Table of Contents
1
UI - 21338552
AU - Manahan KJ; Taylor DD; Gercel-Taylor C
TI -
Clonal heterogeneity of p53 mutations in ovarian cancer.
SO - Int J Oncol 2001 Aug;19(2):387-94
AD - University of Michigan School of Medicine, Ann Arbor, MI, USA.
We analyzed clonal populations of ovarian cancer cells for heterogeneity
in p53 mutations (exons 4-9) and chemosensitivity. UL-3A cells were
developed from a patient with stage IIIC ovarian adenocarcinoma.
Heterogeneity in p53 mutations was demonstrated, ranging from point
mutations to deletions in exons 4, 6 and 7. UL-3A cells contained two
point mutations, in codon 248 of exon 7 and in codon 76 of exon 4. Five
groups of clones were identified according to the p53 mutations. UL-3A
clones with low p53 levels were more sensitive to CDDP (LD50 <8.0
microg/ml). Heterogeneity of p53 mutations may provide growth advantage
during disease progression or chemotherapy.
2
UI - 21340685
AU - Melichar B; Touskova M; Tosner J; Kopecky O
TI -
The phenotype of ascitic fluid lymphocytes in patients with ovarian
carcinoma and other primaries.
SO - Onkologie 2001 Apr;24(2):156-60
AD - Department of Oncology and Radiotherapy, Charles University Medical
School and Teaching Hospital, Hradec Kralove, Czech Republic.
melichar@fnhk.cz
BACKGROUND: Ascitic tumor-infiltrating lymphocytes (TIL) are a potential
source of effectors for adoptive immunotherapy. PATIENTS AND METHODS:
The TIL phenotype was examined by two-color flow cytometry in
malignancy-related ascites of 49 patients with different primaries.
Interleukin-10 (IL-10) and neopterin were determined in ascitic fluid by
enzyme-linked immunoassay. RESULTS: Malignant melanoma patients had
significantly higher CD3(+), CD3(+)CD8(+) and CD3(+)CD95(+), and lower
CD3(+)CD4(+) lymphocyte numbers than patients with other primaries.
Ovarian cancer patients had higher CD3(+)CD45RO(+), CD8(+)CD28(+),
CD19(+)CD86(+), CD19(+) and CD19(+)CD86(+) lymphocyte numbers, and lower
NK cell numbers than patients with gastrointestinal and pancreatic
primaries. Pretreated patients had significantly lower concentrations of
IL-10, lower CD8(+)CD28(+), CD3(+)CD45RA(+), and higher CD3(+)CD80(+)
numbers than chemotherapy-naive patients. Patients with hepatic
metastases had lower CD3(+), CD3(+)CD4(+) and CD3(+)CD45RO(+), and
higher CD3(+)CD25(+) and NK cell numbers than patients without liver
metastases. A substantial number of cells exhibited dendritic cell
phenotype. Significant correlations were observed between neopterin and
IL-10 concentrations, and numbers of CD8(+)CD28(+) and CD3(+)CD80(+)
lymphocytes. CONCLUSIONS: Some parameters of TIL phenotype differ
depending on primary, previous treatment, or the presence of liver
metastases. A negative correlation was observed between IL-10 and
neopterin, and an opposing effect of local concentrations of IL-10 and
neopterin on the numbers of CD8(+)CD28(+) and CD3(+)CD80(+) was noted.
Copyright 2001 S. Karger GmbH, Freiburg
3
UI - 21411913
AU - Gadducci A; Ferdeghini M; Cosio S; Fanucchi A; Cristofani R; Genazzani
TI -
AR
The clinical relevance of serum CYFRA 21-1 assay in patients with
ovarian cancer.
SO - Int J Gynecol Cancer 2001 Jul-Aug;11(4):277-82
AD - Department of Procreative Medicine, Division of Gynecology and
Obstetrics, University of Pisa, Pisa, Italy.
a.gadducci@obgyn.med.unipi.it
CYFRA 21-1 assay, which detects serum fragments of cytokeratin 19, has
been widely assessed as a serum marker of several malignancies.
