvement, oestrogen and progesterone receptor
(ER, PR) status, grading system of Bloom-Richardson
and Ki-67 antigen expresion. 79 patients were
enrolled in this study, with 85 lesions confirmed
as primary breast cancers. Mean age of patients
was 53 years. Scintimammography (SMM) was performed
after intravenous injection of 740MBq. At 5-10
min after injection standard planar images were
obtained in prone latral and anterior supine
views. Assessment fo correlation between known
prognostic factors of breast cancer and uptake
of MIBI (evaluated as a tumour to background
ratio-TBR) was performed used non-parametric
(Kendall-tau correlation) statistical analysis.
There were 85 breast cancers (73 invasive ductal
carcinomas, 11 DCIS (ductal carcinoma in situ)
and 1 lobular carcinoma. There was positive
correlation between TBR Tc-99m MIBI uptake and
size of the tumour (t=0.19, p=0.01), presence
of axilla node invovlvement (t00,2, p=0.006)
and also grade of the IDC tumours evaluated
using Bloom-Richardson´s ctiteria (t=0.18, 0.03).
There were negative correlation between TBR
and presence of PR (t=0.16, p=0.02) and bordeline
negative correlation between TBR and age of
patients (t=0.135, p=0.065). Patients who are
younger and/or have PR or ER negative cancers
have higher Tc-99m MIBI uptake. Patients who
presented with high grade of malignancy (B-R)
also have higher uptake of radiotracer. Also
those with higher uptake of radiotracer often
had axillary node involvement. This would suggest
that more aggressive. |
24 |
Since 1997 they have
prospectively tried to assess/confirm the diagnostic
value of MR-Cholangiopancreaticography (MRCP)
and MR-Angiography in patients suffering from
pancreatic carcinoma. Till today we have studied
116 adult patients with two 1,5 Tesla MRT scanners
using a body phased-array coil. 27 patients
with benign diseases of the pancreas, 58 with
carcinoma of the pancreas, 15 with no disorder
of the pancreatobiliary system, 14 with hepatic
abnormalities and 2 with other tumors. MR examinations
included routinely T1-weighted (TSE, SE), T1-
weighted fat-suppressed (TSE, SE), T2 weighted
fast turbo spin-echo (UTS, Haste), T2- weighted
fat-suppressed fast turbo spin-echo (SPIR),
2D- cholangiopancreaticography (images were
obtained with breath- held) or 3D- cholangiopancreaticography
(images were obtained in coronal and axial plane
with respiratory triggering). In cases with
pancreatic cancer we added MR-angiography. MR
images were retrospectively compared with CT,
ERCP amd sonography data. Summarizing the results
confirm that MRCP is a safe and non-invasive
technique for studying pancreatic and biliary
diseases which yields information in many cases
complemontory to ERCP and PTC. MRCP images can
also be used as a guide for subsequent interventional
procedures. MRCP will, therefore, allow the
restriction of ERCP and PTC to more therapeutical
indications and cases offering special problems.
Considering staging and follow-up of pancreatic
cancer, MRCP crosssectional images and MR-angiography
should be performed, allowing the visualization
of the extraductal anatomy/pathology. These
techniques may provide the clinicians with complementary
information compared to other conventional imaging
methods like US and CT. Clinicians engaged in
pancreatic oncology, therefore, should have
MRCP, MR-angiography and MR imaging available
in addition to the conventional diagnostic tools. |
25 |
The differential diagnostic
utility of AFP, CEA, CA19.9 and TPA was evaluated
in liver tumors. They were determined in the
sera of 61 patients with primary hepatocellular
carcinoma (HCC), 18 with secondary liver metastasis,
61 of benign liver cirrhosis in comparison to
20 normal healthy control subjects. The association
of either HBV or HCV infection and HCC was also
studied through the assay of HbSAg, HbSAb, and
HCV-Ab. The optimal cut-off values were determined
using the diagnostic accuracy measurements and
the receiver operating characteristic 8ROC)
curves. AFP at on optimal cut_off value of 100
ng/ml and TPA at 160 U/L showed the highest
sensitivity and specificity in detecting liver
meta`stasis (100% and 87% for AFP; 100% and
54% for TPA respectively). The obtained data
indicated that the combined assay of AFP and
TPA resulted in a better discrimination of HCC
among patients with hepatic focal lesions. HCV-Ab
was detected in a higher ratio of HCC patients
(83.6%) compared to HbsAg (68.9%), and both
vere detected in (34%) of HCC patiens. This
high incidence of HCV-Ab may suggest the implication
of HCV in the molecular events leading to hepatic
carcinogenesis. |
26 |
In gynecological carcinomas
p53 overexpression has been associated with
an aggressive tumor type and shorter overall
survival. They compared p53 values analysed
by a new quantitative luminometric immunoassay
(LIA) applicable on tumor cytosol immunohistochemistry
(IH). In 83 breast and 43 ovarian cancers p53
was analysed by LIA and IH (Byk- Sangtec, FRG)
and by IH using monoclonal antibodies (MOAB/BP53-
Bio Genex, FRG). In breast cancer 32 cases (39%)
were immunhistochemically (IH) positive. LIA
values renged from 0.01 to 101ng/mg protein
(p), median (IH negative cases) =0.208 and median
(IH positives)=0.857 ng/mg p. Using a cut off
<0.2 ng/mg p for a very low expression only
11% (3/27) were IH positive and ~0.8 for very
high expresion only 16% (3/20) were IH negative.
In ovarian cancer values ranged from from 0.01
to 66.1 mg/mg p. 48.8% (21/43) were IH positive,
median (IH negatives) = 0.234 and median (IH
positives)=1.43ng/mg p. At a cut off `0,2 ng/mg
p 25% (3/12) were IH positive and at a cut off
<0.8 ng/mg p only 14% (2/14) were IH negative.
The quantitative LIA determination of p53 in
cytosols of gynecological carcinomas shows a
good correlation to immunohistochemistry in
cases of very high and very low expression. |
27 |
Soluble interleukin-2
receptors (sIL-2R) are measurable in the sera
of patients with ovarian cancer and several
other benign and malignant diseases. however,
the function of these sIL-2R is still unclear.
Since high levels of sIL-2R are thought to be
an indicator of an activated immune system we
investigated the correlation of sIL-2R concentration
and prognosis of ovarian cancer patients. sIL-2R
measurement was performed on the preoperative
sera of 130 patients with benign, and 119 patients
with malignant ovarian tumors. The IMMULITE®
sIL-2R assay by DPC Biermann, Bad Nauheim, Germany
was used. in ovarian cancer patients sIL-2R
concentrations were significantly higher than
in those with bening tumors. By defining the
95th percentile of the sIL-2R concentration
distribution in patients with benign diseases
as the cut-off (1200 U/ml) 35% of the ovarian
cancer patients had elevated concentrations.
Concentrations. Concentrations of sIL-2R increased
with FIGO stage. FIGO-III patients with highly
elevated sIL-2R concentrations tended to have
better prognosis than those with sIL-2R levels
within normal range in contrast to FIGO IV patients.
Since sIL-2R concentrations indicate on immunological
activation in ovarian cancer patients our data
give hints of the possible role of sIL-2R in
the assessment of the risk of recurrence in
ovarian cancer patients. |
28 |
Angiogenesis is necessary
for growth and invasiveness of malignant tumors.
Vascular endothelial growth factor (VEGF) is
considered to play a key role in tumor angiogenesis.
Few data are available with regard to serum
levels of VEGF in patients with ovarian tumors.
Authors investigated the diagnostic value of
serum VEGF in patients with ovarian neoplasms
841 ovarian carcinomas, 20 cystadenomas) and
20 healthy women were included into the study.
VEGF serum concentrations were determined by
a commercially available ELISA. Statistical
analysis revealed significant differences in
VEGF serum values of ovarian cancer patients
vs. healthy controls or patients with cystadnomas.
No difference could be seen between serum levels
of healthy controls or patients with cystadenomas.
No difference could be seen between serum levels
of healthy controls and women with benign ovarian
tumors. For ovarian cancer patients vs. normal
controls a sensitivity of 71% and a specificity
of 65% resulted. The sensitivity of 71% and
a specificity of 65% resulted. The sensitivity
and specificity of cancer patients vs. patients
with benign neoplasms were 71% and 65%, respectively.
Their results suggest that VEGF has potential
as a serum marker with diagnostic relevance
in ovarian neoplasms. |
29 |
In order to explore
whether apoptosis is associated with angiogenesis
in lung cancer, immunohistochemisty was employed
to determine the pro-apoptotic factors Fas ligand
(Fas) and caspase-3 (Cas-3) in 70 squamous cell
lung carcinomas. Furhermore, the vascular endothelia
growth factor (VEGF) and the microvessel density
(MVD) were analyzed. The comparison between
MVD and the pro-apoptotic factors demonstrated
that the apoptotic factors are inversely related
to MVD (Cas-3: p=0.011, FasL. not significant).
In order to confirm this result, FasL and Cas-3
were also compared with the expression of VEGF.
Again, an inverse correlation between VEGF and
the pro-apoptotic factors was found (Cas-3:
p=0.019, FasL: p=0.008). The inverse correlation
between angiogenesis and apoptosis may be explained
by the activation of pro- apoptotic and anti-angiogenic
factors caused by hypoxia. |
30 |
Histopathological and
genetis studies support the hypothesis that
aberrant crypt foci (ACF) represent on of the
earliest that aberrant crypt foci (ACF) represent
on of the earliest events in colon carcinogenesis.
The purpose of this study is to make use of
1H MRS in conjuncion with multivariate methods
of analysis to ascertain the validity of the
above mentioned hypothesis. ACF, colonic mucosa
and tumor samples taken from thirty- two carcinogen
(azoxymethane)- treated Sprague Dawley rats,
and of colon mucosa taken from ten healthy animals,
were investigated ex vivo by 1H MRS and analyzed
using multivariate methods of analysis. The
H magnetic resonance peak intensities and areas
of ACF lie between those from normal and carcinogen-treated
mucosa samples and tumors. Multivariate analysis
classification of the spectra suggests that
the ACF exibit biochemical characteristic intermediate
between the control and AOM-mucosa samples and
the tumor groups. The use of sophisticated methods
of data classification has enabled us to support
the hypothesis that ACF represent preneoplastic
lesions of the colon. |
31 |
The influence of doxorubicin
and N-acetyl cysteine (NAC) on caffeine metabolism
was examined on an animal model (BALB/c) mice).
The animals were divided into four equal groups
of 10 each. The first group received doxorubicin
only, in a single dose of 15 mg/kg intraperitoneally.
The second group received NAC only, in a single
dose of 400 mg/kg intraperitoneally. The third
group received, doxorubicin and NAC simultaneously
at previously mentioned doses. The fourth group
was the control one and it received 0,9% sodium
chloride solution intraperitoneally (10 ml/kg).
Animals of all groups were kept under the controlled
conditions for 24 hours after the drug administration
and thereafter were given caffeine intraperitoneally
in a dose of 20 mg/kg. Eight-hour urine samples
were collected for measuring the quantities
of caffeine metabolites in urine by the method
of high performance liquid chromatography (HPLC).
After collecting urine samples, all animals
were sacrificed and liver and heart from each
animal were prepared for measuring glutathione
content. To confirm and point out the influence
that doxorubicin and N-acetyl cysteine have
on microsomal caffeine metabolism, aside from
measuring the quantities of caffeine and some
of its metabolites excreted in urine, we also
followed two urinary caffeine matabolites ratios
as well. We calculated the ratio between 3,7-dimethylxanthine
and 3,7-dimethyl uric acid (3,7X/3,7U) and the
ratio between 3,7-dimethyl uric acid and 1 methylxanthine
plus 1,3 dimethyl uric acid (3,7U/1X+1,3U).
The quantities of caffeine metabolites excreted
in urine were lower in the group treated with
doxorubicin and in the group treated with NAC
than in the control group, but the difference
was insignificant. The quantities of caffeine
matabolites excreted in the group treated with
doxorubicin and NAC simultaneously were significantly
lower than in the control group. Generally speaking,
the quantities of caffeine metabolites excreted
in urine were lower in this group when compared
to groups treated with doxorubicin and NAC only.
The ratio between 3,7X/3,7U was significantly
lower in the group treated with NAC and doxorubicin
simultaneously and in the group treated with
NAC only, than in the control group and in the
group treated with doxorubicin only, while the
ratio between 3,7U/1X+1,3U was significantly
higher in the group treated with doxorubicin
and NAC simultaneously than in the other groups.
Glutathione levels in liver and heart showed
no difference among the groups. These differences
seem to suggest that microsomal oxidative metabolism
of caffeine was inhibited, probably by the inhibition
of cytochrome P-450 1A2. NAC did not show any
protective effect when administrated with doxorubicin.
On the contrary, it seemed that it had increased
toxicity of doxorubicin, since all animals in
the group treated simultaneously with doxorubicin
and N-acetyl cysteine had died within 48-72
hours after the drug administration, while that
was not the case in the other groups. |
32 |
High-dose chemotherapy
with autologous stem-cell transplantation is
used increasingly in the treatment of poor-prognosis
primary breast cancer. Because these patients
may be cured with standart multimodality therapy,
it is important to address both the efficacy
of transplantation, and its effect on the delivery
of standard treatments including local radiaton
therapy. Patients with high risk primary breast
cancer were treated with high-dose cyclophosopamide
and thiotepa and stem-cell transplant following
surgery and conventional-dose adjuvant chemotherapy.
Outcome, including sites of failure and delivery
of local radiation therapy, was assessed for
103 patients. Overall and disease-free survival
rates at 18 months were 83% (±4%) and 77% (±4%)
respectively. Twenty patients (19,4%) received
radiation therapy prior to transplant. of the
remaining 83,77 received radiation therapy after
transplant. Overall, 5 (19,2%) of 26 first sites
of recurrence were local alone. For patients
receiving radiation prior to transplant, 3 of
7 (43%, 95% Cl: 6%-80%) sites of first recurrence
were local, while 2 of 19 (10.5%, 95% Cl: 0%-24,5%)
sites of first recurrence were local alone in
patients receiving post-transplant radiation
or no radiation. Transplantation does not appear
to significantly compromise the delivery or
outcome of local radiation therapy for primary
breast cancer. |
33 |
The analysis of ultrasonographic
pictures of malignant ovarian tumours and the
comparison of ultrasonography with post-operative
evaluation. 163 women with the diagnosis of
ovarian tumour were subjected to ultrasonographic
examination. In 38 patients, post-operative
histopathological investigation revealed the
presence of a malignant neoplastic process.
They compared ultrasonographic pictures of the
outline and thickness of the capsule, internal
structure (cystoid, solid, partly cystoid partly
solid), the presence of endo- and exophytic
excrescences, the presence of ascites and enlarged
periaortal lymph nodes or metastases to liver
parenchyma with the status observed during operation.
1. Ultrasonography is an important investigation
in the early diagnostics of ovarian pathologies.
2. Ultrasonographic picture of ovarian tumour
may indicate the presence of malignant process.
3. Malignant tumours coexist significantly more
often with the following ultrasonographic features:
thick capsule of varying thickness and blurred
outline, partly cystoid partly solid structure
of the tumour, non homogenous internal echogenicity,
multilocular lesion. |
34 |
Infliximab (a chimeric
monoclonal antibody to tumor necrosis factor-a)
is an efficacious treatment for fistulas in
patients with Crohn´s disease. This is the result
of a randomized, multicenter, double-blind,
placebocontrolled trial in 94 adult patients
who had draining abdominal or perianal fistulas
of at least three months´ duration as a complication
of the disease. The antibody was administered
in two different doses. Fifty-five percent of
the patients assigned to receive 5 mg of infliximab
per kilogram, and 38% of those assigned to 10
mg per kilogram had closure of all fistulas,
as compared with 13% of the patients assigned
to placebo (p=0.001 and p=0.04, respectively). |
35 |
Postoperative radiation
therapy did not lower the recurrence rate among
patients with ductal carcinomas in situ (DCIS)
that had been excised with margins of 10 mm
or more. This is the result of a retrospective
analysis of data on margin widths (direct measurement
or ocular micrometry), and standardized evaluation
of the tumor for nuclear grade, comedonecrosis,
and size of 469 specimens of DCIS from patients
who had been treated with breast-conserving
surgery with or without postoperative radiation
therapy, according to the choice of the patient
or her physician. The authors come to the conclusion
that patients in whom the margin width between
the tumor and resection is less than 1 mm can
benefit from postoperative radiation therapy. |
36 |
The incidence of Kaposi´s
sarcoma (KS) is increased severalfold in individuals
infected with human immunodeficiency virus-1
(HIV). Human herpesvirus 8 (HHV8) has also been
implicated in KS. They investigated several
factors that may determine the onset of KS,
particularly HHV8 infection in individuals after
becoming seropositive for HIV. They studied
366 individuals belonging to different HIV-exposure
categories (i.e., homosexual activity, intravenous
drug use, and heterosexual contact) for whom
a negative HIV serologictest and then a positive
HIV serologic test were available within a 2-year
period. HHV8 antibody testing was performed
by use of an immunofluorescence assay on the
first serum sample available after the first
positive HIV test. Actuarial rates of progression
of KS and of other acquired immunodeficiency
syndrome (AIDS)-defining diseases were estimated
by use of time-to-event statistical methods.
All statistical tests were two-sided. Twenty-one
of the 366 study participants developed AIDS-related
KS, and 83 developed AIDS without KS. One hundred
forty (38,3%) participants had detectable anti-HHV8
antibodies. The actuarial progression rate to
KS among persons co-infected with HIV/HHV8 was
nearly 30% by 10 years after HIV seroconve sion.
Increasing HHV8 antibody titers increased the
risk of developing KS (for seronegative versus
highest titer a1:125 serum dilutiono adjusted
relative hazard aRHo=51.82; 95% confidence interval
aCIo = 6.08-441.33) but not of other AIDS-defining
diseases (adjusted RH=1.14; 95% CI=0.72-1.80).
HHV8-seropositive homosexual men compared with
HHV8-seropositive participants from other HIV-exposure
categories showed an increased risk of KS that
approached statistical significance (adjusted
RH=6.93; 95% CI=0.88-54.84). Approximately one
third of individuals co-infected with HIV/HHV8
developed KS within 10 years after HIV seroconversion.
Progression to KS increased with time after
HIV seroconversion. Higher antibody titers to
HHV8 appear to be related to faster progression
to KS but not to other AIDS-defining diseases. |
37 |
The efficiency of Chlorambucil
in the induction of apoptosis was investigated
in the study, and measurable apoptosis parameters
were compared to the other prognostic factors
with the aim of possible prediction of clinical
response to the therapy in the patients with
CD5 + B-cell chronic lymphocytic leukemia (B-CLL).
Seven newly diagnosed patients, initially treated
with daily high-doses of Chlorambucil (HD-CLB)
were analyzed. Quantitative analysis of apoptosis
parameters on semi-fine sections obtained from
peripheral blood was performed prior and during
the first five days of therapy. The level of
spontaneous apoptosis (SA) was determined, as
well as the maximal response by apoptosis (MAR),
and the time needed to establish maximal response
by apoptosis (TMAR), respectively. The results
revealed that the level of SA in the studied
group of patients was 11.39%-20.50%. In three
patients with achieved criteria for complete
remission (CR) was observed high level of SA,
TMAR 2-4 days and MAR 23.42-26.36%, respectively.
All patients with CR were with negative LDT,
non-diffuse involvement of bone marrow and clinical
stage B. Criteria for partial remission (PR)
were achieved in 4 patients. Within this group,
all three measurable parameters of apoptosis
could have been determined in only one patient,
while in the rest was noticed the increased
percentage of apoptotic cells on the last day
of follow-up. In all patients was observed negative
LDT, diffuse bone marrow involvement, and 2
out of 4 patients had CLPL of cytomorphological
type and clinical stage B. By comparing the
obtained values of measurable apoptotic parameters
with the clinical response to the applied therapy
with HD-CLB, it is possible to divide our patients
into two groups: patients who have achieved
CR have the highest percentage of cells dying
due to the therapy-induced apoptosis, as well
as the higher values of measurable parameters
compared to the certain parameters of the patients
with the criteria for PR. Our preliminary results
of therapeutic response to the apoptosis might
be useful for the timely decision upon the duration
of therapy and change of modality of treatment
for every patient during the follow-up period. |
38 |
Hospital cancer date
registry is a computerized data base for the
collection, management and analysis of data
on cancer patients. Data is stored on-line using
HR software which is developed in the Institute
of oncology Sremska Kamenica, Novi Sad. It can
be the part of the population registry which
is also developed by the Institute itself. The
HR software collect a minimum database on every
patient primarily treated by this hospital.
The minimum data set includes details of staging,
initial treatment and follow-up. Data searches
can be performed on any data item collected.
HR software is prepared to work on the PC computers
and for the network environment. We finished
the testing period of the program and now we
are educating the staff for coding and for input
the data to the software. The date started of
the registry can be the 1 January, 2000. |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
|
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Issue 4 |
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News
1 |
Positron emission tomography
(PET) with fluorodeoxyglucose (FDG) allows the
visualization of metabolic tissue activity.