Preoperative serum CYFRA 21-1 levels were retrospectively measured in 60
patients with ovarian cancer and in 59 control patients with benign
ovarian disease. CYFRA 21-1 levels were also serially measured in 90
serum samples drawn from patients with advanced (FIGO stage III-IV)
ovarian cancer followed after surgery and chemotherapy. Preoperative
serum CYFRA 21-1 levels were higher in patients with ovarian cancer
compared with controls (median, range = 2.6, 0.1-51.4 ng/ml versus 0.4,
0.0-3.6 ng/ml, P < 0.0001), and among the former, antigen values were
higher in the 39 patients with advanced-stage than in the 21 patients
with early (FIGO stage I-II) disease (P < 0.0001). In advanced ovarian
cancer patients, the 25%, 50%, and 75% quantiles of preoperative CYFRA
21-1 levels were 1.9, 4.8 and 14.4 ng/ml, respectively. Preoperative
CYFRA 21-1 levels were lower in the 11 patients who achieved a
pathologic complete response at second-look compared with those who had
clinically or surgically detectable persistent disease after first-line
chemotherapy (median, range 1.9, 0.6-9.2 ng/ml versus 10.2, 0.1-51.4
ng/ml, P = 0.007). The pathologic complete response rate was
significantly greater in patients with low preoperative CYFRA 21-1
levels compared with those with elevated CYFRA 21-1 levels at any
cut-off limit for the antigen (1.9, 4.8 and 14.4 ng/ml). However, Cox
regression analysis failed to detect a significant association between
preoperative CYFRA 21-1 assay and survival. As for the follow-up of
advanced ovarian cancer patients, CYFRA 21-1 levels were higher in the
42 samples drawn from patients with clinically detectable disease
compared with the 48 specimens collected from patients with no clinical
evidence of disease (median, range = 1.15, 0.3-40.7 ng/ml versus 0.4,
0.1-9.1 ng/ml, P < 0.0001). In conclusion, preoperative serum CYFRA 21-1
assay appears to be predictive of response to chemotherapy, but not
prognostic of survival, for patients with advanced ovarian cancer.
Moreover, the serial measurement of CYFRA 21-1 levels might have a
potential clinical relevance for the assessment of disease status in
patients followed after surgery and chemotherapy.
4
UI - 21445654
AU - Sivridis E; Giatromanolaki A
TI -
Prognostic aspects on endometrial hyperplasia and neoplasia.
SO - Virchows Arch 2001 Aug;439(2):118-26
AD - Department of Pathology, Democritus University of Thrace,
Alexandroupolis, Greece. esivrid@med.duth.gr
There are various forms of endometrial hyperplasia which, in terms of
prognosis and therapy, can be subdivided into those having cytological
atypia and those lacking this feature. The former may progress into
invasive endometrial malignancy through a transitional non-invasive
stage. This is a continuous process and, as a result, the distinction
between an atypical hyperplasia and an intraepithelial adenocarcinoma
(IEA) or an adenocarcinoma with stromal invasion is not histologically
reproducible. The concept of endometrioid neoplasia, which includes the
entire spectrum of the aforementioned proliferating endometrial lesions,
was introduced. Adenocarcinomas arising from an atypical hyperplasia are
invariably of the endometrioid cell type, whereas those developing from
an atrophic endometrium may be either of the endometrioid or of the
non-endometrioid cell type. Endometrioid adenocarcinomas arising through
the hyperplasia-neoplasia sequence are oestrogen induced and tend to be
well differentiated and less invasive of the myometrium, lack lymphatic
and metastatic involvement and have an excellent prognosis.
Oestrogen-induced adenocarcinomas are also endometrioid, arising from an
atrophic or a rather weakly proliferating endometrium, but these
neoplasms are frequently of higher histological grade and have a
somewhat less favourable prognosis. Finally, endometrial carcinomas of
the non-endometrioid cell type, mainly serous papillary and clear cell
carcinomas, are non-oestrogen induced, non-hyperplasia associated and
show adverse aggressive histological features and an extremely poor
prognosis. The antigenic characteristics and the molecular events
associated with the development of these forms of endometrial malignancy
are distinct and allow the description of, at least, two pathogenetic
types of endometrial carcinoma.
5
UI - 21454124
AU - Gjorgov AN
TI -
Tubal ligation and risk of ovarian cancer.
SO - Lancet 2001 Sep 8;358(9284):843-4; discussion 844
6
UI - 21454126
AU - Piek JM; van Diest PJ; Zweemer RP; Kenemans P; Verheijen RH
TI -
Tubal ligation and risk of ovarian cancer.
SO - Lancet 2001 Sep 8;358(9284):844
7
UI - 21450459
AU - Lahti-Domenici J; Rapakko K; Paakkonen K; Allinen M; Nevanlinna H;
TI -
Kujala M; Huusko P; Winqvist R
Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2
in Finnish breast and ovarian cancer families.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):120-3
AD - Department of Clinical Genetics, University of Oulu/Oulu University
Hospital, P.O. Box 22, FIN-90220, Oulu, Finland.
In the Finnish population, identified mutations in BRCA1 and BRCA2
account for a less than expected proportion of hereditary breast and
ovarian cancer. All previous studies performed in our country have
concentrated on finding germ-line mutations in the coding and
splice-site regions of these two genes. Therefore, we wanted to use a
different methodological approach and search for large genomic
rearrangements, to exclude the possibility of biased BRCA1 and BRCA2
mutation spectra due to known limitations of the previously used
PCR-based detection methods. Our results support earlier notions that
other genes than BRCA1 and BRCA2 will explain a majority of the still
unexplained cases of hereditary susceptibility to breast and ovarian
cancer.
8
UI - 21455244
AU - Saegusa M; Machida B D; Okayasu I
TI -
Possible associations among expression of p14(ARF), p16(INK4a),
p21(WAF1/CIP1), p27(KIP1), and p53 accumulation and the balance of
apoptosis and cell proliferation in ovarian carcinomas.
SO - Cancer 2001 Sep 1;92(5):1177-89
AD - Department of Pathology, Kitasato University School of Medicine,
Sagamihara, Kanagawa, Japan. msaegusa@med.kitasato-u.ac.jp
BACKGROUND: Although there are several reports of changes in expression
of cyclin-dependent kinase inhibitors in ovarian carcinomas, little is
known about their associations with tissue kinetics in the various
histologic subtypes. METHODS: In total, 131 carcinomas were
immunohistochemically investigated for expression of p14(ARF) (p14),
p16(INK4a) (p16), p21(WAF1/Cip1) (p21), and p27(Kip1) (p27). The results
also were compared with data for apoptosis, cell proliferation, p53
status, and survival. Western blot and mRNA analyses were conducted on
35 malignant ovarian tumor samples. RESULTS: Significant differences in
tissue kinetics determined by ratios of apoptotic relative to mitotic
indices were observed among histologic subtypes of ovarian carcinomas,
showing a shift toward predominance of cell proliferation in serous and
cell deletion in clear cell types. The expression of p16, p21, p27, and
p53 was associated closely with changes in cell proliferation rather
than apoptosis and survival, dependent on the subtype. Positivity for
p16 and p21 in the Western blot assay was significantly related to the
results for immunohistochemical but not mRNA analyses, indicating
possible posttranscriptional regulation of these genes. CONCLUSIONS: The
findings indicate that the several cyclin-dependent kinase inhibitors
investigated are expressed differently among histologic subtypes of
ovarian carcinomas, associated with differences in tissue kinetics and
the balance of apoptosis and cell proliferation. Copyright 2001 American
Cancer Society.
9
UI - 21423015
AU - Francis-Thickpenny KM; Richardson DM; van Ee CC; Love DR; Winship IM;
TI -
Baguley BC; Chenevix-Trench G; Shelling AN
Analysis of the TGF beta functional pathway in epithelial ovarian
carcinoma.
SO - Br J Cancer 2001 Sep 1;85(5):687-91
AD - Department of Obstetrics and Gynaecology, Research Centre in
Reproductive Medicine, National Women's Hospital, Auckland, Australia.