Use of FDG in in-vivo cancer imaging is based
on enhanced glycolysis in tumor cells. In vivo
exprements have demonstrated the potential use
of FDG PET in squamouscell head and neck tumors
and the detection of tumor involvement in lymph
nodes... The FDG concentration is a representative
of the glycolytic activity of exogenous glucose.
It has to be realized that uptake of FDG in
malignant tumors is not only dependent of an
increased expression of GLUT, but also depends
on physiologic factors, such as tissue oxygenation,
blood flow and peritomoral reactions. Consequently,
FDG PET therefore may be considered as a highly
sensitive techniwue, but with a relative low
specificity. Therefore, a careful selection
of patient groups must be performed to overcome
this problem. In vivo experiments have demonstrated
the potential use of FDG PET in squamous cell
head and neck tumos and the detection of tumor
involvement in lymph nodes. In these studies,
a clear correlation was found between the proportions
of the cells in the S+G2/M phases and the FDG
uptake. The results suggested that enhanced
glucose metabolism is associated with the proliferative
activity of the head and neck tumors and justified
further studies. |
2 |
Thirty-nine oral squamous
cell carcinomas were assessed for bcl-2 protein
expression by immunostaining of tumour sections.
Twenty-three per cent of these tumours showed
strong nuclear staining for bcl-2 protein. Tumours
of the sheek and tongue together accounted for
77% of overexpression of this protein. When
bcl-2 expression was compared with p53 expression,
they were found to be non-overlapping. These
results suggest that overexpression of either
of these genes may substitute each other in
the development of oral carcinomas of Indians. |
3 |
The presence of high
risk human papilloma virus (HPV) 16 and 18 was
examined in 100 oral cancer patients of Indian
descent, 80 patients with potentially malignant
oral lesions and corresponding clinically mucosa
from 48 of these patients. Additionally, presence
of HPV-33, -6 and -11 was also studied in 86
oral cancers, 50 potentially malignant oral
lesions and 30 corresponding normal oral mucosa.
All the patients with oral cancer and oral lesions,
were long term tobacco-chewers, and a majority
of the patients were in Advanced Stages III
and IV. The DNA samples were amplified by polymerase
chain reaction (PCR) using HPV L1 consensus
primers. Typing of HPV was performed by Southern
hybridization analysis of the PCR products using
HPV-16, -18; -33, potentially malignant lesions
and 15 out of 48 (31%) of the corresponding
normal mucosa in the patients with oral lesions.
HPV-18 was not detected in any of the oral cancers,
oral lesions and normal mucosa. HPV-33 and the
low-resk HPV-6 and -11 were also not detected
in the oral cancers, oral lesions and corresponding
normal mucosa. A significantly higher prevalence
of HPV-16 was observed in oral lesions (27 out
of 80,34%) as compared to oral cancers (15 out
of 100,15%). The observed difference of 19%
(95% confidence interval aCIo: 6%, 331%), between
these two proportions was statistically significant
at the 5% level of significance. Our data indicates
that HPV-16 may play a direct role in a certain
proportion of oral cancers; whereas in a subpopulation
of oral cancers HPV-16 infection may be vital
in the early events associated with development
of potentially malignant oral lesions, and the
presence of the virus not essential in the progression
of the oral lesion to frank malignancy. |
4 |
The gene for Cyclin
D1 (CCND1) lies within chromosomal region 11q13
and codes for a cell cycle regulator essential
for G1 phase progresion. This G1-cyclin is a
putative protooncogene whose clonal rearrangement
and/or amplification and mRNA overexpression
occurs in several types of human neoplasias,
including head and neck squamous cell carcinomas.
Data from the literature suggest that amplification
and overexpression of the CCND1 gene could lead
to destabilisation of cell cycle control mechanisms
and uncontrolled cell prolifereation. We developed
a differential PCR system for the determination
of CCND1 gene amplification in head and neck
squamous cell carcinomas. A 115 bp CCND1 fragment
and a 150 bp g-interferon fragment are amplified
simultaneously in the same reaction tube under
optimized conditions. Statistical analysis of
amplification data obtained by differential
PCR revealed excellent correlation with amplification
data obtained by conventional Southern hybridization. |
5 |
Authors reported a
case of primary CD 30-positive anaplastic large
cell lymphoma of the lip. While extranodal involvement
is not uncommon in Ki-1 (CD30) anaplastic large
cell lymphoma, this is first reported case of
primary lip involvement. The clinical features
and clinical outcome in Ki-1 anaplastic large
cell lymphoma are discussed. |
6 |
On the basis of promising
data on the use of fluorine-18-2-fluoro-2-deoxy-D-glucose
(F18-FDG) whole body positron emission tomography
(WB-FDG-PET) in the staging of patients with
lymphoma, we initiated a pilot series to evaluate
the role of WB-FDG-PET in the staging of extranodal
B-cell lymphoma of the mucosa-associated lymphoid
tissue (MALT) type. WB-FDG-PET documented no
lymphoma in any of the 10 patients studied,
as no focal tracer uptake was demonstrated in
either gastric or extragastric lesions or in
involved lymph nodes, irrespective of histologic
grading. In three patients the scan showed a
false negative result with respect to the MALT
lesions but showed focal tracer uptake indicating
tumor spread, which, however, was ruled out
by further follow-up and biopsy, respectively,
and was thus rated false positive. Due to these
results, the study was discontinued prematurely
after the first ten patients. |
7 |
Vaccination with irradiated
granulocyte-macrophage colonuy-stimulating factor
(GM-CSF)-secreting gene-transduced cancer induces
tumoricidal immune responses. In a Phase I human
gene therapy trial, eight immunocompetent prostate
cancer (PCA) patients were treated with autologous,
GM-CSF-secreting, irradiated tumor vaccines
prepared from ex vivo retroviral transduction
of surgically harvested cells. Expansion of
primary cultures of autologous vaccine cells
was successful to meet trial specifications
in 8 of 11 cases (73%); the yields of the primary
culture cell limited the number of courses of
vaccination. Side effects were pruritis, erythema,
and swelling at vaccination sites. Vaccine site
biopsies manifested infiltrates of dendritic
cells and macrophages among prostate tumor vaccine
cells. Vaccination activated new T-cell and
B-cell immune responses against PCA antigens.
T-cell responses, evaluated by assessing delayed-type
hypersensitivity (DTH) reactions against untransduced
autologous tumor cells, were evident in two
of eight patients before vaccination and in
seven of eight patients after treatment. Reactive
DTH site biopsies manifested infiltrates of
effector cells consisting of CD45RO+-T-cells
and degranulating eosinophils consistent with
activation of both Th1 and Th2 T-cell responses.
A distinctive eosinophilic vasculitis was evident
near autologous tumor cells at vaccine sites,
and at DTH sites. B-cell responses were also
induced. Sera from three of eight vaccinated
men contained new antibodies recognizing polypeptides
of 26, 31, and 150 KDa in protein extracts from
prostate cells. The 150-kDa polypeptide was
expressed by LNCaP and PC-3 PCA cells, as well
as by normal prostate epithelial cells, but
not by prostate stromal cells. No antibodies
against prostate-specific antigen were detected.
These data suggest that both T-cell and B-cell
immune responses to human PCAQ can be generated
by treatment with irradiated, GM-CSF gene-transduced
PCA vaccines. |
8 |
Over the last decade,
scientists have produced many recombinant immunotoxins-small,
bioengineered antibodies linked to a toxin-as
part of an experimental strategy to directly
target and deliver deadly poisons to tumor cells.
However, despite the great promise of this approach,
therehave been no published reports of cancer
patients responding to a recombinant immunotoxin.
That is, until now. In the November 15 issue
of the juornal Blood, a team of scientists from
the National Cancer Institute reports that four
of four patients with hairy cell leukemia, an
uncommon cancer of imune B cells, had "major
responses" to a recombinant immunotoxin
called LMB-2. All of the patients previously
had not responded to standard treatments for
the cancer, including chemotherapy and removal
of the spleen. Robert Kreitman, M.D., lead author
on the study, said one patient in this early
stage clinical trial had acomplete remission
after treatment with the immunotoxin and has
not relapsed 16 months later. For the three
other patients, Kreitman and colleagues observed
partial responses, detecting a 98% to 99.8%
reduction in malignant circulating cells. All
of the side effects were reverible and usu eally
lasted less than a week. These included fever,
nausea, vomiting, and rash."This offers
a proof of principl that recombinant immunotoxins
will one day have an important role in treating
cancer", said Ira Pastan, M.D., senior
author on the paper. "But there is still
much work to be done to maximize their potential
for cancer patients". |
9 |
Organ-confined renal
malignancies can be cured in the majority of
patients, whereas more extensive lesions have
a poor prognosis. We sought to develop a noninvasive
test for renal cancer detection based on a novel
molecular approach. Matched urine and serum
DNA samples were obtained before surgery from
30 patients with clinically organ-confined solid
renal masses (25 with malignant tumors and five
with tumors of low malignant potential) and
were subjected to microsatellite analysis. Serum
samples and urine samples obtained from 16 indivuduals
without clinical evidence of genitourinary malignancy
served as controls. Nineteen (76%) of the 25
patients with malignant tumors were found to
have one or more microsatellite DNA alterations
in their urine specimen, and 15 (60) were found
to have alterations in their serum DNA by microsatellite
analysis. In every case, the microsatellite
changes in urine or serum were identical to
those found in the primary tumor. Three of five
patients with tumors of low malignant potential
were found to have DNA alterations in their
urine, but none displaved alterations in their
serum. Moreover, microsatellite alterations
were not identified in either the urine or the
serum samples from normal control subjects and
patients with hematuria due to nephrolithiasis
(renal stones). These data suggest that microsatellite
DNA analysis of urine specimens provides a potentially
valuable tool for the early detection of resectable
kidney cancer. Furthermore, microsatellite analysis
of serum samples reveals evidence of circulating
tumor-specific DNA in approximately half of
these patients and may reflect the propensity
of these tumors to spread to distand sites at
an early stage. |
10 |
To our knowledge, 17-allylamino,
17-demethoxygeldanamycin (17AAG) is the first
inhibitor of heat shock protein 90 (Hsp9=) to
enter a phase I clinical trial in cancer. Inhibition
of Hsp90, a chaperone protein (a protein that
helps other proteins avoid misfolding pathways
that produce inactive or aggregated states),
Ieads to depletion of important oncogenic proteins,
including Raf-1 and mutant p53 (also known as
TP 53). Given its ansamycin benzoquinone sructure,
we quinone-metabolizing enzyme DT-diaphorase.
The antitumor activity of 17AAG and tther Hsp90
inhibitors was determined by use of a spectrophotometric
assay, and protein expression was determined
by means of wesern immunoblotting. In two independent
in vitro human tumor cell panels, we observed
a positive realtionship between DT-diaphorase
expression level and growth inhibition by 17AAG.
Stable, high-level expression of the active
NQO1 gene transfected into the DT-diaphorasedeficient
(by NQO1 mutation) BE human colon carcinoma
cell line resulted in a 32-fold increase in
17AAG growthinhibition activity. Increased sensitivity
to 17AAG in the transfected cell line was also
confirmed in xenografts. The extent of depletion
of Raf-1 and mutant p53 protein confirmed that
the Hsp90 inhibition mechanism was maintained
in cells with high and low levels of DT-diaphorase.
17AAG was shown to be a substrate for purified
human DT-diaphorase. These results suggest that
the antitumor activity and possibly the toxicologic
properties of 17AAG in humans may be influenced
by the expression of DT-diaphorase. Careful
monitorng for NQO1 polymorphism and the level
of tumor DT-diaphorase activity is thereforerecommended
in clinical trials with 17AAG. |
11 |
Our results support
a favourable prognostic significance of cathepsin-D
expression in advanced ovarian cancer, but underscore
the importance of considering both epithelial
and stromal cell expression. We could not confirm
the prognostic significance of nm23 expression
in the present cohort of advanced ovarian cancer
patients. |
12 |
Metyl-b-cyclodextrin
(MEBCD) was investigated for its effect on the
antitumoral activity of various antineoplastic
agents (doxorubicin(DOX), docetaxel (DXL), 5-fluorouracil
(5-FU) and cisplatin (CDDP)) in three different
human parental sensitive cancer cell lines (K562
S, MCF7 S and A2780 S) and their multidrug resistant
variant sublines (K562 R, MCF7 R and A2780 R).
At non-cytotoxic concentrations, MEBCD was able
to increase significantly DOX and DXL cytotoxic
activity in all the cell lines tested. The sensitisation
ratios ranged from 3.1 to 14.3. Moreover, intracellular
DOX accumilation, was also increased when cells
were treated with MEBCD combined with DOX. The
effects of MEBCD in resistant sublines were
greater than in their parental sensitive cell
lines. |
13 |
From 65 studies identified,
ther seems to be no standard therapy for advanced
biliary cancer. Despite anecdotal reports of
symptomatic palliation and survival advantages,
most studies involved only a small number of
patients and were performed in a phase II approach.
In addition, the benefit of adjuvant treatment
remains largely unproven. No clear trend in
favour of radiation therapy could be seen when
the studies included a control group. The only
randomised chemotherapeutic series seemed to
suggest a benefit of treatment in advanced disease,
but due to the small number of patients included,
definitive evidence from large, randomised series
concerning the benefit of non-surgical oncological
intervention as compared with supportive care
is still lacking. |
14 |
The expression of alternatively
spliced CD44 adhesion molecules has been implicated
in the pathogenesis and metastasis of colorectal
cancer. Using RT-PCR authors delineated the
exon composition of CD44mRNAs in normal colorectal
mucosa, including isolated colonic crypts, in
colorectal carcinomas and their hepatic metastases.
They identified by RT-PCR eight variant transcripts
expressed in colorectal carcinomas and their
metastases, but also constitutvely in normal
colorectal epithelia. Despite expression of
these transcripts in colorectal cancers and
their metastases, monoclonal antibodies specific
for standard or variant epitopes encoded by
exons v5 and v6 stained only a few neoplastic
lesions. These data point to a differentiation-specific
CD44 expression and splicing pattern in proliferating
colorectal epithelia. |
15 |
Local reccurrence of
high-grade non-Hodgkin's lymphoma (NHL) is usually
treated with intensive chemotherapy and/or radiotherapy.
When these modalities are inadequate or no longer
possible, selective arterial embolisation can
be an alternative treatment to radiotherapy
and chemotherapy.Authors think that embolisation
may have played a part in achieving and maintaining
complete response of the lymphoma. after radiation
therapy, chemotherapy was inadequate and embolisation
was the only local treatment which could be
applied for this patient. Authors suggest that
in such cases, it could be an alternative for
adjuvant therapy of hypervascularised tumours,
especially if radiotherapy is no longer possible. |
16 |
The study, prompted
by a number of articles presaging the imminent
of biomedical journals due to the rise of their
electronic spread, analysed 54 Web sites of
the journals included in the Oncology section
of the Science Citation Index, Journal Citation
Reports (1994) and the sites of 10 other leading
digitised biomedical journals. The aim was to
determine quantitive and qualitative differences
in terms of information content existing between
the two media. The analysis confirmed theat
there are limits to the information contained
in the scientific journals currently on the
Internet and upholds the authors' conclusion
that, in the oncology field, the printed journal
will continue to have and important role for
a most individual users for some time. |
17 |
The attention of pathologists
is now turned towards the standardisation of
protocols, statistical guidelines and large
conclusive studies in quantitive pathology,
aimed at providing the necessary objectivity
in diagnostic work. Moreover, image analysis
systems have to be frequently upgraded to extend
the spectrum of potential applications. The
benefits of quantitative methods are particulary
tangible in areas where conventional diagnosis
may be difficult. |
18 |
The acid labile derivative
of Daunomycin cis-aconityl Daunomycin (cAD),
was coupled to an amphoteric polypeptide, (EAK),
which was selected for conjugation on the basis
of its pharmacological and immunological properties. |
19 |
Authors report the case
of an infiltrating lobular breast tumour in
a female HIV-seropositive patient (heterosexual
transmission). In this case, the relapse observed
after the first diagnosis occured despite good
clinical and bilogical prognostic factors, and
when the patient's CD4 count was more than 500/mm3.
Neither biological characterisation nor the
CD4 count predicted the progression of the disease.
Their results may also support the hypothesis
that HIV infection may have a permissive effect
on breast cancer development regardless of tumour
biology and CD4 lymphocyte count. |
20 |
Cell kinetic data may
be important indicators of clinical behaviour
in many types of cancer. Recently, several antibodies
to cell-cycle associated antigens have been
characterised. This overview summarises the
advantages and disadvantages of different methods
for the assessment of cell proliferation. Moreover,
the prognostic value of proliferative activity
in gastric cancer is discussed and suggestions
for future research are given. |
21 |
The aim of the study
was to analyse retrospectively the clinical
features and effect of treatment in 94 MCL patients
diagnosed and treated in one centre between
1980 and 19996, and to find out different factors
influencing the treatment results and prognosis.
The median age of patients was 66 years, and
77% were over 60 years old. Of the patients,
76% had advanced disease, the performance status
(PS) was WHO 0-1 in 86%, and B symptoms were
present in 35% of the cases. Bone marrow infiltration
was found in 61% and overt leukaemia in 12%
of the patients. Of the patients, 47% achieved
complete remission with first-or secind-line
therapy. The median duration of remission, time
to treatment failure (TTF), and survival were
28, 18, and 41 months, respectively. In multivariate
analyses, age, stage and leukaemic disease were
significantly associated with TTF, and age,
stage, leukaemic disease and lactate dehydrogenase
(LDH) with survival. Long-term prognosis is
poor in MCL. None of the conventional chemotherapies
seems curative. A prospective randomised trial
should be made to evaluate the benefit of anthracycline-containing
regimens in MCL. |
22 |
Authors reviewed the
relationships between ERBB2 amplification and/or
overexpession in human breast cancer and the
clinicopathological patrameters described in
the literature (97 studies involving 22 616
patients) in order to draw conclusions regarding
its clinical interest. |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Volume 6 |
Issue 1 |
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News
1 |
The classification of
receptors involved in the emetic reflex has
completely changed during the past 10 years.
Today investigational agents acting as combined
5HT3 antagonists/5-HT4 agonists, dopamine D2/D3
antagonists and the neurokinin1 antagonists
are in focus. Positron emission tomography (PET)
is rapidly advancing as an investigational tool
in the detection and staging of cancer and in
the evaluation of response to treatment. It
is emphasized that PET could also be useful
in further investigations of the pathophysiology
of emesis. Though antiemetic treatment has been
optimized, delayed emesis, emesis during multiple
cycles and, especially, refractory emesis after
chemotherapy continue to present significant
challenges requiring further clinical investigations,
as does the syndrome of chronic nausea and vomiting
in patients with advanced cancer. |
2 |
The emergence of herpesvirus
resistance to antiviral drugs is a matter of
concern, and its clinical importance among patients
with malignancy needs to be elucidated. Future
investigations may furthermore help to clarify
the role of novel antiviral agents, such as
cidofovir, lobucavir, and compound 1263W94,
and of the adoptive immunotherapy with virus-specific
CTL clones in severely immunodeficient cancer
patients. |
3 |
Heparan sulfate proteoglycans
are one of the major components of extracellular
matrix and are secreted at different levels
by several normal and tumoral cells. Perlecan,
the basement membrane proteoglycan, has structural
domains involved in cell/matrix interactions
and growth factor storage. Metastatic melanoma
cells show an increase in perlecan expression
as compared to low metastatic ones. We examined
whether reduction of perlecan expression could
down-modulate the malignant phenotype in melanoma
clones.
These results further indicate the importance
of perlecan as a regulator of growth factor
activity affecting the biological properties
of metastatic cells, and suggest the potential
use of antisense perlecan DNA in anti-melanoma
gene therapy approaches. |
4 |
Liver diseases associated
with chronic hepatitis B virus (HBV) infection,
including hepatocellular carcinoma, account
for more than 1 million deaths annually worldwide.
The recently developed individual biochemical
and molecular markers of aflatoxin exposure,
i.e., aflatoxin-albumin adducts in blood and
a specific GC to TA transversion mutation in
codon 249 of the p53 gene (249ser p53 mutation)
in hepatocellular carcinomas, permit a better
quantitative estimation of aflatoxin exposure
in different populations of the world.
Experimental and epidemiologic studies demonstrate
an interaction between HBV infection and aflatoxins
in hepatocarcinogenesis. |
5 |
Fig. 2. Structures of
Nicotine, N' nitrosonor-nicotine (NNN), and
4-(methyl-nitrosami-ino)-1-(3-pyridyl)-1-butanone
(NNK) |
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6 |
Fig. 1. Scheme linking
nicotine addiction to lung cancer through the
major pulmonary carcinogens of tabacco smoke
- polynuclear aromatic hydrocarbons (PAH) and
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK). |
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7 |
A ribonucleoprotein
enzyme, telomerase, is a key component in maintaining
telomere length. Because the majority of cancers
express telomerase but most normal somatic tissues
do not, we measured the level of telomerase
expression in primary breast cancer specimens
for correlation with traditional prognostic
indicators and disease outcome. Telomerase activity
was measured in frozen human breast cancer specimens
by use of the Telomeric Repeat Amplification
Protocol (TRAP) assay.