Epithelial ovarian carcinoma is often diagnosed at an advanced stage of
disease and is the leading cause of death from gynaecological neoplasia.
The genetic changes that occur during the development of this carcinoma
are poorly understood. It has been proposed that IGFIIR, TGFbeta1 and
TGFbetaRII act as a functional unit in the TGFbeta growth inhibitory
pathway, and that somatic loss-of-function mutations in any one of these
genes could lead to disruption of the pathway and subsequent loss of
cell cycle control. We have examined these 3 genes in 25 epithelial
ovarian carcinomas using single-stranded conformational polymorphism
analysis and DNA sequence analysis. A total of 3 somatic missense
mutations were found in the TGFbetaRII gene, but none in IGFRII or
TGFbeta1. An association was found between TGFbetaRII mutations and
histology, with 2 out of 3 clear cell carcinomas having TGFbetaRII
mutations. This data supports other evidence from mutational analysis of
the PTEN and beta-catenin genes that there are distinct developmental
pathways responsible for the progression of different epithelial ovarian
cancer histologic subtypes. Copyright 2001 Cancer Research Campaign.
10
UI - 20334601
AU - Brun JL; Feyler A; Chene G; Saurel J; Brun G; Hocke C
TI -
Long-term results and prognostic factors in patients with epithelial
ovarian cancer.
SO - Gynecol Oncol 2000 Jul;78(1):21-7
AD - Department of Obstetrics and Gynecology, Centre Hospitalier
Universitaire de Bordeaux, France.
OBJECTIVES: The aim of this study was to evaluate long-term results and
to assess prognostic factors which have an impact on overall survival in
patients with epithelial ovarian cancer. METHODS: A retrospective
analysis of 287 patients treated between 1975 and 1995 was performed.
All operations were performed by senior surgeons. Histologic sections
were reviewed by the same pathologist. Successive adjuvant chemotherapy
regimens are described. Survival was evaluated in 1997. Follow-up lasted
25-260 months (median 90). Statistical methods included Kaplan-Meier
survival curves, log-rank test, and multivariate analysis. RESULTS: The
5-year survival rates were 76, 42, 21, and 6% for patients with stage I,
II, III, and IV disease, respectively. Age, FIGO stage, cytology of
ascites, histologic type and grade, extent of surgery, and number of
residual tumors were significant prognostic indicators in univariate
analysis. Multivariate analysis showed that the risk of mortality
according to FIGO stage was 2.8, 95% CI [1.2-6.3], P = 0.01 for FIGO II,
5.6, 95% CI [2.9-10.8], P < 0.001 for FIGO III, and 10.5, 95% CI
[4.9-22. 1], P < 0.001 for FIGO IV in comparison with FIGO I. Patients
with a serous epithelial carcinoma had a 1.7-fold higher risk of
mortality than patients with other histologic types: RR = 1.7, 95% CI
[1.1-2. 8], P < 0.001. Patients whose tumors distribution permitted
optimal surgery had a 2.3-fold lower risk of mortality than patients
treated with sub- or nonoptimal surgery: RR = 0.43, 95% CI [0.29-0.64],
P < 0.001. The risk of mortality for patients treated with alkylating
agents, platinum-based combination chemotherapy without taxanes, or
carboplatin plus paclitaxel regimens compared with patients who did not
receive treatment was reduced by 47%, 95% CI [8-69%], P = 0.025, 55%,
95% CI [22-74%], P = 0.005, and 70%, 95% CI [35-86%], P = 0.002,
respectively. CONCLUSION: Our study confirms the benefit of
cytoreductive surgery and the efficacy of platinum plus paclitaxel
first-line chemotherapy which has recently been recognized as the
standard treatment for advanced epithelial ovarian cancer. Copyright
2000 Academic Press.
11
UI - 21468601
AU - Gershoni-Baruch R; Dagan E; Israeli D; Kasinetz L; Kadouri E; Friedman E
TI -
Association of the C677T polymorphism in the MTHFR gene with breast
and/or ovarian cancer risk in Jewish women.
SO - Eur J Cancer 2000 Dec;36(18):2313-6
AD - Institute of Human Genetics, Rambam Medical Center, Haifa, Israel.
rgershoni@rambam.health.gov.il
The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR)
gene is associated with reduced enzyme activity, hyperhomocysteinaemia
and increased risk for atherosclerosis in homozygotes. We examined the
frequency of this mutation and its association with disease pattern in
491 Jewish women with either sporadic (n = 355; 72%) or hereditary (n =
136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2
mutation carriers, genotyped for the three predominant Jewish founder
BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes
were equally distributed among women with sporadic breast and/or ovarian
cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205;
21.0%) (P=non-significant). 677T homozygotes were equally distributed
among women diagnosed with breast cancer prior to (22/122; 18.0%) and
after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate
of 677T homozygotes in manifesting cancer (32/136; 23.5%) and
asymptomatic individuals (11/69; 15.9%) was not significantly different.
The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among
women with bilateral breast cancer and those with both breast and
ovarian carcinoma than among those with unilateral breast cancer
(64/365; 17.5%). Differences in morbidity (one versus multiple
breast/ovarian tumours) are mainly attributed to 677T homozygosity and
partly to BRCA1/2 mutations. Confirmation of these data, namely, that
the 677T allele is significantly more common in cases of bilateral
breast cancer or combined breast and ovarian cancer would have important
clinical implications.
12
UI - 21468602
AU - Sengupta PS; McGown AT; Bajaj V; Blackhall F; Swindell R; Bromley M;
TI -
Shanks JH; Ward T; Buckley CH; Reynolds K; Slade RJ; Jayson GC
p53 and related proteins in epithelial ovarian cancer.
SO - Eur J Cancer 2000 Dec;36(18):2317-28
AD - Cancer Research Campaign Department of Medical Oncology, Christie
Hospital National Health Trust, Withington, Manchester, UK.
We conducted a retrospective immunohistochemical evaluation of the
prognostic significance of the expression of p53 and the related
proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine
double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken
from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell
proliferation) was also evaluated immunohistochemically, while apoptosis
within malignant cells was determined with the terminal
deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL)
assay. The expression of each of the following proteins was
significantly associated in the tumours (P < 0.05 unless otherwise
stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with
Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate
analysis showed that expression of p53, Bax, bulk residual disease and
International Federation of Gynecology and Obstetricians (FIGO) stage
were all strongly correlated with response to chemotherapy (P < 0.01).
Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as
pathological subtype and bulk residual disease (P < 0.05), were
prognostic factors for disease progression. The FIGO stage and Ki-67
expression were significant prognostic factors for overall survival (P <
0.01), with Gadd45 expression and pathological subtype also significant
(P < 0.05) in a univariate analysis. Multivariate analysis for response
to chemotherapy showed that expression of p53, Bax and FIGO stage were
all independent prognostic factors (P < 0.01). The FIGO stage was the
most important independent prognostic factor for progression and
survival on multivariate analysis (P < 0.01). However, Ki-67 expression
was also an independent prognostic factor for disease progression (P <
0.05) and approached significance for survival (P = 0.055). Taken
together, these data suggest that determination of Ki-67 expression
could supplement established prognostic factors.
13
UI - 21190909
AU - Davidson B; Reich R; Goldberg I; Gotlieb WH; Kopolovic J; Berner A;
TI -
Ben-Baruch G; Bryne M; Nesland JM
Ets-1 messenger RNA expression is a novel marker of poor survival in
ovarian carcinoma.
SO - Clin Cancer Res 2001 Mar;7(3):551-7
AD - Department of Pathology, The Norwegian Radium Hospital, Oslo.
bend@ulrik.uio.no
Ets-1 proto-oncogene is a transcription factor involved in several
cellular functions, including the activation of several proteases
participating in tumor invasion and metastasis. The objective of this
study was to analyze the possible correlation between Ets-1 mRNA
expression and survival in advanced-stage ovarian carcinomas, studying
two patient groups with extremely different disease outcome. Sections
from 66 primary ovarian carcinomas and metastatic lesions from 41
patients diagnosed with advanced-stage ovarian carcinoma (International
Federation of Gynecologists and Obstetricians stages III and IV) were
evaluated for expression of Ets-1 using mRNA in situ hybridization.