Telomerase activity in human breast cancers
is associated with a more aggressive tumor phenotype
in patients. |
8 |
Pregnancy associated
breast cancer (PABC) includes cancers concurrent
with pregnancy, diagnosed up to 1 year following
delivery, or at anytime while the patient is
lactating. However, assuming a long latency
period, breast cancer diagnosed even up to 5
years following a delivery may have concurrently
existed with pregnancy and therefore been subjected
to the hormonal milieu of pregnancy.
Pregnancy is not a cause of breast cancer. Breast
cancer occurs coincidentally with pregnancy
and lactation. PABC has been associated with
a poor prognosis that may be related to an incompletely
understood hormonal influence and an often reported
diagnostic delay.
Options in the treatment of breast carcinoma
during pregnancy are limited by potential fetal
injury secondary to both radiation and chemotherapy.
Surgery is a treatment of choice when breast
cancer occurs early in the first and second
trimesters. In general, surgical breast procedures
may be undertaken in pregnant women with essentially
no risk to the fetus or the continuation of
pregnancy.
If a diagnosis of breast cancer is made during
the third trimester of pregnancy definitive
surgical management can be immediately instituted
followed by little to no radiation treatment
delay after delivery.
M.D. Anderson Cancer Center in conjunction with
The Baylor College of Medicine recently presented
data on a 5-fluorouracil, doxorubicin, and cyclophosphamide
treatment protocol given to second and third
trimester pregnant patients following MRM. Early
results from their study demonstrated no severe
neonatal abnormalities and generally good maternal
outcome. However, in utero exposure to these
chemotherapeutic agents may cause difficulty
later in life.
Tumors from patients with PABC are more commonly
estrogen negative although high false negative
rates may occur with standard assay techniques.
The treatment of breast cancer during pregnancy
is complicated by potential fetal injury secondary
to both radiation and chemotherapy. Currently,
MRM remains the treatment of choice when this
disease occurs during the first trimester and
early during the second trimester. Although
there is little data on breast conservation
therapy in these women, this type of treatment
may be considered later during pregnancy with
avoidance of the radiotherapy until after delivery. |
9 |
Free and N1-acetylated
polyamine levels were higher in the neoplastic
tissue than surrounding mucosa of the same patient.
On the contrary, PAO activity was significantly
lower in the neoplastic tissue than surrounding
mucosa. It seems that PAO activity dose not
play an important role in the increased free
polyamine levels in human colorectal carcinoma.
Instead, the low PAO activity observed in our
study let us to hypothesize that polyamine analogues
can have an antitumoral effect on colorectal
carcinoma.
Table 1. Polyamine levels and PAO activity in
neoplastic and normal colorectal tissue (Number
of cases = 30). |
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10 |
Diastolic left ventricular
parameters and R-R intervals significantly differed
before and after completed chemotherapy in our
patients: peak filling rate (PFR: 1.8±0.6 vs.
2.2±0.7 EDV/sec) and time to filling rate (TPFR:
182±48 vs. 2.25±50 msec), R-R: 723±51 vs. 620±45
msec, p<0.01. Ejection fraction, as a systolic
parameter /did not significantly differ before
and after completed chemotherapy (EF: 59±7 vs.
58±6%), p<0.05.
Table 2. Left ventricular systolic and diastolic
parameters in 32 female patients with breast
cancer before and after the end of chemotherapy. |
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11 |
In the intact stomach,
Helicobacter pylori associated gastritis is
considered to be a risk factor for cancer. After
partial gastrectomy increased mucosal cell proliferation
associated with chronic bile reflux has been
claimed to increase the risk for cancer in the
gastric stump, whereas the influence of H. pylori
infection is not so clear.
The mean labelling index (LI) was 30.8%. There
was no clear association between H. pylori infection
and proliferation rate. A significant difference
in proliferation rate was seen between patients
with a reconstruction type known to be associated
with bile reflux and those with a reconstruction
without bile reflux. The difference was small
in H. pylori negative patients but strong in
those with bile reflux and H. pylori infection.
The LI increased with age. Smoking had no significant
effect on proliferation whereas use of NSAIDs
seemed to inhibit proliferation. Ki-67 is a
convenient method for assessing the proliferation
rate of the gastric epithelium. Bile reflux
and H. pylori infection seem to have a synergistic
effect on cell proliferation in the gastric
remnant and may explain the increased risk of
cancer after partial gastrectomy.
Table 2. Ki-67 labeling index (LI) and Helicobacter
pylori status according to reconstruction type |
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12 |
Several dimethylsilane
tetramines [homologs of spermine with an Si(CH3)2
group in the central carbon chain], a carbon
analog of the dimethylsilane tetramines [containing
C(CH3)2 instead of Si(CH3)2] and a dimethylsilane
hexamine were studied with regard to their cytotoxic
activity and their ability to interact with
double-stranded DNA. All polyamine analogs exerted
cytostatic effects to several cell lines at
micromolar concentrations. Their ability to
condense DNA was comparable to and their ability
to displace ethidium bromide from binding to
DNA was superior to that of spermine. Their
cytostatic effect was not correlated with the
depletion of cellular spermidine concentrations.
It is suggested that the new polyamine analogs
act mainly by displacing spermidine from binding
sites which are essential for the promotion
of cell growth. |
13 |
Vascularization is an
important step in tumor growth and metastasis.
Tumor neovascularization can be considered,
therefore, as a good target for antineoplastic
therapy. In order to target saporin, a powerful
plant toxin, in proximity of the tumor we fused
the saporin coding sequence to that for placental
growth factor-2 (P1GF-2). P1GF is an angiogenic
factor involved in tumor neovascularization.
The fusion protein P1Gt transfection of mammalian
cells and released in the culture medium as
a 57.5 kDa polypeptide. Selectivity and cytotoxic
activity are reported as a preliminary step
towards the evaluation of its in vivo antitumor
activity. |
14 |
In this article authors
evaluated the role of gallium-67 scintigraphy
in the staling of low-grade non-Hodgkin's lymphomas
(LGNHL), the relationship between the expression
of CD71 on the surface of the neoplastic cells
and the 67Ga uptake by the tumour, and the contribution
of 67Ga scan in defining the prognosis of LGNHL.
They concluded that because of the low sensitivity
in tumour detection and, in general, the low
interest in evaluating the extension of disease
at diagnosis in LGNHL patients, 67Ga scan should
not be used for staging, but should be considered
an adjunctive tool in defining the prognosis
and the therapeutic strategy in patients with
follicular lymphomas. |
15 |
Single-photon emission
tomography (SPET) with technetium-99m sestamibi
(MIBI) was used in the assessment of 30 patients
with previously resected malignant melanoma
when the clinical examination raised the suspicion
of lymph node metastasis. Using MIBI, 16 out
of 17 lymph node metastases were detected and
confirmed by histology. No false-positive results
were obtained during this prospective study.
It is concluded that MIBI scintigraphy may be
useful in the early detection of lymph node
metastases of malignant melanomas. |
16 |
In this article, the
classification of cervical lymph nodes, the
status of current imaging studies for the detection
of nodal metastases, the classification of variable
neck dissection, and the potential effect of
imaging studies on the management of head and
neck cancer patients are reviewed. A single
nodal metastasis reduces the patients' prognosis
by approximately one - half, regardless of location
or size of the primary tumor in the head and
neck. Sensitivity and specificity of the physical
examination for the diagnosis of nodal metastasis
is unsatisfactory, resulting in both false negatives
and false positives of 25 to 40%. CT and MRI
have improved the accuracy of nodal staging
over physical examination. Clinically occult
normal-sized nodes with central necrosis or
with extracapsular spread can be identified
as metastases by CT or MR. Many borderline-sized
nodes without necrosis or extracapsular spread
remain indeterminate, however, by current #state
of the art# CT or MR. Size has been a widely
used criterion to determine the presence of
nodal metastases. Because size data are a continuum,
the relative sensitivity and specificity of
any size criteria can be adjusted by changes
in the threshold, depending on clinical setting.
Small metastatic nodes can still be missed,
and conversely, large reactive nodes cannot
be differentiated consistently from metastatic
nodes. Many authors consider contrast-enhanced
CT a standard method for assessment of extracapsular
spread. Although the incidence of extracapsular
spread increases as lymph node size, it has
been reported that 23% of nodes less than 1
cm in diameter revealed extracapsular spread
on pathologic analysis. Accurate preoperative
diagnosis of extracapsular spread in normal-size
nodes is an extremely important factor that
affects surgical management of the N0 neck.
Despite the superior contrast resolution of
MR over CT, MR has added little to the ability
to differentiate benign from malignant adenopathy.
Signal intensity of metastatic nodes does not
differ consistently from that of normal nodes
on T1w and T2w images. Central necrosis is considered
to be a characteristic finding for metastatic
lymph nodes, which appears high in signal intensity
on T2w images and low in signal intensity on
T1w images. US has been used extensively for
evaluation of cervical nodal metastasis. US
criteria for metastasis include size, grouping
of nodes, and shape of nodes. Reactive benign
nodes as well as small metastatic nodes appear
as homogeneous hypoechoic tissue. None of the
US-specific criteria have been found to accurately
predict presence of metastases. With development
of more tissue-specific imaging techniques,
patients can be better characterized according
to the status of nodal disease. |
17 |
The Third International
Congress on Peer Review in Biomedical Publication
was held in Prague (Czech Republic) from September
18-20, 1997. The Conference on peer review and
global communication, with special reference
to the importance of using electronics in editing,
reviewing and publishing of scientific reports,
was held the day after the Congress. All participants
have generally agreed that the peer review system,
in spite of its numerous deficiencies, is still
the best way for the evaluation of the manuscripts.
British researches have found out that the best
reviews are those written by the referees who
are familiar with statistics. They have also
noticed that the reviews of manuscripts, when
the authors and the institutions they come from
are not known to the referee, do not lag in
quality from those when the authors are known.
The majority of the editors are of the opinion
that reviews should not be done in a single
blind, not even in double blind manner. Some
of them believe that referees should sign their
reviews. It would make them more responsible
and would prevent data stealing from competitive
researches which happens in completely closed
system. The participants of the Congress expressed
their discontent with the evaluation of journals,
particularly clinical ones, by means of JIF
(Journal impact factor). JIF presents a ratio
between the number of citations and the number
of published articles. Therefore, BMJ (British
Medical Journal) has recently constituted a
working group with an assignment to establish
more unabridged criteria for the evaluation
of the journals. Because of the increase of
the average number of authors signing one paper,
Rannie et al (JAMA 278:585,1997) suggest to
replace the word author with the word contributor.
During the Conference on peer reviews and global
communication an interesting debate was raised
on the subject of prospective disappearing of
paper issues of biomedical journals up to 2020.
It seems that the arguments of the skeptics
are much stronger, at least for the moment being,
and I believe that printing of many biomedical
journals will continue in the next century.
My report titled Civil War and Scientific Activity
in Former Yugoslav Republics has excited inters
of many participants and a number of reporters.
The international co-authorship has been expressed
by an undimensioned "Salton's Index"
- SI - which has been defined as a number of
co-authorial articles between two countries
divided by a square root of the number of papers
in the given period - SI=NAB/sq.root(NA X NB).
The existing data clearly show an increase of
the co-authorship between Serbia and Croatia
till 1990, when it suddenly drops (almost to
50%), and slowly begins to increase again since
last year.. The co-authorship between Serbia
and Slovenia has been always very low, at this
moment it is only half of the range it had in
1991. Co-authorship between Slovenia and Croatia
had a trend of increase till 1992 when it gradually
begins to decline. The scientists from Croatia
and Slovenia have been mostly cooperated with
the scientists from Germany and Italy. Scientists
from Serbia cooperated most frequently with
the colleagues from France in previous times
but now prevails the co-authorship with the
scientists from Great Britain and USA. The use
of typical Serbian and Croatian names did not
show any "ethnical cleansing" among
Croatian and Serbian scientists in Belgrade
and Zagreb. However, the changes have happened
outside the capitals of these former republics.
It would be very useful if appropriate ministries
in Serbia and Croatia prepare a detail report
on the migration of scientists during the war
and after war period. |
18 |
INSTANT TEST FOR OSTEOPOROSIS
A new non-invasive test kit instantly identifies
osteoporosis of those who are in danger from
developing the crippling disease. The kit which
has been developed by the United Kingdom company
Cortecs Diagnostics is now being used by general
practitioners. Cortecs is also working with
pharmacists throughout Britain to make the test
available in shops.
Called Osteosal, the kit enables the doctor
or pharmacist to sample the patient´s urine
in a hand-held optical diagnostic tool called
InstaQuant. It measures the resorption of bone
markers in urine which, if found in high quantities,
indicate osteoporosis, its potential development
and an increased risk of fracture.
To quantify this accurately the rapid test is
placed in the hand-held InstaQuant optical reader
to provide a quantitative definition.
Cortecs Diagnostics Ltd
Newtech Square
Deeside Industrial Park
Deeside CH5 2NT
Tel. 44 1244 288 781
Fax. 44 1244 280 221 |
Journals Received
Meetings and Congress Reports
Medical and Scientific Meetings
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1 |
The health care policy
is closely determined and defined in the form
of thirty -two aims presented in the document
titled "The aims and measures of the health
care policy in Serbia up to 2010". They
clearly show that health care policy has been
formulated as an organized and comprehensive
social activity, as twenty out of thirty-two
aims require for their fulfillment the predominant
role and contribution of other nonhealth-care
social structures. First of all, it refers to
aim 1 (health and quality of life), aim 2 (better
living conditions for handicapped persons),
aim 4 (health for old people), aim 11 (injuries
and poisoning), aim 12 (mental disorders and
suicides), aim 13 (smoking, the abuse of alcohol
and psychoactive substances), aim 14 (quality
of waters), aims 15 an 16 (disposition of liquid
and solid waste materials), aim 17 (quality
of air), aim 18 (quality and sanitary conditions
in food preparation) and aim 19 (occupational
health protection ).
Till the year 2000 all health care priorities
will be defined within a unique health care
system and insurance, to ensure the most favorable
conditions for the most delicate groups of population
and diseases of special social and medical significance.
Health care priorities are:
-health improvement measures and disease prevention
-preschool and school age children
-women in pregnancy, including delivery time
and one year after delivery
-all above 65 years of age
-physically and mentally handicapped persons
-certain ineffective diseases
-identification and control of disease risks
factors
-persons affected with renal diseases and subject
to dialysis and after the transplantation
-persons affected with severe mental diseases
-persons with no income
The equity in the implementation of health care
protection, primary health care protection,
hospital care, family health care and family
doctor, health care protection within a municipality
and a district and the priorities of the health
care protection, as well as the aims, are the
key reforming actions but they are also the
results and partly unfulfilled obligation of
the present system.
Generally, the suggested aims and measures of
health care protection are unavoidable necessity
and real potentiality of the Republic of Serbia
for the period up to 2000.
The greatest guarantee for the implementation
of the aims and measures through the activity
of health care and other sectors lies in the
well but not uniformly expanded network of health
care institutions - 264 state-owned and about
3000 of other forms of health care institutions,
mainly in private ownership. Qualified personnel
is the second guarantee. With 19,885 physicians
(one physician/495 inhabitants), 3,814 stomatologists
(one stomatologist/2,961 inhabitants) and 1,914
pharmacists (one pharmacist/5,149 inhabitants),
the Republic of Serbia is in the level of mid
developed and developed countries European countries.
A positive feature level of health care personnel
is that 56,048 (66%) of medical workers are
engaged in outpatient institutions which present
a cheaper part of health care system, while
29,126 are engaged in hospital treatment, a
more expensive part of the system.
This way of medical workers allotment and a
well organized network of outpatient health
care institutions enable us to perform a rational
hospital treatment with only 51-53,000 hospital
beds. This is confirmed by the fact that hospital
treatment share in the overall structure of
health care expenditures is only 35%, contrary
to many other countries where this share is
above 59% of overall health care costs.
To summarize, the basic and primary aim of health
care policy and essential and integral component
of overall social and economic development of
the Republic of Serbia in this period is in
the preserving and improvement of health and
health care protection of the inhabitants, on
the basis of suggested aims and measures, current
achievements of medicine and other sciences,
improvement of efficiency and rationalization
of health care and insurance system and equalized
conditions in the implementation of health care
protection. |
2 |
Risk concentrations
of selenium in the soil, food and in the serum
of examined people have induced us to initiate
the investigation with the purpose to identify
the specific factors influencing the concentration
of selenium in serum and development of malignant
diseases. The investigation included two groups
- cancer patients group and a healthy control
group - from two Belgrade communities - Barajevo
and Stari Grad. The content of selenium in serum
was measured by means of atomic absorption spectophotometry.
The difference in the concentrations of selenium
in both groups proved to be of no statistical
significance, but we found a great difference
between the two communities. The conducted questionnaire
(the analysis of the data about the risk factors
for malignant diseases and the concentration
of selenium in the sera of examined people)
pointed out dwelling conditions and food consumption,
while smoking, alcohol consumption, heredity
malignancies and exposure to toxic substances
were not significantly correlated (p.>0.1).
As dwelling in the region with selenium deficiency
(Baraje-vo), the age of examined population,
chronic diseases and the consumption of food
with low content of selenium were the most significant
factors for the concentration of selenium in
serum, we assume that the modification of dietary
habits (more frequent consumption of cereals,
fruit and vegetable, fish and poultry and provision
of food from the various agricultural regions)
would be more favorable in the combination with
the improvement of selenium content in the soil.
TABLE AVERAGE VALUES OF SELENIUM CONCENTRATION |
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3 |
The purpose of this
study was to find out whether there were elevated
values of antibody titers to Epstein-Barr virus
in patients suffering from Hodgkin's diseases
in comparison to healthy population. We examined
a group of 49 patients with Hodgkin's disease
and of various age, clinical stages of disease
and histologic type. Serologic tests were used
for finding specific antibodies against Epstein-Barr
virus: antibodies against viral capsid antigen,
early antigen and nuclear antigen. Elevated
antibody titers against Epstein-Barr virus in
diseased persons were determined in case of
69% of patients as antibodies against capsid
antigen, in 41% as antibodies against early
antigen and in case of 55% patients as antibodies
against nuclear antigen. The average titer values
for these antibodies were significantly higher
in diseased than in healthy population. |
4 |
The nine basic models
of electron have been presented in the paper
on the basis of its link with proton in the
atom of hydrogen. The basic principles of electron
tunneling have been presented and the technological
principles of scanning tunneling microscopy
have been explained.. A review of the results
achieved by STM in the field of microscopy,
spectroscopy and nanotechnology has been given.
The obtained STM -image of C60 molecule shows
its icosahedral symmetry with the energy concentration
(be it electronical, vibrational or rotational)
in pentagons. In order to explain both structural
and energy properties of C60 molecule obtained
by STM, as well as the phenomenon of its isotropic
rotation (3x1010s-1) experimentally confirmed
by NMR, a new model of electron has been proposed.
STM method has been used in the study of various
inorganic and organic substances and in the
examination of different biologic structures.
We used STM for the purpose of structural characterization
a) polymerization forms of tubulin - microtubules
(MT) and Zn++- induced plates, b) dehydrogenated
polymer of coniferyl alcohol (DHP) and c) enzymes
of luciferase in different biochemical conditions.
Our comparative investigation of microtubule
structure and Zn++- induced plates with STM
method revealed the differences in the shape
of heterodimers and their position within the
crystal grid of these two polymerization forms
of tubulin sub-units. STM also helped us to
identified the changes of proteins within a
three-dimensional structure of tubulin (that,
according to literature data, has not been achieved
yet).
For the first time STM investigations have been
used for the presentation of spacial organization
of DHP and to show that CA polymerization in
vitro, that imitates the process of in vivo
production of lignin, is not a chaotic but highly
specific (on account of which a quasi-crystal
structure of DHP is formed).
This is the reason why luciferase is used as
a model system for examination of anesthetics.
According to literature data it is not clear
whether anesthetic binds and activates or inactivates
enzyme activity causing conformational changes
of proteins. Our results suggest conformational
change of luciferase influenced by ethanol.
The importance of these results is in the fact
that they for the first time present the "seeing"
of direct anesthetic effect to the application
of one molecule.
Experimental and epidemiologic studies demonstrate
an interaction between HBV infection and aflatoxins
in hepatocarcinogenesis. |
5 |
Kaposi's sarcoma-associated
herpes virus (KSHV), possibly through alterations
in the BM microenvironment and production of
viral interleukin-6 (vIL-6), may stimulate and
maintain abnormal plasma cell proliferation
in myeloma and related disorders. These are
the results of a study which demonstrated the
presence of Kaposi's sarcoma-associated herpes
virus (KSHV) in cultured bone marrow (BM) stromal
dendritic cells from all patients with myeloma.
The BM from normal subjects and patients with
lymphoma and leukemia did not contain KSHV. |
6 |
Gene therapy using wt-p53-expressing
adenovirus in combination with a chemotherapeutic
DNA-damaging drug could be a useful strategy
for treating human colon cancer. These are the
results of a study on the anti-tumor effects
of adenovirus-mediated wt-p53 gene transfer
in combination with a chemotherapeutic drug
on the human colon cancer cell line WiDr, which
is homozygous for a mutation in the p53 gene.
Treatment with the chemotherapeutic drug cisplatin
following infection with a replication-deficient,
recombinant adenoviral vector expressing wt-p53
(termed AdCMVp53) significantly suppressed the
growth of WiDr cells compared to single treatments
alone. |
7 |
This article summarizes
and updates the smoking habits among Swedish
men in the age groups 35-54 and 55-70, years
between 1963 and 1994, with special focus on
smoking cessation. In this period there was
a significant and continuous decrease in the
prevalence of smoking among Swedish men. During
this time ex-smoking men increased from 20%
to 41%. With the continuing fall in the numbers
of smoking men, a greater drop in lung cancer
incidence than predicted by the association
of the Nordic cancer registers in 1987. may
be expected in Sweden within the coming decade. |
8 |
In this study, specific
aspects of the cancer chemopreventive activity
of triphenylselenonium chloride were investigated.
The research was carried out in three in vivo
models of MNU-induced mammary carcinogenesis
in rats. This work indicated that a) triphenylselenonium
was able to delay the progression of premalignant
to malignant lesions; b) chronic exposure to
triphenylselenonium was required to sustain
its cancer inhibitory activity; and c) triphenylselenonium
failed to induce regression of established mammary
carcinomas or suppress the emergence of new
tumors when it was given at the late stage of
carcinogenesis. |
9 |
Proliferating cell nuclear
antigen (PCNA) is a 36 KD auxiliary protein
of DNA polymerase delta and appears to be an
essential requirement for DNA synthesis and
replication.
Authors studied immunohisto-chemical PCNA expression
with pc10 monoclonal antibody in 109 renal tumor
paraffin sections.
Nuclear immunostaining for PCNA showed a statistical
correlation with Robson«s stage, cellular type
and nuclear grade. Moreover, the number of positive
nuclei was higher in tumors presenting an elevated
mitosis count and higher degree of necrosis.
Survival was significantly poorer in patients
whose PCNA index was greater than 5%.
These results show PCNA to be a prognostic marker
for renal cell carcinoma. |
10 |
The normal p53 protein
is undetectable by standard immunohistochemistry
beca-use of its low cellular levels and very
short half-life of about 20 min. Point mutations
in the gene lead to expression of nonfunctional
mutant forms with substantially longer half-lives
and an elevation of cellular levels to 10-100
fold above normal values which can be detected
by immunohistochemistry.
The purpose of this study was to investigate
the relationship between levels of mutant p53
expression and the clinical outcome of patients
with node-positive and node-negative breast
cancer.
There was no significant correlation between
the expression of p53 and tumor size, nodal
involvement, age or histological type. However,
p53 overexpression was clearly related to histological
grade and steroid receptors, with a trend to
higher overexpression in ER-tumors or in those
with a high histological grade.
These results suggest that the immunoreactivity
of p53 may be a biologic marker of prognostic
significance in both node-positive and node-negative
patients. |
11 |
The role of hsp27 in
the regulation of cell growth has been investigated
in the breast cancer cell line MDA-MD-23 1.
Cells were co-transfected with an expression
vector carrying the human hsp27 gene (pSG-2711)
and a plasmid conferring neomycin resistance
(pWlneo). Transfected cells were selected for
neomycin resistance.
Growth analysis of transfected cell lines in
vitro revealed a lower proliferation rate of
the hsp27 overexpressing cells compared to controls.
These data suggest that hsp27 in involved in
downregulation of cell proliferation in this
human breast cancer cell line. |
12 |
This study was conducted
to elucidate the differences of clinicopathologic
findings and treatment results between patients
with gastric remnant cancer (GRC) and patients
with primary proximal gastric cancer (PGC).
There was no significant difference in the incidence
of lymph node metastasis between GRC and PGC.
However, changes in the metastatic pattern to
lymph nodes were observed in GRC. In GRC, the
tumor easily invaded the neighboring organs
due to the adhesions around the remnant stomach,
resulting in a low resectability with curative
intent. The 5-year survival rate after curative
resection for advanced GRC was 50.9%.
Although the survival rate after curative resection
for GRC patients was similar to that of PGC,
GRC patients without serosal invasion had a
better prognosis. Therefore, early detection
is an important way to improve overall survival
in GRC. |
13 |
Recently, authors described
glycosylceramide, a new marker for multiple
- drug resistance.
Glucosylceramide is the initial glycosylated
product of ceramide in the biosynthetic pathway
for glycosphingolipids. Cellular levels of glucosylceramide
are regulated by glucosylceramide synthase,
via degradation by glucocerebrosides, or through
further glycosylation or produce more complex
glucocerebrosides. Accumulation of these compounds
is pathologic.
Examination of human tumor (melanoma and breast
tumor) specimens documented presence of the
marker in all patients who had failed chemotherapy,
and absence of the marker in each of the patients
with known clinical response to chemotherapy.
These findings suggest that glucosylceramide
may hold clinical significance for the early
identification of drug-resistant tumors. |
14 |
Between November 1973
and December 1996, the in situ freezing of tumor,
i.e., cryotherapy, was performed with liquid
nitrogen (-195oC) on 235 patients with primary
liver cancer (PLC). There were no operative
mortalities or severe complications. The 5-year
survival was 39,8% for the 235 PLC patients,
and 55.4% for the 80 patients with small PLC
((<=)5cm). When analyzed with respect to
treatment modalities without considering the
size of the tumor, the 5-year survival was 26.9%
for 78 PLC. |
15 |
Pneumatic compression
is a frequently prescribed physical therapy
for patients affected by postmastectomy lymphedema.
The aim of the present phase III study was to
compare intermittent pneumatic compression to
no treatment in the management of patients with
postmastectomy lymphedema.
No statistically significant differences in
response rates between the two groups were observed. |
16 |
This study describes
that the MR appearances of malignant hypervascular
liver lesions pre and post-hepatic-arterial
chemoembolization correlate with response determined
by serial imaging studies and clinical findings. |
17 |
Technical advances permit
extensive use of MRI in the evaluation of abdominal
pathologies. The combination of MR imaging,
MR cholangiopancreatography, and MR angiography
can provide sufficient information for the diagnosis
and assessment of resectability of pancreatic
adenocarcinoma, which otherwise would require
three different exams.
Using a single procedure to obtain comprehensive
information on lesion, vessels and biliary tree
may reduce the expenses and the lenght of hospital
stay, with the additional attractive feature
of being completely noninvasive. |
18 |
Based on the combination
of a photoreactive agent which localises in
proliferating cells, and a light source directed
at the target site, PDT results in the production
of highly reactive free radicals and a cytotoxic
effect.
After administration, photosensidising agents
are known to localise selectively in certain
cell types, in particular, hyperproliferative
cells including tumour cells.
Following intravenous injection, the drug is
activated at the tumour site by the non-thermal
laser light.
The light activation produces a toxic form of
oxygen that subsequently and selectively destroys
the cancer cells, minmising damage to surrounding
normal tissue.
PDT has been used mainly for the treatment of
cancers of the skin, bladder, lung, and upper
respiratory and digestive tracts. |
19 |
Neutral endopeptidase
24.11 (NEP) protein expression is commonly decreased
in cancer cells of metastatic prostatic cancer
specimens from patients with a ndrogen-independent,
but not those with androgen-dependent, tumors.
Overexpression of NEP in androgen-independent
prostate cancer cells or incubation with recombinant
NWP inhibits cancer cell growth. Further-more,
in adrogen-dependent prostate cancer cells,
expression of NEP is transcriptionally regulated
by androgen and decreases with androgen withdrawal. |
Books Review
Journals Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 3 |
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News
1 |
Kaposi's sarcoma (KS)-associated
herpesvirus, also known as human hepesvirus
8 (HHV-8), is the first known human member of
the genus Rhadinovirus. It is regularly found
of Casteleman's disease, and in body cavity-based
B-cell lymphoma. Other members of this virus
group occur in nonhuman primates, ungulates,
rabbits, and mice and cause in part fulminant
lymphomas and other neoplastic disorders of
the hematopoietic system. Rhadinoviruses share
a typical genome structure; most characteristically,
they contain numerous sequences that appear
to be sequestered from cellular DNA.
HHV-8 reading frame K1, the positional analogue
of Stp/Tip, was found to be significantly variable
between diferent strainst. Authors found, the
reading frames for homologues of cellular interleukin
6, macrophage inflammatory proteins and an interferon-responsive
factor, and two inhibitors of apoptosis. |
2 |
Authors investigated
the prevalence of antibodies against the HHV-8
latent nuclear antigen (LNA-1) by use of an
immunofluorescence assay in 747 blood donors
from different regions of Italy; and in 163
lymphoma patients (78 of these patients had
Hodgkin's lymphomas). The prevalence of antibodies
against HHV-8 LNA-1 in the healthy population
from Italy was 13.8%. HHV-8 seroprevalence in
patients with Hodgkin's disease (24.3%) and
non-Hodgkin's lymphoma (12.9%) is not significantly
higher than that found in the healthy population
from the same regions. |
3 |
Authors described trends
in the presence of lung cancer at the time of
death in the United States from 1979 to 1992.
The mortality rate, age-adjusted to the 1980
population, increased 23.0% from 47,9 per 100
000 in 1979 to 58.9 per 100 000 in 1992. Mortality
rates of lung cancer, which are decreasing among
men, continue to increase among women. |
4 |
Authors performed a
prospective assessment of the current epidemiology
of bacteraemia in cancer patients hospitalized
in 70 different haematology and oncology departments.
A total of 494 different strains were isolated
from 1,038 blood cultures taken from 403 different
patients. Coagulase-negative straphylococci
were the ledading pathogens followed by E. coli
S. aureus sterptococci and P. aeruginosa. S
aureus and Enterobacteriaceae bacteriaemia were
more frequent in patients with end-stage disease,
while oral streptococci, Enterobactriaceae and
P. aeruginosa infections were more frequent
in patients who where severely neutropenic. |
5 |
Us researchers previously
identified immunodominant peptides in melanoma-associated
antigen gp 100. To improve antigen presentation,
the researchers introduced an aminoacid substitution
into one of these peptides, g209-217. Ten out
of 11 patients immunised with the substituted
peptide, g209=2M, developed reactiviry aginst
g209-217 and against melanoma cells. There was
no objective tumour reduction in any of these
patients, but in a further 31 patients treated
with g209-2M and interleukin-2 42% of patients
showed objective cancer regresion. Only 17%
of patients treated with IL-2 alone showed tumour
regression. European team pulsed dendritic cells-antigen-presenting
cells specialised for the induction of a primary.
T-cell response-with tumour lysate or a cocktail
of peptides known to be recognised by cytotoxic
T cells. 16 patients with advanced melanoma
were immunised with autologus dendritic cells.
Delayed-type hypersensitivity was induced to
peptide pulsed dendritic cells in 11 patients,
objective tumour responses were seen in five. |
6 |
Authors have developed
a non-invasive method utilizing feces, containing
colonocytes, in order to quantitating luminal
mRNAs. This method is capable of isolating and
quantitating specific mRNAs as candidate biomrkers
in feces by incorporating the sensitivity of
reverse transcriptase polymerase chain reaction
(RT-PCR). It is now clear that signals mediated
via select isozymes of protein kinase C (PKC)
are involved in colonic tumor development PKCs
are a family of serine-threonine kinases thought
to regulate colonic cell proliferation and differentiation.
PKCs can be divided into three different sub-categories
based on the cofactors needed for acitivation:
classical PKCs. Novel PKCs and atypical PKCs.
PKC bII protein levels increase in. Rat colonic
tumors as compared with normal colonic mucosa.
In contrast, PKC j mRNA levels are significantly
lower in human colorectal tumors than in normal
colonic mucosa PKC j protein levels also are
lower in preneoplastic colonic epithelium from
rats injected with azoxymethane (AOM) as compared
with saline-inject control rats. Therefore,
PKC bII and j may serve as biomarkers to monitor
the development of colon cancer. |
7 |
It is not yet known
at what stage of cancer development telomerase
is reactivated, but scientific interest has
recently been focused of defining the utility
of assaying for telomerase as a diagnostic and
prognostic tool. Authors prospectively assessed
the diagnostic accuracy of findings of telomerase
activity in a consecutive series of FNAs from
116 solid breast lesions that were subsequently
submitted for histologic examination. Results
of this study confirm that differences exist
in telomerase activity between neoplastic and
benign breast lesions. Low specificity of the
trap (telomeric repeat amplification protocol)
assy indicated the need for assay improvements
to increase predictivity. Mor-eover, false-positive
cases should be followed to minitor the evolution
of the lesions, although the occurrence of a
positive trap signal in fibroadenomas and dysplasias
may reflect the presence of a proliferative
disease, mainly in young patients. |
8 |
There is growing evidence
that the pienal gland has anti-neoplastic properities,
which include the action of its principal hormone,
melatonin (MLT), on the immune system through
the release of cytokines by activated T-cells
and monocytes. Study was caried out on 31 patients
with advanced solid tumor (7 gastric, 9 enteric,
8 renal, 5 bladder, 2 prostate) who either failed
to respond to chemotherapy and radiotherapy
or showed insignificant responses and were therefore
shifted to MLT therapy (10 mg/die orally for
3 months). Plasma samples were measured by immunoradiometric
assays for tumor necrosis factor alpha (TNF),
interleukin-1,2 and 6 (IL-1, IL-2, IL-6) and
interferon gamma (IFN). In adidtion compredeach
patients cytokine circulating levels before
and after MLT adminstration and found a significant
differences (p<0.05). Nineteen patients (61%)
showed disease progression. The other 12 (39%)
however, achieved disease stabilization with
no further growth of either the primary tumor
or of secondaries. |
9 |
While there are many
challenges that must be met before antiagiogenesis
can be used to effictively treat human tumors,
gene transfer strategies have the potential
to provide sustained, high, local concentrations
of antiangiogenic mediators specifically targeted
to organs containing tumors, minimizing systemic
toxicity. Antiangiognesis gene therapy strategies
will most likely be effective in a state of
low tumor burden, where this ²genetic tourniquet²
can provide trans suppression of the growth
of endothelial cells in the milieu of micrometastases.
Table 1. Gene therapy antangiogenesis strategies |
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|
10 |
Adenovirus (ADV) mediated
thymidine kinase (TK) gene therapy followed
by ganciclovir (GCV) administration is widely
used in different types of cancer. Acyclovir
(ACV) shares the same mechanism of selective
cell killing in ADV/TK positive cells as GCV
and can be used at 4.5 times higher doses in
patints wihtout significant side effects. Toxicity
and cell killing efficacy were assessed in three
ovarian cancer cell lines with different proliferation
patterns. At the same concentration, equal or
higher cell killing efficacy and bystander effect
were observed using ACV rather than GCV 2.5
and 5 times higher concentrations of ACV always
resulted in more effective cell killing than
GCV. |
11 |
The cytomegalovirus
(CMV) promoter is considered one the strongest
positive regulators. In this study toxicity,
cell killing efficacy and bystander effect of
Rous Sarcoma Virus (RSV) driven herpes simplex
thymidine kinase (TK) gene therapy was compared
with CMV driven TK gene therapy in three ovarian
cancer cell lines with different growth patterns.
ADV/CMV-TK was shown to be 2 to 10 times more
effective in tumor cell killing than ADV/RSV-TK.
ADV/CMV-TK also showed a stronger bystander
effect than ADV/RSV-TK in all three ovarian
cancer cell lines. |
12 |
Interactions between
Bcl-2 and its related proteins regulate cell
death in a number of tissues inculuding the
ovary. Some Bcl-2 related proteins (Bcl-2, Bcl-xLong,
Mcl-1, and Dad-1) function as cell death repressors,
whereas others (Bax, Bcl-xShort, Bak, and Bad)
facilitate apoptosis. In this paper all Bcl-2
related proteins were expressed in normal and
malignant ovarian tissues. Higher levels of
Bcl-2 versus Bcl-xLong were observed in normal
ovary, compared to a majority of cancer samples.
Increased levels of death inducing Bax were
related to malignant transformation across all
types of ovarian cancer inculded in this study.
The results provide further evidence that a
balance of expression among Bcl-2 family members
may regulate ovarian cancer cell survival. |
13 |
Both normal tissue and
tumors have an elaborate control system for
inducing endothelial cells to grow and form
new blood vessels. Angiogenesis is induced and
regulated in part by physiologic hypoxia in
the tumor, inducing production of vascular endothelial
growth factor (VEGF) that stimulates growth
or, conversely, by the suppresion of the production
angiogenesis inhibitors, such as endostatin
or angiostatin. Endothelial cells are also a
critical new target for controlling metastasis.
Cancer cells that escape the primary lesion
and survive in the circulation must first dock
at the specific site of metastasis, locking
onto the ednothelial cell surface through adhesion.
The atteched tumor cell must then cause the
endothelial cell barrier to retract, following
which the tumor cell undocks and passes thorugh
the vascular wall to establish tumor growth
and induce angiogenesis. In an important earlier
study, Pienta et al. had reported that a modified
citrus pectin blocked the metastatic ability
of rat prostate cancer cell lines to metastasize
in vivo. The current study reports a potentially
valuable new model for in vitro studies of human
bone endothelial cells and their role in tissue-specific
metastasis through the adhesion of cancer cells.
This model could be expanded to determine how
specific the binding to endothelial cells from
different organs is and to measure the specificity
of endothelial cell adhesion to other types
of cancer cells. |
14 |
Endometrial induction
of the angiogenic factor adrenomedullin by tamoxifen
is part of the mechanism by which tamoxifen
causes endometrial hyperplasia. Adrenomedullin
is a novel growth factor for endothelial cells
and is angiogenic in vivo in the chich chorioallantoic
membrane assay. Immunohistochemical analysis
of endometrial sections have shown that while
macrophages in the endometrijum express adrenomedullin
at a low level, endometrial macrophages of women
receiving tamoxifen strongly express adrenomedullin.
This observation leads to an additional hypothesis
about the mechanisms by which tamoxifen, induces
endometrial hyperplasia in premenopausal women. |
15 |
Because Tamoxifen has
both oestrogenic and antioestrogenis effects,
it can induce lipid metabolism dysfunction.
Authors have carried out abdominal computed-tomography
(CT) examinations annually for all patients
with breast cancer in the past 8 years. 24 (36.4%)
of 66 patients who are receiving or have received
oral tamoxifen (40 mg daily) for 3-5 years showed
fatty changes of the liver. The onset of fatty
liver was observed at 1-44 months after the
start of tamoxifen intake. The area of fatty
changes of liver usually progressed from focal
to diffuse. The changes disappeared between
1 and 14 months after termination of tamoxifen
treatment. Abnormalities were seen earlier on
CT examination than in laboratory data. |
16 |
Alarge nationwide cohort
study showed no evidence of an association between
breast implants and connective tissue disease.
This retrospective cohort study of all of the
women in the Swedish national inpatient registry
from 1964 to 1993 included 7.442 women with
implants for cosmetic reasons or for reconstruction
after breast cancer surgery and 3.353 women
with breast reduction surgery. Twenty-nine women
with implants were hospitalised for definite
connective tissue disease compared with 25.5
expected on the basis of general population
rates. There were no diagnoses of systemic sclerosis,
and no significant excess of risk for polymyalgia
rheumatic, fibromyalgia, or several other related
disorders. Among women who underwent breast
reduction surgery, 14 were hospitalised for
definite connective tissue disease compared
with 10.5 expected. |
17 |
Tea is one of the few
agents known to inhibit carcinogenesis at the
post-initiation stages. Black tea polyphenols,
green tea extract and EGCG (-) epigallocathe
hin-3-galate have been shown to inhibit the
growth of rat hepatoma, mouse erythroleukemia
and several human cancer cell lines. Induction
of apoptosis in human lymphoid leukemia cells
has also been demonstrated. The results suggest
that the growth inhibitory activity of tea extracts
is caused by the activities of different tea
polyphenols, and that tea polyuphenol-induced
production of H202 may mediate apoptosis and
that this may contribute to the growth inhibitory
activities of tea polyphenols in vitro. |
18 |
Radiology Department
of the Catholic University of Leuven, Belgium,
organized the ERASMUS Course from magnetic resonance
- module CNS I. Foruteen themes were presented:
Clinical application of basic principles of
MR; Normal brain on MR; MR angiography; AV malfomations;
Ichemic diseases of brain; Brain hemorrhage;
Hydrocephalus; Diseases of white matter; MR
in epilepsy; Inffective diseases of brain; Supratentorial
tumors; MR of sellar an aparsellar region; MR
of cranial nerves; New MR techniques - diffusion,
perfusion. After the lectures had been given
there was a test examination for the participants
- multiple choicefifty questions. Within the
class of radiologists from Eastern Europe, Dr.
Robert Seminc from the Institute of Oncology,
Sremska Kamenica won the first prize. |
19 |
PROMOTIONS IN SCIENTIFIC
DEGREES IN 1998
Ljubomir Muzikravic - Ph.D. Sc.
Med. Marko Erak - Ph.D. Sc.Med.
PROMOTIONS IN UNIVERSITY RANKS IN 1998
Marica Miladinov-Mikov - assoc.Prof.
Jovan Babic - assoc.Prof. |
20 |
The topics presented
on the meeting of Oncologic Forum in 1998
1. February 11, 1998: Clinical and Pathological
Consultations
2. April 1, 1998: Interdependence of the Structure
and Activity in Certain Antiestrogens and Antiandrogens;
- Lecturer: Slobodanka Stankovic, M.D., Ph.D.,
Institute of Physics, Novi Sad
3. April 4, 1998: Clinical and Pathological
Consultations (Thanatological Analysis)
4. April 15, 1999: Taxol in Oncology Carboplatil
- AUC Dosage - Lecturer: AnicaVlahovic, M.Pharm.
Andrej Sortic, M.D., TT Medic-Beograd-Bristol
Mayers Squibb
5. April 29, 1998: Blood Flow Velocity in Blood
Vessels by the Method of Magnetic Resonance
- Lecturer: Maja Stevanov, physicist, Strasbourg |
21 |
Titles of the lecture
GIVEN at the meeting of Oncologic Forum for
nurses from JANUARY 1 to May 31, 1998.
1. January 27, 1998: Cytological Diagnostics
(PAPA) - Lecturer: Milica Zivaljevic, M.D.
2. February 3, 1998: Immunogenetcs - specter
of analyses and importance - Lecturer: Mira
Baltic, biologist
3. February 24, 1998: Clinical Pharmacology
(6-CSF) - Lecturer: Natasa Djurasinovic, M.D.
4. March 3, 1998: Conditions for good laboratory
analyses - Lecturer: Julije Klenanc
5. March 10, 1998: Basic principles of Magnetic
Resonance Imaging - Lecturer: Mladen Prvulovic,
M.D., Ph.D.
6. May 19, 1998: Magnetic resonance in diagnostics
of tumors and other diseases of CNS and spinal
cord - Lecturer: Robert Seminc, M.D.
7. May 26, 1998: Magnetic resonance in oncologic
diagnostics - Lecturer: Oto Adjic, M.D. |
Commentary
Books Received
Books Review
Meetings and Congress Reports
Medical and Scientific Meetings
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Issue 4 |
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News
1 |
There is a substantial
body of experimental evidence that supports
the oncogenic role of HGF/SF-Met signaling pathways.
This is putatively mediated by autocrine or
paracrine mechanisms that promote tumor cell
growth, invasion and angiogenesis. Autours review
the evidence that HGF/SF and Met receptor play
significant roles in the pathogenesis and biology
of human cancers. |
2 |
In this study authors
reported an in vitro 1H magnetic resonance spectroscopy
(MRS) characterization of water soluble metabolites
obtained from 17 low grade extra and intracerebral
human tumors (8 meningiomas, 5 oligodendrogliomas,
2 subependimomas and 2 ependimomas). In addition,
the in vivo localized 1H MRS results for 4 of
the meningiomas are reported. The main metabolic
features characterizing low grade tumors were
investigated. Meningiomas are characterized
by high Cho/Cr and Ala/Cr ratios; in many cases
both in the in vitro and the in vivo spectroscopy
these ratios cannot be evaluated, due to the
absence of the Cr metabolite. Low grade oligodendrogliomas
are characterized by low Cho/Cr ratios. High
amounts of myoinositol are found in the spectra
of ependimomas and subependimomas which are
distinguished by different Cho/Cr ratio values
and by a different Ala content. |
3 |
Transient transfection
studies of human HepG2 and mouse Hepa hepatocarcinoma
cells with a reporter gene construct regulated
by a human antioxidant responsive element (ARE)
from the NQO1 gene demonstrated that the element
is responsive to low oxygen conditions. The
antioxidant N-acetyl l-cysteine (NAC) strongly
inhibited basal aerobic reporter gene activity
in HepG2 cells without obviously affecting the
hypoxic induction, as is consistent with ARE
sensitivity to oxidative stress in aerobic cultures.
Electophoretic mobility shift (EMS) assays of
nuclear extracts of HepG2 and Hepa cells lysed
under aerobic or hypoxic conditions or after
exposure to the phenolic compound 3-(2)-tert-butyl-4-hydroxyanisole
(BHA), showed specific and constitutive protein
binding to the ARE under all of these conditions.
Taken together, these findings show that the
ARE can mediate gene expression in response
to low oxygen conditions. Co-ordinately regulated
expression of ARE-dependent genes, such as phase
II detoxification enzymes, may be an important
phenotype of solid tumors containing significant
regions of pathophysiological hypoxia. |
4 |
The data obtained indicate
that heme oxygenase, known to be a stress-inducible
gene, may be involved in cellular pathways critical
to the carcinogenic activity of Cr(VI) in normal
human lung cells. Intracellular glutathione
levels and reactive oxygen species do not appear
to be primarily responsible for the stress response,
induced by Cr(VI)in the studied human cells.
|
5 |
Rebeck at al. determined
that a single base change in the 5' flanking
region of the CYP3A4 gene was associated with
higher clinical stage and grade in men with
prostate tumors. Their results sugest that mutations
in the CYP3A4 gene may influence prostate carcinogenesis. |
6 |
With the goal of restoring
the tumorsuppressing function of the p53 gene,
Y. Zou et al. investigated the feasibility of
treating precancerous and cancerous endobronchial
cells by in vivo gene replacement, through use
of a regionally administered nonviral delivery
system-the DP3-p53 cationic liposome. The researchers
studied the ability of DP3 to deliver a plasmid
containing a wild-type p53 gene to normal bronchial
epithelium in transgenic mice that lack the
p53 gene and to bronchial tumor cells (lacking
functional p53 genes) implanted in immunodeficient
nude mice. In therapeutic experiments, DP3-p53
significantly inhibited lung tumor formation
and prolonged survival in their in vivo model.
In an accompanying editorial, R. Scheule assesses
alternative gene therapies for lung cancer,
such as the cationic lipid-mediated gene delivery
system, which are needed because patients with
lung cancer have low rates of overall 5-year
survival (13% or less) with current treatments.
Scheule writes that before cationic lipid vectors
can be routinely used to treat lung cancer by
replacing defective genes like p53, additional
information needs to be generated regarding
the vectors toxicity, metabolism, and effects
on the physiology of the lung. |
7 |
Cancers associated
with BRCA 1 and BRCA 2 gene mutations that predispose
women in certain families to breast cancer have
been shown to differ from each other in histopathologic
appearance. Further, both of these classes of
tumors differ from sporadic (control) cancers
found individuals unselected for family history.
S. Lakhani et al, on behalf of the Breast Cancer
Linkage Consortium, report a multifactorial
analysis of cytologic and tissue-architectural
features of these cancers. They find that cancers
associated with BRCA 1 and BRCA 2 mutations
exhibit statistically significant differences
from sporadic cancers and that the sets of significant
differences associated with the two mutations
are not identical. Identification of such key
histologic differences may ultimately aid in
the clinical management of patients. |
8 |
The development of drug-resistant
cells can lead to relapses in patients with
lymphoma, requiring the development of new therapeutic
approaches for this disease. Because overexpression
of the c-MYC proto-oncogene has been observed
in B-cell lymphomas, J. Smith and E. Wickstrom
investigated the effectiveness of a series of
oligonucleotides containing antisense c-MYC
sequences in inhibiting the development of these
tumors. The researchers tested the antisense
oligonucleotides and an immunostimulatory oligonucleotide
(mcg) in immunocompetent mice injected with
tumor cells from a transgenic mouse model of
Burkitt's lymphoma. In comparison with control
treatments during a 7-day treatment regimen,
two of the antisense oligonucleotides (myc 6
and myc 55) substantially delayed tumor onset,
decreased final tumor mass, and decreased the
relative expression ofc-Myc protein. A 14-day
regimen of myc 55 alternating with mcg resulted
in complete inhibition of tumor formation during
the therapeutic schedule. |
9 |
According to the Decision
of the increase of health care services all
diagnostic and therapeutic services with an
item price above din. 57 are to be invoiced
separately from the price for each hospital
day. It is also stated that the price of daily
used drugs which is above 28 dinars should also
be invoiced separately. This decision shall
be applied in practice from October 1. |
10 |
At the beginning of
this year the government of the Republic of
Serbia approved the Information on family planning
strategy. This 43 pages long document was elaborated
by a group of experts from the Ministry for
family care and the Republic center for family
planning, Institute for health protection of
mother and child in Serbia. This program character
document is the first attempt in making a comprehensive
strategy government action in the sphere of
family planning in our environment. Family planning
has been defined as a simultaneous - individual
need, powerful prevention measure, style of
living, element of individual and reproductive
social consciousness. |
11 |
Hemomed, the biggest
Yugoslav manufacturer of dialyzers, is planning,
in compliance with GMP and ISO standards, to
win CE sign for all products from its scope
of production. Semisulphone dialyzer with water
sterilization manufactured by Hemomed , an affiliated
firm of Hemofarm koncern from Vrsac, is the
first product in Yugoslavia that was awarded
with CE sign. The company plans to finalize
procedures for obtaining the right to use this
sign for dialyzers with ethyleneoxide sterilization
and AV systems.
Being aware that since June this year only medical
equipment with CE sign can be distributed on
the EC market, the company has made all preliminary
works for the elaboration of documentation necessary
for the evaluation and obtaining of this sign.
The production capacity of Hemomed , a joint
venture enterprise of Hemofarm and a manufacturer
of dialyzers from Germany, covers the annual
manufacture of 800 thousand dialyzers of various
types and the auxiliary dialyzing material. |
12 |
The hypothesis that
patients whose breast tumors exhibit high erbB-2
expression benefit from dose-intensive CAF should
be further validated before clinical implementation.
Interactions between erbB-2 expression, p53
expression, and CAF dose underscore the complexities
of predictive markers where multiple interactions
may confound the outcome. |
13 |
Mutagen sensitivity
assays may aid in identifying individuals at
risk of cancer, and use of parallel assays with
two mutagens may improve risk predictability. |
14 |
The correlation between
hTERT mRNA and telomearse activity shown here
indicates that hTERT mRNA has potential for
hepatocellular cancer diagnosis. |
15 |
Onoda et al. quantified
telomerase activities in thyroid tumors by a
telomeric-repeat-amplification-protocol-based
assay in an attempt to determine its clinical
significance. Telomerase activity was detected
in 10 of 18 (55.6%) malignant tumors, but in
none of the four benign lesions, and the level
of telomerase activity correlated significantly
with the progression of the clinical stages.
High activity was determined in 4 (80%) of 5
mestastatic lesions in the lymph nodes. Five
(45.5%) of 11 non-tumoral specimens from malignant
cases showed telomerase activity, while none
of the four from benign cases did. In conclusion,
the determination of telomerase activity might
be useful in determining the existence and progression
of thyroid cancer. |
16 |
Authors enrolled 19
cancer patients (11 females, 8 males) with thrombocytopenia
after standard dose of chemotherapy to receive
IL3 10 mg/kg/day s.c. until hematologic recovery.
Therapeutic success was obtained in 69.6% of
cycles: a major response in 39.3% and a minor
response in 30.3% of cycles. They obtained the
best results in case of platelet count`49.000/mm3.
The main toxicity was a flu-like syndrome. In
two cycles (6%) authors registered allergic
episodes with flushing and lipothymia. In the
47% of cycles evaluable for toxicity no side
effect was registered. |
17 |
Prostatic carcinoma
is the most common type of male cancer found
in the Western world and its distant metastasis
becomes a life threatening event in tumour bearing
patients. However, the biology of prostate cancer
and metastasis is poorly understood. Authors
were review the progress made in the last decade
on the molecular and cellular biology of cell-cell
adhesion molecules in the invasion and progression
of prostate cancer, with emphasis being placed
on E-cadherin and its associated molecules. |
18 |
Authors used stage of
disease at the time of diagnosis to evaluate
how inclusion of people at different stages
in the disease process can influence associations
between environmental exposures and colon cancer.
For most environmental exposures evaluated,
including physical activity, body size, use
of aspirin and of non-steroidal anti-inflammatory
drugs, and dietary intake of folate and fiber,
authors did not observe differences in patterns
of association by stage of disease at diagnosis.
However, for total energy and red meat intake
(men only), alcohol consumption, cigarette smoking,
and family history of colorectal cancer among
first degree relatives, patterns of associations
were stronger when colon cancer was detected
at an earlier stage of disease progression than
when it was detected at a more advanced stage. |
19 |
In this paper 1178 glioma
and 330 meningioma cases were individually or
frequency matched to 2236 controls. Only exposures
that occurred at least 5 years before diagnosis
and head injuries that received medical attention
were considered. Risk for ever having experienced
a head injury was highest for male meningiomas
(odds ratio OR=1.5, 95% confidence interval
CI : 0.9-2.6 but was lower for "serious"
injuries, i.e. those causing loss of consciousness,
loss of memory of hospitalization (OR=1.2, 95%
CI:0.6-2.3). Among male meningiomas, latency
of 15 to 24 years significantly increased risk
(OR=5.4; 95% CI:1.7-16.6), and risk was elevated
among those who participated in sports most
correlated with head injury (OR=1.9; 95% CI:0.7-5.3).
Odds ratios were lower for male gliomas and
in females in general. |
20 |
MVC is a potent prognostic
indicator in papillary thyroid carcinoma. |
21 |
Authors concluded that
inhibition of spontaneous apoptosis induced
by either phenobarbital or clofibrate is accompanied
by increases in the endogenous levels of peroxides
and by significant induction of catalase gene
expression. Furthermore, the lack of effect
of both compounds on TGFbeta1 - induced apoptosis
could be a consequence of the inability of these
two compounds to counteract the epressing effect
of TGFbeta1 on expression of catalase. |
22 |
Bronchogenic carcinomas
arise from bronchial epithelial cells (BECs).
Inhalation exposure of BECs to nitrosamines
in cigarette smoke is an important exogenous
risk factor for malignant transformation of
BECs. Among the cytochrome P450 enzymes capable
of metabolizing nitrosamines, CYP2A6, CYP2A1
and CYP2B6 are expressed in BECs. CYP2A6 was
expressed in 20/20 cases and quantifiable in
18/20 cases, CYP2E1 expression was observed
in 9/20 cases. Further, the mean level of CYP2A6
among smokers (260mRNA/106 b-actin mRNA) was
significantly lower than among non-smokers. |
23 |
Glutathione S-transferases
(GSTs) are a family of enzymes involved in the
detoxification of a wide range of chemicals
including chemical carcinogens. Human cytosolic
GSTs are divided into four major classes; a,
m , p, and q. This study was performed to evaluate
the influence of age and gender on the GST isoenzyme
expression and glutathione (GSH) content in
lymphocytes. GST isoenzyme levels were determined
by densitometrical analysis of western blots
after immunodetection with monoclonal antibodies.
Lymphocytic GSTm and p levels were not correlated
with age or gender. GSTa was not detectable
in lymphocytes. In age group 60-80, GSH content
was significantly lower as compared with age
groups 20-40 and 40-60 in both sexes. Since
high GSH is an essential factor in the detoxification
of many compounds, these data indicate that
the detoxification potential of the GSH/GST
system in lymphocytes may decrease with age
in man. |
24 |
Brazilian multimillionaire
Mucio Athayde has established a fund and assigned
UICC to award scientists for their achievements
in the filed of cancer treatment. This year,
during the International Congress of Oncologists
held in Brazil on August 24, 1998 the award
was granted to Prafulla Bhagubhai Desia, a surgeon
and clinical scientist from India. Performing
his duties as a director, chief surgeon, educator
and a researcher in Tata Memorial Center in
Mumbai, India, (1965-1989) this distinguished
scientist has created and established a cancer
register, a computerized information system,
a department for cancer prevention, an educational
center and a section for professional education
and a clinic for rehabilitation of children
cured from cancer. |
25 |
Subcortical cyst of
the femoral neck (SCFN herniation pit) is a
degenerative, clinically asymptomatic alteration,
with typical radiological finding for location,
size and shape, which should be differentiated
from other pathological conditions of the femur.
In our material SCFN was found in 14 (3.5%)
cases among 402 patients with verified malignant
disease. These results are in agreement with
the reported incidence of 4% in the adult population.
Difference of frequency of SCVF between patients
with malignant diseases and adult population
was not found. |
26 |
This paper presents
results of several year long study on chromosomal
aberration in presons professionally exposed
to radionuclides. Cytogenetic investigations
showed different incidence of chromosomal aberration
within the period 1986-1990. When it is percentage
was even 28%, but in 1996 that percentage was
19.1%. |
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
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Volume 5 |
Issue 1 |
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News
1 |
Non-Hodgkin's lymphomas:
histopathological subtypes, clinical stages,
treatment and disease evolution
S. RISTIC, M.
DRAGOVIC, V. JOVANOVIC, M. RADOJKOVIC, M. RASIC,
D. BEGOVIC
Results of treatment and disease evolution were
analyzed in 20 patients with different histopathological
subtypes/Working Formulation (WF)/and clinical
stages (Ann Arbor) of Non-Hodgkin lymphoma.
More than half ot the analyzed patients were
male, over the age of 50 years. Fifty percent
of patients had histopathological subtypes of
high grade lymphoma. Different chemotherapeutical
regimens were applied (COP, CHOP, M-BACOP).
Additional radiotherapy, combined with chemiotherapy
was used in 30 percent of patients. Positive
therapeutical response was observed in 75 percent
of patients. Complete remission (CR) was achieved
in 50 percent, and partial remission (PR) in
25 percent of patients. Poor therapeutic response
was present in 25 percent of analyzed patients.
Relapse was observed in 30 percent of patients.
Survival rate more than 24 months was present
in 70 percent of patients, and 25 percent of
patients survived more than 60 months (5 years).
Bilt Hematol 1996;24:19-22 |
2 |
An effect of treatment
of patients with Hodgkin's lymphoma with the
new salvage protocol: Cyclophosphamide, etoposide,
methotrexate, methyl-prednisolone, chlorambucil
SRETENOVIC M,
MIHALJEVIC B, JANKOVIC S, BANICEVIC B, PETROVIC
M.
The effects of the treatment of patients with
Hodgkin's lymphoma, using the new salvage combination
are presented. The protocol consists of the
following drugs: cyclophosphamid, etoposide,
methotrexate, chlorambucil and methyl-prednisolone.
Median age of ten patients treated was 48 years.
The most of them werew in the cilinical stadium
IV. The indications for the usage of this protocol
were: resistant disease, the first and the second
relaps. One partial remission and one minimal
response were achieved. This pilot study dose
not justify prospective randomized study with
other effective salvage protocols.
Bilt Hematol 1996;24:26-8 |
3 |
Helicobacter pylori
and Primary Gastric Lymphoma
A histiopathologic and Immunohistochemical Analysis
of 237 Patients
Shotaro NAKAMURA,
Takashi YAO, Kunihiko AOYAGI, Mitsuo LIDA, Masatoshi
FUJISHIMA, Masazumi TSUNEYOSHI
H. pylori was detected in 145 of 237 patients
(61%) with gastric lymphoma. The frequency of
H. pylori positivity was higher in patients
with lymphoma restriceted to the mucosa and
submucosa (76%) than in those with lymphoma
invading beyond the submusoa (48%) (P<0.001),
and was also higher in patients with low grade
mucosa-associated lymphoid tissue lymphoma (72%)
than in those with high grade tumors (55%) (P<0.05).
The frequency of H. pylori positivity in patients
with lymphoma was lower than in those with chronica
acitve gastritis (100%) (P<0.001) or peptic
ulcer (91%) (P<0.05). In patients with lymphoma
restricted to the mucosa and the superficial
portion of the submucosa, the frequency of H.
pylori positivity (90%) was as high as that
observed in patients with chronic active gastritis
and peptic ulcer. The H. pylori grading score
for patients with lymphoma (0.9±1.0) was lower
than for those with chronic active gasritis
(1.9±0.8) (P`0.001) peptic ulcer (2.2±1.0) (P<001),
or gastric carcinoma (1.2±1.1) (P<0.05).
Cancer 1997;79.3-11 |
4 |
High incidence of
Helicobacter pylori infection detected serologically
in the residual stomach caused by gastric cancer
Naoto KURIHARA,
Tetsuro KUBOTA, Yoshihide OTANI, Kochiro KUMAI,
Masaki KITAJIMA
Helicobacter pylori (HP) may be involved in
the pathogenesis of chronica gastritis, gastric
ulcer and intestinaltype gastric cancer. In
the present study, we detected HP infection
serologically after gastric surgery by measuring
the serum anti-HP IgG levels and determinig
their correlation with the serumu gastrin levels.
The HP-infection rate after distal gastrectomy
was 81.5% (75/92). The s11erum gastrin levels
after distal gastrectomy were within the normal
range and there was no significant correlation
between the serum gastrin level and serologically
detected HP infection, nor between the number
of days after distal gastrectomy and HP infection.
The high HP infection incidence after distal
gastrectomy was confirmed serologically and
endoscopically, suggesting HP infection plays
some role in the superficial gastritis of the
residual stomach without correlating with the
serum gastrin levels.
Oncol Rep 1997;4:103-6 |
5 |
ras genes, p53 and
HPV as prognostic indicators in human cancer
(Review)
D.A. SPANDIDOS,
G. SOURVINOS, M. KOFFAThe
role of oncogenes and onco-suppressor genes
in carcinogenesis has been well documented.
Among oncogenes and onco-suppressor genes, ras
and p53 genes respectiely are involved in the
majority of human tumours. Alost all genes in
various frequencies. the clarification of their
role in humor tumours may be useful in the early
diagnosis and treatment of the disease. Human
papillomaviruses (HPV) types 16, 18 and a number
of additional HPV types have in other anogenital
cancers. The aim of the present study is to
summarise available information of the role
of ras and p53 genes and HPVs in carcinogenes
and to reveal their potential application in
the clinical practice.
Oncol Rep 1997;(Suppl
4):2161-8 |
6 |
Two distinct commonly
deleted regions on chromosome 13q suggest involvement
of BRCA2 and retinoblastoma genes in sporadic
breast carcinomas
Kazuhiro TSUKAMOTO,
Noriko ITO, Masataka YOSHIMOTO, Takuji IWASE,
Taksahi TADA, Fujio KASUMI, Yusuke NAKAMURA,
Mitsuru EMI
The results indicate that BRCA2 and RB are independent
targets of allelic loss and that inactivation
of either of these genes may play a role in
the development of some sporadic breast carcinomas,
particularly those of the solid tubular type.
Cancer 1996;78:1929-34 |
7 |
A comparison of
proliferation markers and their prognostic value
for women with endometrial carcinoma
Ki-67, Proliferating cell nuclear antigen, and
flow cytometric S-phase fraction
Britta NORDSTRÖM,
Peter STRANG, Reinhold BERGSTRÖM, Sten NILSSON,
Bernhard TRIBUKAIT
Conclusions: Ki-67 and, to a lesser extent,
PCNA, give approximate estimates of the growth
fraction, whereas SPF only reflects the proportion
of cells in S-phase. However, SPF is by far
the strongest predictor of survival. Cancer
1996;78:1942-51.
Cancer 1996;78:1942-51 |
8 |
Genetic testing may
prevent hereditay nonpolyposis colorectal cancer
A. de la CHAPELLE
Fortunately, the development is faster in the
case of diagnostics. Usually the cloning of
a disease gene quckly leads to more accurate
diagnostics. In diseases with Mendelian inheritance,
the gene tests are accurate and reliable, can
be made before the appearance of symptoms, and
even allow the screening of large numbers of
people. Clearly, there is one group of individuals
that immediately benefit from genetic testing:
those who are found not to carry the defect.
Regrettably, the detection of a gene defect
often does not bring immediate benefit, at least
not in a way that would affect the prognosis
of the patient. This is the case in Huntington
disease which is often given as an example;
a disease with adult age onset and for which
no cure or prevention methods are currently
available. In contrast, cancer patients have
immediate benefits beause the cancer can be
more effectively treated, even after onset,
and the earlier the treatment is started the
better hte prognosis. For example, n terinoblastoma
families prenatal or early postnatal genetic
testing can provide a tool for well-focused
clinical surveillance of infants at high risk.
Ann Oncol 1996;7:883-5 |
9 |
Gene therapy for
cancer: what have we done and where are we going?
Jack A. ROTH,
Richard J. CRISTIANO
Gene-based therapies for cancer in clinical
trials include strategies that involve augmentation
of immjnotherapeutic and chemotherapeutic approaches.
These strategies include ex vivo and in vivo
cytokine gene transfer, drug sensitization with
genes for prodrug delivery, and the use of drugresistance
genes for bone marrow protection from hihg-dose
chemotherapy. Inactiation of oncogene expression
and gene replacement for tuor suppressor genes
are among the strategies for targeting the underlying
genetic leions in the cancer cell. A review
of clinical trial results to date, primarily
in patients with very advanced cancers refrectory
to conventional treatments, indicates that these
treatments can mediate tumor regression with
accepably low toxicity. Vector development remains
a critical area for future research include
modifying viral vectors to reduce toxicity and
immunogenicity, increasing the transduction
efficiency of nonviral vectors, enhaning vector
targeting and specificity, regulating gene expression,
and identifying synergies between gene-based
agents and other cancer therapuetics. (J Natl
Cancer Inst 1997:88:21-39)
J Natl Cancer Inst,1997;89:1 |
10 |
p53 and Rb1 protein
expression: are they prognostically useful in
colorectal cancer?
DN POLLER, KJ
BAXTER And NA SHEPHERD
The expression of the p53 and Rb1 proteins was
examined in an unselected consecutive series
of 250 primary operable colorectal carcinomas
with a mean follow-up of 4.3 years (range 43-77
months). The overall cancer-specific mortality
was 34,8%, with 87 cancer deaths and 35 deatsh
as theresult of other causes. Expression of
p53 protein was identified in 152 of 250 (60,8%)
cases, with expression of Rb1 protein in 207
of 250 (82,8%) cases. There was no association
of p53 or Rb protein with patient age, sex,
tumour site, tumour sixe, tumour type, tumour
grade, peritumoral fibrosis, tumour lymphocytic
infilrate, nature of the tumour margin, extramural
vascular invasion, number of lymph nodes or
high apical ymph node involved or local peritoneal
infiltration by tumour, Dukes' stage or Jass
group. There was no difference in overall survival
or recurrence-free survival for those cases
that showed p53 expression or Rb1 protein expression
compared with those cases showing absence of
p53 or Rb1 protein expression, although patients
with tumours showing aberrant (reduced) Rb1
protein expression demonstrated shorter recurrence-free
survival and ovarall survival. The effect of
'aberrant' Rb1 protien expression and shorter
recurrence-free and overall survival did not,
however, achieve independent statistical significance.
The results from this study would suggest that
expression of p53 and Rb1 proteins does not
appear be useful in determining the prognosis
of operable colorectal cancer.
Br J Cancer,1997;75:87-93 |
11 |
Summary of the epidemiological
situation concerning malignancies in the province
of Vojvodina in the period 1985 to 1994
Marica MIKOV,
Nenad VRANJES
Based on the data from the Cancer registry of
Vojvodina , in the observed period 1985 to 1994,
a total of 38,224 newly diagnosed cases of malignancies
of various localisation in men and 26,325 in
women were registered (sex ratio: 1.45:1). It
means that , on average, 6,455 new cases were
diagnosed annually. In the same period 26,325
men and 19,865 women died from the various malignancies.
(Sex ratio: 1.33:1), i.e. theoretic lethality
was 68.9% for men and somewhat lower 75.5% for
women.
The average incidence rate for all malignancies
was 391.6, the average mortality rate 269.7
per 100.000 men. For women it was 331.1 and
193.2/100.000 respectively.
Age standardized incidence rate (World population)
was 284.8 for men and 205.2/100.000 for women.
Age standardized mortality rates were 195.0
and 114.0 respectively.
The highest average incidence rate in the observed
period for men counts for the lung cancer 108.4/100.000,
followed by the stomach cancer with 31.6 and
skin malignancies (excluded melanoma of the
skin) with 27.6/100.000.
In women the breast cancer is the leading one
concerning the average incidence rate of 69.4/100.000.
The carcinoma of cervix uteri with 27.9 and
skin malignancies with 26.6/100.000 were the
second and third frequent localisation diagnosed
by women. |
12 |
A three-center Phase
1 clinical trial of diethymorspermine
Sinisa RADULOVIC
Phase I-II
A three-center Phase 1 clinical trial of diethymorspermine,
an anticancer agent from SunPharm Corporation
(Jacksonville, FL) and Warner-Lambert Company
(Morris Plains, NJ), determined the maximum
tolerated dose. The synthetic polymine analogue
was developed to replace naturally occurring
polyamines and reduce the ability of cancer
cells to proliferate.
A Phase I-II trial of a proprietary compound
from Alkermes Inc. (Cambridge, MA) as a combination
therapy with the chemotherapeutic agent carboplatin
for patients with metastatic brain tumor began
at two European centers. RMP-7 is designed to
improve drug delivery to the brain by transiently
increasing the permeability of the blood-barrier.
The study involves 14 patients with brain tumors
resulting from metastasized lung cancer.
Aphton (Woodland, CA) completed a Phase I-II
trial of its vaccine-like product Gastrimmune
for the treatment of gastrointestinal adenocarcinomas.
Nearly 50 terminally ill patients with colon
cancer that had metastasized t the liver participated
in the dose-ranging study. The drug was shown
to be safe and efficacious. Pivotal Phase 3
trials will follow.
Cel:Sci Corporation (Alexandria, VA) began a
Phase I-II clinical trial of an immune modulating
drug for the treatment of advanced head and
neck cancer that has resisted previous therapies.
The open-label, randomized, dose-ranging study
of Multikine, a natural combination of cytokines,
is being conducted at several Canadian health
centers. The 30 patient volunteers will receive
the drug for at least two treatment cycles (a
total of at leas 45 days).
Imutec Corporation (Toronto, Ontario, Canada)
began a Canadian Phase I-II clinical trial of
a treatment for drug-resistant, HIV-related
Kaposi's sarcoma. The 14-month, single-center
study will examine tumor response, specific
immunological parameters, quality-of-life data,
and survival rate in 16 patients treated with
Virulizin.
ML Laboratories PLC (Liverpool, UK) initiated
a three-center, 30-patient Phase II clinical
trial of a prostate-cancer vaccine. The vaccine
is the first product to come from Gonadotrophin
Releasing Hormone Immunotherapeutic (GnRHI),
the novel compound that the company licensed
from Proteus International earlier this year.
Preclinical studies indicated that the vaccine
avoids the painful side effects normally associated
with the standard treatments, and requires less
frequent administration.
Phase III
Progenics Pharmaceuticals Inc. (Tarrytown, NY)
began pivotal Phase trials of a proprietary
cancer vaccine for the treatment of melanoma.
GMK, the company s lead product, is based on
GM2 ganglioside, a defined tumor antigen. The
first study, sponsored by the National Cancer
Institute ( NCI), is now enrolling patients
at hundreds of NCI affiliated oncology centers
in the United States.
Ilex Oncology Inc. (San Antonio, TX) is conducting
a randomized, 17-center Phase III clinical trial
of an antitumor agent in patients newly diagnosed
with glioblastoma multiform and who have completed
surgery and radiotherapy. The study seeks to
determine whether adjuvant therapy with crisnatol
mesylate provides survival rates better than
those for standard adjuvant therapy with BCNU.
In other Ilex news, the company has studied
more than 700 patients in Phase I and II trials
of piritexim, is conducting a Phase I study
of aminopterin, and is planning its second Phase
1 study of intoplicine.
DynaGen Inc. (Cambridge, MA) began a 750-patient,
multicenter, multinational Phase III trial of
NicErase-SL, a non nicotine sublingual tablet,
as an aid to smoking cessation. In previous
pilot studies involving 18 subjects, the treatment
group had twice the success of the placebo group
at stopping smoking. Subjects who received the
drug but did not stop smoking significantly
reduced the number of cigarettes smoked per
day.
A Phase III trial by Immunex Corporation (Seattle,
WA) found no compelling evidence supporting
the use of its Investigational new drug Pixykine
with bone marrow transplants. In a 177- patient
study conducted at 18 medical centers inn Canada,
Spain, and the United States, the company determined
that Pixykine offered nod significant improvement
over the control drug. Leukine, in raising platelet
and neutophil counts. Another Pixykine study,
a Phase III trial comparing it with G-CSF in
canter patients undergoing high dose chemotherapy,
is scheduled for completion in early 1996.
New drug applications
Guilford Pharmaceuticals Inc. (Baltimore, MD)
submitted an NDA for its Gliadel wafer, a biodegradable
polymer implant designed to heal surgical cavities
created during the removal of brain tumors.
A placebo-controlled, double-blind Phase III
trial in Europe involved 32 patients undergoing
initial surgery for malignant glioma. One-year
survival rates were 63% for patients in the
treatment and 19% in the placebo group. In an
earlier North American Phase III trial, involving
222 patients undergoing surgery for recurring
malignant glioma, the six-month survival rate
for the treatment group was 60% and for the
placebo group, 47%. No clinically important
adverse effects attributable to the drug were
observed in either trial.
Marketing approval
Following the recommendation of the Oncology
Drugs Advisory Committee, the FDA granted marketing
approval to the NeoRx Corporation (Seattle,
WA) for an imaging kit for detecting small.-cell
lung cancer. The Verluma kit includes a monoclonal
antibody Fab fragment linked by proprietary
technology to Technetium Tc 99m, a diagnostic
radionuclide. The Radiopharmaceutical Division
of the DuPont Merck Pharmaceutical Company (Wilmington,
DE) will market the product in North America.
The FDA approved the NicoDerm SQ patch for over-the-counter
sale as a smoking-cessation aid. The product
is a joint venture of Alza Corporation (Palo
Alto, CA), SmithKline Beecham (Philadelphia.
PA) and Hoechst Marion Roussel (Somerville,
NJ).
Rhone-Poulenc Rorer Inc. (RPR) (Collegeville,
PA) submitted marketing applications in 13 European
Union countries for a new treatment for standard-chemotherapy-resistant
advanced metastatic colorectal cancer. Campto
(irinotecan\CPT-11) is licensed to RPR by Yakult
Honsha Co. Ltd. (Tokyo, Japan). In Phase II
trials in Europe involving 455 patients, objective
tumor-shrinkage response rates were 14-18% in
patients whose disease had progressed during
treatment with 5-flourouracil and folinic acid.
Disease stabilization occurred in 42% of patients.
The median duration of tumor response was seven
to eight months, that disease stabilization
was five months.
In other news from RPR, nine more countries
granted regulatory approval to the company s
anticancer agent Taxotere (docetaxel), bringing
the total to 33. Argentina, Russia, Israel,
Pakistan, the Philippines, Romania, Slovakia,
and Ukraine cleared the drug for the treatment
of advanced breast and non-small-cell lung cancers,
Morocco approved it for advanced breast cancer
only.
FDA granted clearance to Schering-Plough Corporation
(Madison, NJ) to market Intron A for injection
as an adjuvant to surgery for patients with
recurring malignant melanoma. The drug (interferon
alfa-2b, recombinant) had previous US marketing
approval for treating hairy-cell leukemia, AIDS-related
Kaposi's sarcoma, condylomata acuminata, and
chronic hepatitis B and C.
The Australian Drug Evaluation Committee recommended
Taxotere, a Rhone Poulenc Rorer, Inc. (Collegeville,
PA) product, fro approval as a treatment for
advanced breast and non-small-cell lung cancers
that so not respond to initial therapy. Taxotere
is already approved for use in Canada, South
Africa, Mexico, Uruguay, and Brazil. In Phase
II clinical trials, the drug demonstrated a
significant response rate in patients advanced
non-small-cell lung cancers who were resistant
to cisplatin, a commonly used anticancer agent. |
Mettings and Congress
Reports
Medical and Scientific Meetings
Books Received
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Issue 2 |
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News
1 |
Non-progression and
duration of preclinical neoplastic lesions of
the cervix uteri were studied using screening
data from a previously unscreened population,
Maribo County, Denmark (1966-82). To estimate
regression rates, the incidence of clinical
cancer before the screening programme was related
to the prevalence and incidence of preclinical
lesions estimated from the detection rates of
first smear and third and subsequent smears
respectively. Duration was estimated from the
time lag between the cumulative incidence of
preclinical lesions and the combined cumulative
incidence of clinical cancer and the estimated
incidence of regression. Of all preclinical
lesions in women aged 25-50,24% progressed,
39% regressed and 38% remained. Even if we assume
no onset of preclinical lesions above age 50,
we estimated that 48% of the preclinical lesions
would not progress to clinical cancer in the
women ‘s lifetime. The estimated mean duration
of preclinical lesions was 16 years. In Maribo
County during the 1970s, the positive rate (1,6%)
was low compared with current rates in several
countries. We conclude that the detection of
non-progressive lesions was outweighed by the
prevention of clinical cancer. |
2 |
Extrapolations from
underground miner studies, which found exposure
to radioactive radon and its decay products
linked to increased lung cancer risk, have suggested
that radon accumulating in houses might cause
thousands of lung cancer deaths each year. It
is not clear how well extrapolations from mines
apply to indoor exposure levels. A meta-analysis
of eight case-control studies of indoor radon
generally supports these miner-based extrapolations.
It found increased relative risks (RRs) at higher
radon concentrations and estimated a 1.14 RR
(95% confidence interval = 1.0-1.3) at 150 Bq/m3
(4 pCi/L), a level equalled or exceeded in about
6% of U.S. houses. Lubin and Boice (p. 49) conducted
a meta-analysis of every indoor radon case-control
study with at least 200 lung cancer case subjects
and that used long-term indoor radon measurements.
The eight studies included a total of 4263 case
and 6612 control subjects. The investigators
urge that heir results be interpreted with caution,
given the limitations of meta-analysis. Nonetheless,
they suggest that until ongoing indoor radon
case-control studies are completed, miner-based
studies appear to provide valid estimates of
lung cancer risk from indoor radon exposure.
In an editorial, Samet (p.4) writes that the
meta-analysis by Lubin and Boice provides some
assurance that risk models based on miner studies
are not markedly off target in predicting indoor
radon risks. The next summary of the evidence
and a new risk model will come with the publication
of the Biological Effects of Ionizing Radiation
(BEIR) VI Committee of the National Research
Council, possibly in the spring of 1997, he
says. Additional informative data, however,
should be available by the year 2000, when the
results of 11 further residential studies now
under way are pooled and analyzed. |
3 |
Kerlikowske et al.
(p. 77) report that risk factors for ductal
carcinoma in situ (DCIS) are similar to those
for invasive breast cancer, a finding consistent
with the notion that some DCIS lesions may be
precursors of invasive disease. The researchers
recommend studies to determine what proportions
of DCIS lesions become invasive, remain dormant,
and resolve spontaneously. The investigators
studied 39 542 women who underwent screening
mammography, provided breast cancer risk information,
and had follow-up of their abnormal mammographic
examinations. They found that, among women aged
30-40 years, a family history of breast cancer
was associated with increased DCIS risk, whereas
high body mass index was associated with decreased
risk; similar trends for these factors were
observed for invasive disease. Among women aged
50 years and older, a family history of breast
cancer and nulliparity or being 30 years or
older at birth of first child were associated
with increased risk for DCIS and invasive cancer. |
4 |
Mutation of the p53
tumor gene has been associated with clinical
outcome in several cancers, but the reported
frequency of p53 mutation in prostate cancer
has varied widely. Gumerlock et al. (p. 66)
report here that polymerase chain reaction-single-strand
conformation polymorphism (PCR-SSCP) analysis
of complementary DNA (cDNA) is more sensitive
than PCR-SSCP analysis of genomic DNA (DNA-PCR-SSCP)
in cell line studies and detected more abnormal
fragments in human primary prostate carcinoma
tissues. Together, however, the assays detect
more abnormalities than either alone, and the
investigators recommend use of both for comprehensive
screening for p53 mutations in prostate carcinomas.
The researchers used PCR-SSCP analysis of cDNA
(RT-PCR-SSCP) and DNA-PCR-SSCP to analysis had
indicated 14 were mutant and five were wild-type.
The study identified 18 abnormal p53 fragments,
including two each in three carcinomas. Ten
(56%) of the 18 were identified by RT-PCR-SSCP
alone, two (11%) by DNA-PCR-SSCP alone (including
one in a specimen previously reported to be
wild-type for p53), and six (33%) by both. (11) |
5 |
No group of researchers
has benefited more from the recent boom in genetics
and biotechnology than those who study the rare
hereditary non-polyposis colon cancer, or HNPCC.
Over the last few years, HNPCC has gone from
a controversial concept to a fairly well-defined
inherited cancer syndrome, with five genes linked
to the condition now cloned. But doctors say
it hasn't yet gotten any easier to diagnose
a patient with HNPCC. One long-standing problem
is that a colon tumor biopsied from a person
with HNPCC looks the same as a sporadic colon
tumor, making diagnosis of the syndrome extremely
tricky. And doctors still use the same diagnostic
guidelines, called the Amsterdam criteria, that
were around before researchers found any of
the genes involved in the syndrome. These criteria
have been criticized as too narrow, offering
no guidance on how doctors can incorporate the
newly identified HNPCC genes and biomarkers
into the diagnostic process. Given these difficulties,
some top researchers and pathologists interested
in the syndrome met for the first time recently
in Rockville, Md., and hammered out broader,
more genetically oriented criteria for diagnosing
HNPCC. the workshop, sponsored by the National
Cancer Institute, was held in collaboration
with the American Joint Commission on Cancer
and the International Collaborative Group on
HNPCC. Miguel Rodriguez-Bigas, M.D., who chaired
the session and is a surgeon at Roswell Park
Cancer Institute in Buffalo, N.Y., said the
new guidelines will be called the #Bethesda
criteria.#. He added that efforts are under
way to have the criteria published in a cancer
research journal within a few months. According
to Rodriguez-Bigas and colleagues, the Bethesda
criteria start with the narrow definition of
HNPCC that is used in the Amsterdam criteria:
at least three relatives with colon cancer,
at least two successive generations affected,
and colon cancer before age 50. But the Bethesda
criteria take the next step and expand the largely
in light of recent research advances. Rodriguez-Bigas
said the broader Bethesda criteria "lay
the framework" for clinicians to identify
more people with HNPCC, a syndrome that many
researchers say is underdiagnosed. Most experts
suspect HNPCC accounts for about 2% to 4% of
all colon cancer, with some suggesting that
this number could rise as high as 10% with broadened
diagnostic criteria and techniques. But Rodriguez-Bigas
said that while it's interesting to speculate
about the prevalence of HNPCC, the real value
of the new criteria lies elsewhere. "Every
time a doctor sees a patient now who meets the
new criteria, it will allow that patient to
get the appropriate genetic counseling, screening,
and chemoprevention that he or she might not
have otherwise received" he said. "The
bottom line is: The patient wins". The
Bethesda criteria start with seven points that,
like a checklist, allow physicians to more systematically
run through the clinical features that are suggestive
of HNPCC. These include the Amsterdam criteria:
the appearance of colon cancer before age 40:
a higher incidence of other cancers known to
occur in HNPCC, especially those in the endometrium,
stomach, and ovary; and various other features
seen in HNPCC. Should a doctor suspect HNPCC
based on the seven points, the Bethesda criteria
advise that after offering genetic counseling
to the patient, the doctor should test the tumor
for genetic instability. Genetic instability
is caused by mutations that pile up in DNA,
like typographical errors, when a cell loses
its ability to edit out mismatched DNA during
each cell cycle. Studies show that, although
genetic instability occurs in some sporadic
colon cancer, about 90% of HNPCC tumors are
genetically unstable. According to the Bethesda
criteria, cells from the tumor should be tested
for changes in short, reccurring sequences of
DNA, called microsatelites. If frequent changes
are found in at least two of the four microsatelites
listed in the Bethesda criteria, the tumor will
be considered genetically unstable. If genetic
instability is found in the tumor, the Bethesda
criteria advise testing for mutations in the
HNPCC genes, MSH2 and MLH1. Studies suggest
that nearly 70% of the known HNPCC-causing mutations
reside in these tow genes. Testing for mutations
can be done in a variety of ways ranging from
protein truncation assays to "brute force"
sequencing of the gene. (14) |
6 |
TYR appears to be a
good tracer for imaging malignancies. The PSR,
which was higher in malignant tumors than in
normal tissue and the studied benign lesions,
could be quantified and correlated with the
SUV. |
7 |
We conclude that PCR-TGGE
is an appropriate method for detection of p53
point mutations in paraffin-embedded material.
We show that loss of wild-type p53 is an adverse
prognostic factor in patients suffering from
vulvar cancer. |
8 |
K-ras mutations, present
in a subset of NSCLC, are associated with tumor
progression and shortened patient survival.
Cancer 1997;79:462-7. |
9 |
The correlations of
CerbB-OPE with Ki-GF and pMI suggest that c-erb
B-2 oncoprotein may play an important role in
the cell proliferation status of cervical carcinoma. |
10 |
In the past decade,
cancer cytogenetics has become widely recognized
both as a basic research tool for investigations
of tumor biology and a clinical methodology
providing vital insights into cancer development
and progression. Now, this new edition of the
acclaimed reference Cancer Cytogenetics offers
a comprehensive, expanded, and up-to-date conceptual
synthesis of the dramatic advances in this rapidly
moving field from both basic and clinical investigations.
Authored by two leading figures in the field,
Cancer Cytogenetics, Second Edition begins by
reviewing the core concepts of the cytogenetic
approach, then moves on to specific neoplastic
disorders - This revised edition now offering
elevan entirely new chapters on different types
of non-hematoligic tumors. With its in-depth
and authoritative coverage of the cytogenetics
of neoplasia, this text is certain to prove
a vital resource for all researchers and clinicians
involved in the diagnosis, prognosis, and treatment
of cancaaer. Topics new to the second edition
include: • chronic and acute myeloid leukemia
• myelodysplastic syndromes • malignant lymphomas
• extensive coverage of solid tumors, including
respiratory, digestive, urinary, breast, genital,
endocrine, nervous system, eye, skin, and bone
and soft tissue tumors. |
11 |
These findings suggest
that activation of K-ras in colorectal carcinoma
may inhibit apoptosis and thus favor tumor progression.
Alternatively, this association may reflect
an accumulation of K-ras mutations in cells
in which normal apoptotic pathways have been
impared. |
12 |
Two different tumors
were found synchronously in 10 patients (5 with
independent tumors and 5 with contiguous/collision
tumors) and metachronously in 2. The size of
the lymphomas (mean. 7.2 cm) was larger than
that of the adenocarcinomas (mean, 3.6 cm) (P`0.005).
Histologically, 9 of the 12 lymphomas (75%)
were mucous-associated lymphoid tissue lymphomas,
and all lymphomas invaded the deep portion of
the submucosa or deeper. Conversely, 10 of the
12 adenocarcinomas (83%) were early carcinomas.
Six adenocarcinomas were intestinal type, whereas
the other 6 were diffuse type. The MIB-1 index
of the adenocarcinomas (mean, 50.4%) was higher
than that of the lymphomas (mean, 29.3%) P`0.05).
Helicobacter pylori (H. pylori) was documented
in all 12 patients, whereas Epstein-Barr virus-encoded
RNA 1 was detected in only 2. During the follow-up
period after surgery, 6 patients died, 4 due
to adenocarcinoma. The survival probability
of all 12 patients appeared to be similar to
that of previously reported patients with gastric
adenocarcinoma alone, and was significantly
worse than that of the 217 patients with gastric
lymphoma alone P<0.05). |
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PHARMACOLOGY-UPDATED
NEWS |
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Topotecan (Hycamptin®) kills
cancer cells by inhibiting topoizomerase I,
essential enzyme in the replication of DNA.
Topotecan has been licensed in November 1998.
by European Medicines Evaluation Agency (EMEA)
for the use in the 15 EU member states for the
treatment of metastatic ovarian cancer after
failure of the first-line or subsequent therapy.
In May 1996, topotecan received clearance from
the U.S. food and Drug administration. The agent
has also received marketing approval in Switzerland,
Brazil and Venezuela. Letrozole significantly
prolongs time to treatment failures and survival
time in second-line treatment for post-menopausal
patients with breast cancer. This was concluded
by Dr. G. Falkson from Pretoria who reported
a trial of 551 patients investigating two doses
of letrozole versus megestrol acetate in patients
previously received tamoxifen. The overall response
rate of letrozole 2.5 mg was 23.6 vs. 16.4%
for megestrol acetate. The median time to treatment
failure was significantly longer (155 vs.118
days) and the median survival time was 731 days
on letrozole and 660 days on megestrol. |
|
EORTC Study shows that combined
LH-RH-agonist (buserelin) and tamoxifen is more
effective than treatment with either drug alone
in pre menopausal women with metastatic breast
cancer. The objective response rate was 50%
in combined treatment vs. 29-33% with each drug
alone. The duration of response and the time
to treatment failure nearly doubled and constructed
actuarial survival curves significantly favored
combined treatment. |
|
Ansan, Inc. (Menlo Park, CA)
an operating company of Titan Pharmaceuticals
Inc., will begin Phase I testing of AN-9, an
anticancer agent for which it received FDA approval
of its investigational new drug application
(IND). The agent is based on butyric acid -
a non toxic, naturally occurring molecule -
which is said to have a lower toxicity level
than other forms of chemotherapy. Phase I/II
clinical trials began for Leuvectin, a cancer
gene therapy product of Vical Inc. (San Diego,
CA). The trial will involve 25 patients with
advanced solid malignancies or lymphoma at two
U.S. sites. It is designed to evaluate the product‘s
safety and biological activity. Intended for
direct injection into tumor lesions, Leuvectin
contains a gene that encodes the immunostimulator
interleukin-2. When injected, it is expected
that the product will cause malignant cells
to produce and secrete interleukin-2 near the
lesion. It is hoped that the presence of the
interleukin-2 will then stimulate the patient‘s
immune system to attack and destroy the tumors
cells. |
|
CellPro Inc. (Bothell, WA)
and the Fred Hutchinson Cancer Research Center
(Seattle, WA) have begun a pilot clinical trial
in patients with chronic lymphocytic leukemia
(CLL). The study is designed to demonstrate
that CellPro‘s Ceprate SC (stem cell concentration
system) can positively select CD34 antigen-expressing
stem cells from peripheral blood and also results
in significant depletion of tumor cells from
the resulting stem cell transplant. Primary
objectives of the 15-patient pilot trial are
to evaluate the product‘s ability to purge CLL
cells from the peripheral blood stem cell (PBSC)
graft and to evaluate engraftment after PBSC
transplantation. The CD34 antigen is a surface
marker for the hemotopoietic (blood-forming)
stem and early progenitor cells essential to
posttranspalant engraftment in the bone marrow
and renewal of the immune and blood systems.
Because the antigen is believed not to be expressed
on malignant leukemia cells, or their potential
precursors, positive selection of CD34+ stem
cells should result in a significant depletion
of tumor cells from the PBSC population. |
|
Genetic Therapy, Inc. (Gaithersburg,
MD) and a development partner are conducting
a Phase I/II clinical development program using
the HS-tk/ganciclovir gene therapy approach
to destroying brain tumor cells. |
|
Argus Pharmaceuticals, Inc.
(Woodlands, TX), in conjunction with Genzyme
Corporation, is conducting a Phase II/III trial
of TretinoinLF (a liposomal intravenous formulation
of retinoic acid) in patients with Kaposi‘s
sarcoma. The company is also conducting Phase
II dose-ranging trials of Nystatin LF in patients
with candida infections. Ribi ImmunoChem Research,
Inc. (Hamilton, MT) received FDA approval to
initiate Phase III clinical studies of its Melacine
in combination with interferon alfa-2b (IFN).
The regimen will be tested in patients with
Stage IV (disseminated) melanoma and will compare
Melacine plus IFN with IFN alone. Endopoints
for the study will be comparative overall survival,
disease-free survival, quality of life, clinical
response rates (tumor regression, and safety
and toxicity. The study will involve 300 patients
at about 30 sites. Bristol-Myers Squibb Co.
(Princeton, NJ) will complete Phase III clinical
trials for the anticancer drug UFT (tegafur
and uracil) and will have exclusive rights to
the drug in most parts of the world, according
to its agreement with Taiho Pharmaceutical Co.,
Ltd (Tokyo, Japan). The orally administered
oncology drug is currently marketed in Japan,
several Assia-Pacific countries, and Spain and
is indicated for the treatment of colorectal
cancer, gastric, breast, and other tumor types.
|
|
Matrix Pharmaceutical Inc.
(Menlo Park, CA) reported data from Phase I/II
clinical trials of two formulations of its IntraDose
products. The data for five esophageal cancer
patients are a subset of the company‘s lager
Phase I/II studies in patients with head and
neck cancer and accessible (that is, visible
or palpable) tumors. Two of the four patients
treated with cisplatin-based injectable gel
showed stable disease, and the other two showed
a decrease in tumor volume of 58% and 75%. The
one patient treated with methotrexate-based
injectable gel showed no change in tumor volume.
No evidence of systemic toxicity was noted.
ImClone Systems Incorporated (New York, NY)
conduced a Phase I, single-injection, dose-escalation
study of C225, its epidermal growth factor receptor
(EFr) antagonist for the treatment of patients
with cancer. The product is designed to block
the EGF receptor (overexpressed on several varieties
of cancer), and, in combination with chemotherapy
or radiation, to eliminate cancerous cells through
a mechanism that may involve the induction of
apoptosis, the natural process of cellular death.
Sugen, Inc. (Redwood Ciy, CA) received FDA orphan
drug designation for SU 101 in the treatment
of patients with malignant glioma (a category
of highly aggressive brain tumors). The drug
is a specific inhibitor of TK signaling pathways,
used to block the platelet-derived growth factor
(PDGF) receptor.
Rhone.Poulenc Rorer Inc. (Collegeville, PA)
received approval from the Canadian Health Protection
Branch for Taxotere (docetaxel), an anticancer
agent for breast and non-small-cell lung cancer
after initial therapy (an anthracycline-containing
regiment) has failed. Possible side effects
include hair loss, a reduction in the number
of white blood cells (neutropenia), skin rash,
fluid retention, hypersensitivity, nausea, and
diarrhea.
Biomira Inc. (Edmonton, Alberta) received FDA
clearance to initiate a Phase II/III clinical
trial of its Tru-Scint AD monoclonal antibody
kit for the detection of recurrent breast cancer.
The trials will enroll 150 patients; enrollment
should take one year.
Genetic Therapy, Inc. (Gaithersburg, MD) initiated
a Phase I clinical trial for a gene therapy
protocol designed to protect patient‘s blood
systems from the destructive effects of high-dose
chemotherapy. The treatment uses the company‘s
vector technology to transfer a gene for multiple
drug resistance (MDR-a) into progenitor cells
that serve as a guide, or pattern, to all other
cells in the blood system. Expression of the
MDR-1 gene is said to make cells resistant to
certain chemotherapeutics by enabling cells
to pump out toxic drugs before cell death occurs.
Senofi Research Division (Malvern, PA) began
recruiting subjects for its Phase III trial
of tirapazamine for stage IIIb lung cancer.
The trial is a mulitcenter, twoarm trial comparing
the patient survival rate for treatment with
cisplatin alone to treatment with cisplatin
alone to treatment with cisplatin and tirapazamine
together.
Vical Inc. (San Diego, CA) initiated Phase II
trials of Allovectin-7 with 100 patients at
up to 10 centers in the United States and Canada.
The gene based product is administered by direct
injection into tumor lesions of patients with
different types of cancers, including lymphoma,
melanoma, and colorectal, and those of the kidney
and breast.
Chiron Corporation (Emeryville, CA) and Ciba
Pharmaceuticals (Summit, NJ) received approval
to market Aredia to treat the pain and bone
fractures associated with multiple myeloma.
The drug is being tested as a treatment for
patients whose breast cancer has spread to bone.
Chiron Corporation (Emeryville, CA) and DepoTech
Corporation (San Diego, CA) announced interim
results of a Phase III trial of DepoCyt, an
aticancer therapeutic. Results indicate an increased
response rate and extended survival compared
to the current standard therapy in patients
with neoplastic meningitis arising from solid
tumors. Two of the 15(13%) patients who took
the new product died during either the study
or follow-up compared to 7 of the 17 (41%) who
received methotrexate. The median survival rate
for those taking DepoCyt was 277 days, and for
those taking methotrexate was 68 days. Based
on these results, the companies amended the
protocol to allow patients who failed to respond
to one treatment to be switched to the other.
Protein Design Labs, Inc. (Mountain View, Ca),
is enrolling up to 168 subjects for its Phase
II trial of a human anti-CMV antibody to prevent
cytomegalovirus infections in patients undergoing
bone marrow transplants. The randomized, double-blind
study will take place at three U.S. medical
centers. Reduction in the number of patients
with CMV infection within 100 days after surgery
is the primary measure of efficacy. The company
is in Phase II testing of the antibody for CMV
retinitis in a trial conducted by AIDS Clinical
Trials Group (ACTG) of the National Institute
of Allergies and Infectious Diseases (NIAID).
Protein Design Labs, Inc. (Mountain View, CA),
began Phase I trials in Japan for its SMART
M195 antibody. Kanebo Ltd. (Osaka, Japan) is
sponsoring the 16-subject trial at medical centers
in Osaka, Tokyo, and several other cities. Groups
of four patients with myeloid leukemia will
be given one of four doses for a total of seven
doses in a month.
Lidak Pharmaceuticals (La Jolla, CA) received
clearance from FDA to begin Phase I/II trials
of its large multivalent immunogen technology,
LP 2307, for malignant melanoma. |
|
Sugen, Inc. (Redwood Ciy,
CA) received FDA orphan drug designation for
SU 101 in the treatment of patients with malignant
glioma (a category of highly aggressive brain
tumors). The drug is a specific inhibitor of
TK signaling pathways, used to block the platelet-derived
growth factor (PDGF) receptor. |
|
Rhone.Poulenc Rorer Inc. (Collegeville,
PA) received approval from the Canadian Health
Protection Branch for Taxotere (docetaxel),
an anticancer agent for breast and non-small-cell
lung cancer after initial therapy (an anthracycline-containing
regiment) has failed. Possible side effects
include hair loss, a reduction in the number
of white blood cells (neutropenia), skin rash,
fluid retention, hypersensitivity, nausea, and
diarrhea. |
|
Biomira Inc. (Edmonton, Alberta)
received FDA clearance to initiate a Phase II/III
clinical trial of its Tru-Scint AD monoclonal
antibody kit for the detection of recurrent
breast cancer. The trials will enroll 150 patients;
enrollment should take one year. |
|
Genetic Therapy, Inc. (Gaithersburg,
MD) initiated a Phase I clinical trial for a
gene therapy protocol designed to protect patient‘s
blood systems from the destructive effects of
high-dose chemotherapy. The treatment uses the
company‘s vector technology to transfer a gene
for multiple drug resistance (MDR-a) into progenitor
cells that serve as a guide, or pattern, to
all other cells in the blood system. Expression
of the MDR-1 gene is said to make cells resistant
to certain chemotherapeutics by enabling cells
to pump out toxic drugs before cell death occurs.
|
|
Senofi Research Division (Malvern,
PA) began recruiting subjects for its Phase
III trial of tirapazamine for stage IIIb lung
cancer. The trial is a mulitcenter, twoarm trial
comparing the patient survival rate for treatment
with cisplatin alone to treatment with cisplatin
alone to treatment with cisplatin and tirapazamine
together. |
|
Vical Inc. (San Diego, CA)
initiated Phase II trials of Allovectin-7 with
100 patients at up to 10 centers in the United
States and Canada. The gene based product is
administered by direct injection into tumor
lesions of patients with different types of
cancers, including lymphoma, melanoma, and colorectal,
and those of the kidney and breast. |
|
Chiron Corporation (Emeryville,
CA) and Ciba Pharmaceuticals (Summit, NJ) received
approval to market Aredia to treat the pain
and bone fractures associated with multiple
myeloma. The drug is being tested as a treatment
for patients whose breast cancer has spread
to bone. |
|
Chiron Corporation (Emeryville,
CA) and DepoTech Corporation (San Diego, CA)
announced interim results of a Phase III trial
of DepoCyt, an aticancer therapeutic. Results
indicate an increased response rate and extended
survival compared to the current standard therapy
in patients with neoplastic meningitis arising
from solid tumors. Two of the 15(13%) patients
who took the new product died during either
the study or follow-up compared to 7 of the
17 (41%) who received methotrexate. The median
survival rate for those taking DepoCyt was 277
days, and for those taking methotrexate was
68 days. Based on these results, the companies
amended the protocol to allow patients who failed
to respond to one treatment to be switched to
the other. |
|
Protein Design Labs, Inc.
(Mountain View, Ca), is enrolling up to 168
subjects for its Phase II trial of a human anti-CMV
antibody to prevent cytomegalovirus infections
in patients undergoing bone marrow transplants.
The randomized, double-blind study will take
place at three U.S. medical centers. Reduction
in the number of patients with CMV infection
within 100 days after surgery is the primary
measure of efficacy. The company is in Phase
II testing of the antibody for CMV retinitis
in a trial conducted by AIDS Clinical Trials
Group (ACTG) of the National Institute of Allergies
and Infectious Diseases (NIAID). |
|
Protein Design Labs, Inc.
(Mountain View, CA), began Phase I trials in
Japan for its SMART M195 antibody. Kanebo Ltd.
(Osaka, Japan) is sponsoring the 16-subject
trial at medical centers in Osaka, Tokyo, and
several other cities. Groups of four patients
with myeloid leukemia will be given one of four
doses for a total of seven doses in a month.
|
|
Lidak Pharmaceuticals (La
Jolla, CA) received clearance from FDA to begin
Phase I/II trials of its large multivalent immunogen
technology, LP 2307, for malignant melanoma. |
Books Review, Books
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Issue 3 |
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Fullerenes-Updated
News
1 |
The ability of C60 fullerene
("Bucky Ball") derivatives to interact
with the active site of HIV-1 protease (HIVP)
has been examined through model building and
simple physical chemical analysis. The model
complexes generated via the program DOCK3 suggest
that C60 derivatives fit snugly in the active
site, thereby removing 298 A2 of primarily nonpolar
surface from solvent exposure and driving ligand/protein
association. The prediction that these compounds
should bind to the active site and thereby act
as inhibitors has been borne out by the experimental
evidence. Kinetic analysis of HIVP in the presence
of a water-soluble C60 derivative, bis (phenethylamino-succinate)
C60 suggests a comperitive mode of inhibition.
This is consistent with and supports the predicted
binding mode. Diamino C60 has been proposed
as a "second-generation" C60 derivative
that will be able to form salt bridges with
the catalytic aspartic acids in addition to
van der Waals contacts with the nonpolar HIVP
surface, thereby improving the binding relative
to the tested compound. |
2 |
The room temperature
solubility of pure C60 has been determined in
47 solvents. The solubilities cover a wide range,
from 0.01 mg/mL in methanol to 50 mg/mL in 1-chloronaphthalene.
The solubilities in CS2 toluene, and hexane,
three of the commonly employed solvents, are
7.9, 2.8, and 0.04 mg/mL, respectively. An examination
of the solubilities of C60 as a function of
the solvent properties such of refraction, dielectric
constant, molecular size, Hildebrand solubility
parameter, and H-bonding stength reaffirms the
century-old principle "like dissolves like".
No single solvent parameter can uniformly predict
the solubility of C60, but a composite picture
of solvents with high solubility for C60 emerge:
large index of refraction, dielectric constant
around 4, large molecular volume, Hildebrand
solubility parameter equal to 10 cal1/2, cm
-3/2, and tendency to act as a moderate stregth
nucleophile. |
Patents
Books Review, Books Received
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Medical and Scientific Meetings
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Issue 4 |
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News
1 |
The MR images were reviewed
to characterize the size, structure, and signal
intensity of papillary projections. Pathologic
correlation was performed on these and on fours
surgical specimens imaged with high resolution
technique. Pathologic correlation showed that
larger papillary projections had a distinctive
structure of a fibrous stalk supporting clumps
of edematous papillae with signal intensity
similar to that of fluid on T2-weighted images.
Smaller papillae showed nondescript intracystic
projections of intermediate signal intensity
on T2-weighted images. All papillary projections
in vivo enhanced after injection of gadopentetate
dimeglumine. Papillary projections have an appearance
on MRI that reflects their histologic structure. |
2 |
The mapping near Kras2
of pulmonary adenoma susceptibility 1 (Pas1),
a major locus affecting inherited predisposition
to lung cancer in mice prompted us to test the
homologous human region (12p12) for association
with lung adenocarcinoma, by a population-based
study. We genotyped 213 lung adenocarcinoma
patients and 219 healthy blood donor subjects
for five polymorphic markers mapping in the
putative region of interest. Three marker polymorphisms,
located in a region spanning ~ 700 kb, were
significantly associated with lung adenocarcinoma
risk. Furthermore, polymorphisms in KRAS2 and
PTHLH loci were also associated with tumor prognosis.
These results suggest the existence of a human
Pas1 homologous locus on chromosome 12p12. |
3 |
Heterocyclin amines
are possible human carcinogens and fried meat
is an important source of exposure in the Western
diet. To study the effect of heterocyclic amines
in humans, accurate assessment of individual
food consumption is essential. Parameters influencing
the intake include the amount and type of meat
ingested, frequency of consumption, cooking
method, cooking temperature and the duration
of cooking. The aim of the present study was
to develop a practical method for assessing
individual intakes of specific heterocyclic
amines in a large sample of people. This has
been done by combining information on food consumption
and laboratory findings of heterocyclic amines
in food products. Diet was assessed using a
semi-quantitative food frequency questionnaire
including photos of fried meat and, in all,
22 dishes were cooked and chemically analyzed.
The method was employed in an elderly population
in Stockholm to estimate the daily mean intake
of the five heterocyclic amines 2-amino-3-methylimidazo
(4,5-f) quinoline (IQ), 2-amino-3,4-dimethylimidazo
(4,5-f) quinoline (MeIQ), 2-amino-3,8-dimethylimidazo
(4,5-f) quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo
(4,5-f) quinoxaline (DiMeIQx) and 2-amino-1-methyl-6-phenylimidazo
(4,5-b) pyridine (PhIP). The total daily intake
ranged from none to 1816 ng, with a mean intake
of 160 ng, which is well below estimates reported
previously. Highest amounts ingested were of
PhIP (mean 72, range 0-865 ng/day) and MeIQx
(mean 72, range 0-1388 ng/day), followed by
DiMeIQx (mean 16, range 0-171 ng/day), while
MeIQ and IQ were ingested only in very small
amounts (mean <1 ng/day). |
4 |
The Minnesota Colon
Cancer Control Study had reporte that annual
fecal occult blood testing reduced colon cancer
mortality by 33.4%. Sensitivity of the screening
test ranged from 85% to 95%. |
5 |
Colorectal epithelium,
in association with these genetic changes, may
give rise to adenoma, adenocarcinoma, and/or
neuroendocrine tumor cells, the invesligators
say. |
6 |
Kidney or ureter stones
have been thought to be related to the development
of urinary tract cancers. A study in Sweden
of patients with kidney or ureter stones reports
finding no increased risk for renal cell cancer,
but risks for cancers of the bladder and renal
pelvis (including ureter) were elevated.
The study by Chow et al. (p.1453) involved 61144
patients hospitalized for kidney or ureter stones
who were followed for up to 25 years via national
inpatient and cancer registries.
The standardized incidence ratios (SIRs) for
renal cell, renal pelvis, and bladder cancers
were 1.1, 2.2, and 1.4, respectively; the latter
two were statistically significant. For renal
pelvis and bladder cancers, the SIRs for women
were twice those for men. Stones were on the
same side of the body as tumors in most patients
with renal pelvis cancer who had this information
available, suggesting the influence of chronic
irritation and infection. |
7 |
National golas for colorectal
cancer (CRC) screening by the year 2000 are
for 50% of Americans more than 49 years of age
to have received fecal occult blood testing
(FOBT) in the past 2 years and 40% to have ever
received sigmoidoscopy. As of 1992, however,
just 26% of this population reported FOBT in
the previous 3 years, and only 33% reported
ever having sigmoidoscopy. In a review of 132
relevant articles, Vernon (p. 1406) describes
the prevalence of FOBT and sigmoidoscopy and
explores interventions and other factors that
affect screening adherence.
Depending on the type of study population, the
median rate of adherence to FOBT was 40%-50%.
Fewer studies have examined adherence to sigmoidoscopy,
but they did indicate higher adherence among
relatives of CRC patients.
Vernom concludes that little is known about
determinants of CRC screening behavior, and
she discusses potential directions for future
research. |
8 |
These results suggest
that taxol induces apoptosis in cells arrested
in G2/M phase which might be partly explained
by Bcl-2 inactivation by phosphorylation in
human colon carcinoma cell lines. |
9 |
Aging patients with
cancer #will progressively dominate the practice
of medical oncology in the 21st century#, writes
B.J. Kenedy, M.D, of the University of Minnesota
Medical School, Minneapolis.
Driving the need for more research and training
in geriatric oncology are demographic realities.
About 60% of cancer occur in people age 65 and
over, a group that now makes up about 12% of
the population. By 2030, this high-risk-for-cancer
age group will make upo 20% of the population.
But oncologists of the 21 st century will also
need skills now often considered to belong in
the realm of primary care, say proponents of
geriatrics training. These include the ability
to perform comprehensive geriatric assessments,
to deliver paliative care, and to deal with
other medical and non-medical conditions that,
particularly in older patients, affect the management
of cancer.
Paul Carbone, M.D., of the University of Wisconsion
Medical School, Madison, told the panel that
"we need to get away from the fact that
because somebody is old, you need to do this
or that. ... What you need to do is be a physician,
look at the total patient, and based on physiological
factors as well as other factors, treat the
patient based on that."
Lee Moffitt Cancer Center and Research Institute
in Tampa, Fla. Balducci advocates dose adjustment
for renally excretable drugs; use of hematopoietic
growth factors and prophylatic antibiotics with
regimens of moderate toxicity; avoidance of
high-dose chemotherapy until proven to be of
benefit in younger people; and preferance for
intermediate doses over high doses of cytarabine
in patients with acute leukemia or high grade
lymphoma.
Calabresi pointed to anti-angiogenic therapies
now under development as examples of agents
that may allow oncologists to control tumor
growth just as internists now control high blood
pressure or diabetes. "There are going
to be new strategies in dealing with older people,"
he predicted.
Now is geriatrics to be integrated into oncology
training? One proposal is to develop a joint
certification program. |
10 |
Retinoids are proposed
chemopreventive agents that inhibit cell proliferation
and induce differentiation. Their ability to
prevent azoxymethane (AOM)-induced aberrant
crypt foci (ACF) and tumor and to modulate cell
proliferation was investigated in the colon
of male F344 rats. Thirteen retinoids were evaluated
for prevention of ACF and two of them, 9-cis-retionic
acid (RA) and 4-(hydroxyphenyl) retinamide (4-HPR),
were also evaluated for prevention of colon
cancer. In summary, retinoids were demonstrated
to reduce cell proliferation and to prevent
ACF and tumors in the colon, suggesting promise
as preventive agents for colon cancer. |
11 |
The goal of the present
study was to measure the levels of DNA adducts
in human nasal mucosa cells and in total white
blood cells in relation to smoking. DNA was
isolated from samples of 20healthy volunteers
(six smokers and 14 non-smokers). The levels
of DNA adducts were measured by 32P-postlabelling
assay. Combining the sensitivity of the 32P-postla-belling
assay with the specificity of the nasal mucosa
to the airborne chemical exposures, the DNA
adduct analysis from human nasal mucosa cells
represents a method of choice in the assessment
of exposure to airborne carcinogens. |
12 |
Exposure of animals
in vivo and cells in vitro to a variety of xenobiotics
leads to increased mdrl gene expression and
higher levels of P-glycoprotein. This response
may protect cells from the cytotoxic effects
of these compounds. In this investigtion we
functionally expressed the rat mdr 1b gene in
NIH 3T3 cells and assessed the ability of the
encoded p-glycoprotein to protect thesecells
from the cytotoxicity of xenobiotics known to
induce mdr 1b expression. In long-term colony
survival assays, stably expressed mdr1b conferred
resistance to cytotoxic drugs such as colchicine,
vinblastine and doxorubicin, but not to 5-fluorouracil
nor to the carcinogens aflatoxin B1 and N-hydroxy-acetylaminofluorene.
The mdr reversal agent verapamil restored cytotoxicity
of colchicine, doxorubicin, actinomycin D, vinblastine
and taxol, but had no effect on the sensitivity
of these cells to 5-fluorouracil, aflatoxin
B1 or N-tydroxy-acetylaminofluorene. In a competitive
transport assay, verapamil and, to a lesser
extent, colchicine blocked the increased efflux
of the fluorescent dye rhodamine 124 from mdr1b-transfected
cells, wheras aflatoxin B1 did not compete for
this export. These data demonstrate that expresseion
of the rat mdr1b encoded P-glycoprotein can
protect cells from a diverse group of compounds
previously identified to be mdr substrates,
however, other effective inducers of mdr expression,
such as aflatoxin B1 and N-hydroxy/acetylaminofluorene,
remain potent cytotoxins despite high levels
of P-glycoprotein. The fact that compounds which
are not themselves substrates can induce P-glycoprotein
expression may have implications for pharmacokinetic
interactions and chemotherapy. |
13 |
The ability of C60 fullerene
("Bucky Ball") derivatives to interact
with the active site of HIV-1 protease (HIVP)
has been examined through model building and
simple physical chemical analysis. The model
complexes generated via the program DOCK3 suggest
that C60 derivatives fit snugly in the active
site, thereby removing 298 A2 of primarily nonpolar
surface from solvent exposure and driving ligand/protein
association. The prediction that these compounds
should bind to the active site and thereby act
as inhibitors has been borne out by the experimental
evidence. Kinetic analysis of HIVP in the presence
of a water-soluble C60 derivative, bis (phenethylamino-succinate)
C60 suggests a comperitive mode of inhibition.
This is consistent with and supports the predicted
binding mode. Diamino C60 has been proposed
as a "second-generation" C60 derivative
that will be able to form salt bridges with
the catalytic aspartic acids in addition to
van der Waals contacts with the nonpolar HIVP
surface, thereby improving the binding relative
to the tested compound. |
14 |
When given during pregnancy,
the drug 3', 3' - dideoxytymidine (AZT) substantially
reduces maternal-fetal transmission of human
immunodeficiency virus type 1 (HIV-1)., However,
AZT has been shown to be carcinogenic in adult
mice after lifetime oral administration. In
this study, we assessed the transpacental tumorigenic
and genotoxic effects of AZT in the offspring
of CD-1 mice and Erythrocebus patas monkeys
given AZT orally during pregnancy. At 1 year
of age, the offspring of AZT-trated mice exhibited
statistically significant, dose dependent increases
in tumor incidence and tumor multiplicity in
the lung, liver, and female reproductive organs.
AZT incorporatio into nuclear and mitochondrial
DNA was detected in multiple organs of transplacentally
exposed mice and monkeys. Shorter chromosomal
telomeres were detected in liver and brain tissues
from most ATZ- exposed newbron mice but not
in tissues from fetal monkeys. AZT is genotoxic
in fewtal mice and monkeys and is a moderately
strong transplacental carcinogen in mice examined
at 1 year of age. Careful long-term follow-up
of AZT-exposed children would seem to be appropriate. |
15 |
Telomerase enzyme activity
is not detected in most normal cells, a phenomenon
believed to be associated with limitations on
cellular proliferation. Since this activity
is detected in nearly all human tumors, including
non-small-cell lung cancers, it has been suggested
that telomerase activation may be coupled to
acquissition of the malignant phenotype. We
determined whether telomerase activity was associated
with tumor pathologic stage, tumor cell proliferation
rates, and clinical outcome in a cohort of patients
with resected non-small-cell lung cancer for
whom long-term fol-low-up was available. Telomcerase
activity was detected in 84 of the 99 tumors
treated with surgery alone; this activity was
not detected in specimens of adjacent, benign
lu7ng tissue. Telomerase was detected in only
three of six tumors resected after chemotherpay.
For the surgery-alone group, statistically significant
positive associations were found between the
level of telomerase activity and tumor stage,
lymph node metastasis, pathologic TNM (tumornode-metastasis)
stage, and Ki-67 immunostaining; a statistically
significant inverse association was found between
telomerase activity and patient age. No statistically
significant differences in telomere length were
found in relation to telomerase activity of
pathologic stage. Telomerase activity was not
found to be associated with clinical outcome
in a multivariate Cox proportional hazards analzsis
adjusted for tumor stage and lymph node status. |
16 |
Aprospective, randomized,
open study comparing two doses of teicoplanin
with no therapy administered at the tim of insertion
of a central venous catheter was performed in
patients with hematological malignancies and
in patients scheduled to undergo allogeneic
or autologous stem cell transpalntion. The results
of our study indicate that teicopolanin prophylaxis
is not indicated at the time of insertion of
central venous catheters before cytoreductive
chemotherapy. |
17 |
A new general outline
of metastatic development of breast cancer incorporating
tumor dormancy in specific micrometastatic phases,
stochastic transitions between them, and start
signals from surgerry for micrometastatic growth
was designed. The proposed model suggests new
views concerning scheduling of current chemotherapy,
new treatment approaches aimed at keeping micrometastases
in a dormant state for the patient's entire
life, and the careful reappraisal of the timig
of surgery within the multimodal treatment of
operable breast cancer. |
18 |
We believe that the
use of paediatric IVAD chemotherapy regimens
in adults with ES/PNET (Ewing's sarcoma and
primitive neuroectodermal tumour) is both desirable
and feasible and we recommend that all adults
should be included in the current multicentre
trials of dose intensive chemotherapy strategies
such as the European Intergroup Ewing's Sarcoma
Study EICESS 95. |
19 |
This metastatic bladder
tumor animal model was treated with two doses
of new platinum analog Pt(cis-dach) (DPPE) 2NO3
for the evaluaton of antimetastatic efficacy
compred to two doses of cisplatinum. The results
obtained with this patient-like nude-mouse model
of bladder cancer indicate that the new platinum
analog appears to be a valuable lead compound
with antimetastic efficacy and clinical potential. |
20 |
The results obtained
strongly support the ability of a potential
anti-bcl-2 ribozyme therapy to synergize with
other agents in inducing apoptosis of hormone-resistan
human prostate cancer cells. |
21 |
The results su7ggested
that in Panc-1 cells cisplatin and VP-16 induced
apoptotic cell death which was mediated through
the interaction of Bax expression in the presence
of mutated p53. |
22 |
The overexpression of
p53, c-ebrB-2 and p21 ras gene products was
evaluated immunohistochemically in ovarian carcinomas,
borderlin, and benign neoplasms. All studies
were performed on cytospin preparations of cyst
and/or ascitic fluid cells and mutual relations
between oncoproteins were analysed p53 and c-erbB-2
immunostaining was observed in 50% and 48,5%
of ovarian carcinomas and in 30% and 35% of
ovarian borderline tumors respectively, however
in the last group the intenssity and percentage
of stained cells were considerably lower. In
ovarian benign neoplasms there was no evidence
of p53 and/or c-ebB-2 expression. Th trend for
serous carcinoma to have a higher p53 and c-erbB-2
expression than endometrioid and mucinous carcinomas
was observed. P53 and c-erbB-2 oncoproteins
were detected more frequently in the III/IV
than in the I/II stages of the disease. The
expression of p21 ras was detected in 91% of
malignant, 65% of borderline and 50% of benign
neoplasms. P21 ras reactivity was independent
of the histopathological structure of ovarian
carcinomas and it was comparable in I/II and
III/IV FIGO stages. Our results indicate that
p21 ras overexpression appears to be on early
genetic alteration in ovarian tumorigenesis,
foolowed by the appearance of p53 and c-erbB-2
oncoproteins. It is likkely that enhanced p53
and c-erbB-2 expression may cooperate with ras
gene activastion to produce a particularly agressive
phenotype. Our study supports the concept that
development of ovarian carcinoma is the end
result of a complex multistep process involving
the complementary action of different cancer
causing genes. |
23 |
In humans CS 34 is a
valid and realiable marker for hematopoletic
stem and progenitor cells. In general, solid
tumors, with the exception of endothelial cancers,
do not express CD34. Accordingly, immunological
selection of CD34+hematopoietic stem/progenitor
cells can be used to remove CD34-malignant cells
in the setting of autotransplantation. To rule
out CD34 expression on tumor cells from small
cell lung cancer (SCLC), eleven SCLS cell lines
were analyzed by flow cytometry. Interestingly,
two of these were positive for CD34 and their
expression of full-length CD 34 eas further
confirmed by reverse transcriptase and polymerase
chain reaction (RT-PCR). This finding indicates
that prior to subjecting SCLS patients to the
above treatment modality, preparing CD34+ hmatopoietic
stem/progenitor cells from SCLC patients for
autotranspalntation, CD34 expression on their
tumor cells should be screened using immunohistochemistry
and/or flow cytometry. |
24 |
Cyclin D1 immunoreactivity
was observed exclusively in the nuclei of tumor
cells in 27/41 (65%) of the cases examined.
Immjunoreactivity for cyclin E and cdk2 was
detected in all the cases and observed in the
nuclei of both carcinoma and non-carcinoma cells.
Cdk4 immunoreactivity was detected in 39/41
(95%) cases and found in carcinoma and non-carcinoma
cells. In all carcinomas examined, a significant
correlation was observed only between Ki67 and
cyclin D1 (p=0.0037). However, when examining
only invasive ductal carcinomas, a significant
correlation was detected betwen Ki67 and cyclin
D1 (p=0.0069), Ki67 and cdk2 (p=0.0043) and
cyclin D1 and cdk4 (p=0.0069). Only cyclin D1
correlated with the pathologic stages of the
disease and histological grades of invasive
ductal carcinoma. Among these cyclinss and cdk,
overexpression of cyclin D1 is considered to
play an important role in the developmnt of
human breast malignancy through abnormal proliferation.
No significant correlation was observed between
steroid receptor status and any of cyclins and
cdks examined. Cyclin D1 and cdk 2 expression
correlated with cell proliferation (Ki67) and
cyclin D1 expression with expression of cdk4
in invasive ductal carcinoma but not invasive
lobular carcinoma. Cyclin E expression did not
correlate with cell proliferation, cyclin D1
or cdks, possibly due to deregulation of its
expression. These results also indicate different
patterns of cyclin D1, cyclin E, cdk2 and cdk4
expression between invasive ductal and lobular
carcinoma of human breast. |
Books Review, Books
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Volume 4 |
Issue 1 |
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Literature and Book
Review
Meetings and Congress Reports
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Issue 2 |
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Meetings and Congress
Reports
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Issue 3 |
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Meetings and Congress
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News
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Issue 4 |
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Meetings and Congress
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News
Books Receiveed
Indexes of Volume 4
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Volume 3 |
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Issue 2 |
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Book Review
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Symposium Articles
Book Review and Literature Review
Meetings and Congress Reports
Abstracts-6th Congress of Yugoslav Association of
Nuclear Medicine
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Issue 4 |
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Meetings and Congress
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Indexes of Authors
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Volume 2 |
Issue 1 |
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Letters to the Editor
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None
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Book Review
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Meetings and Congress Reports
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Volume 1 |
Issue 1 |
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Institute of Oncology
1965-1990
Meetings and Congress Reports
Book Review - V. Baltic. Induction of differentiation
Book Review - M. Opric, Lj. Markovic. Pigment
skin tumors
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