Patients were divided into long-term (n = 17) and short-term (n = 24)
survivors. The mean values for disease-free survival and overall
survival were 116 and 133 months for long-term survivors, as compared to
3 and 21 months for short-term survivors, respectively. Expression of
Ets-1 mRNA was detected in carcinoma cells and stromal cells in 28 of 66
(42%) and 22 of 66 (33%) lesions, respectively. Ets-1 expression showed
an association with mRNA expression of vascular endothelial growth
factor (P = 0.001 for carcinoma cells; P = 0.004 for stromal cells),
basic fibroblast growth factor (P = 0.049 for carcinoma cells), and
membrane type-1 matrix metalloproteinase (P = 0.045), which were
previously studied in this patient cohort. Ets-1 mRNA was detected more
often in both carcinoma and stromal cells in tumors of short-term
survivors (P = 0.038 for carcinoma cells). In univariate survival
analysis for all cases, Ets-1 expression in both tumor (P = 0.018) and
stroma (P = 0.026) correlated with poor survival. These findings were
reproduced in an analysis of primary tumors alone (P = 0.039 for tumor
cells; P < 0.001 for stromal cells). Ets-1 mRNA expression in stromal
cells retained its predictive power in a multivariate survival analysis
in which all molecules studied previously in this patient cohort were
included (P = 0.007). To our knowledge, this is the first evidence
associating Ets-1 mRNA expression and poor survival in human epithelial
malignancy. Ets-1 is thus a novel prognostic marker in advanced-stage
ovarian carcinoma. The association between Ets-1 mRNA expression and the
expression of membrane type-1 matrix metalloproteinase and angiogenic
genes, first documented here in a study of patient material, points to
the central role of this transcription factor in tumor progression in
ovarian carcinoma.
14
UI - 21317608
AU - Gad S; Scheuner MT; Pages-Berhouet S; Caux-Moncoutier V; Bensimon A;
TI -
Aurias A; Pinto M; Stoppa-Lyonnet D
Identification of a large rearrangement of the BRCA1 gene using
colour bar code on combed DNA in an American breast/ovarian cancer
family previously studied by direct sequencing.
SO - J Med Genet 2001 Jun;38(6):388-92
15
UI - 21328978
AU - Sarantaus L; Vahteristo P; Bloom E; Tamminen A; Unkila-Kallio L; Butzow
TI -
R; Nevanlinna H
BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma
patients.
SO - Eur J Hum Genet 2001 Jun;9(6):424-30
AD - Department of Obstetrics and Gynecology, Helsinki University Central
Hospital, Biomedicum Helsinki, P.O. Box 700 (Haartmaninkatu 8),
FIN-00029 HUS, Finland.
Germline mutations of BRCA1 and BRCA2 predispose to hereditary
breast-ovarian cancer syndrome. In Finland, 20 different BRCA1/2
mutations have been identified, and 13 of them are founder mutations
that account for the vast majority of Finnish BRCA1/2 families. The
purpose of our study was to determine the prevalence of BRCA1/2
mutations in unselected Finnish ovarian carcinoma patients and to
evaluate the relationship between mutation carrier status and
personal/family history of cancer. Two hundred and thirty-three patients
were screened for all the 20 BRCA1/2 mutations known in the Finnish
population. Additionally, a subgroup of patients with personal history
of breast cancer and/or family history of breast and/or ovarian cancer
was screened for novel BRCA1/2 mutations. Thirteen patients (5.6%) had
mutations: eleven in BRCA1 and two in BRCA2. All the mutation-positive
patients were carriers of the previously known Finnish BRCA1/2
mutations, and seven recurrent founder mutations accounted for 12 of the
13 mutations detected. A logistic regression analysis was used to
determine the odds of mutation for ovarian carcinoma patients. The most
significant predictor of a mutation was the presence of both breast and
ovarian cancer in the same woman, but family history of breast cancer
was also strongly related to mutation carrier status. Although BRCA1/2
mutation testing is not warranted in the general Finnish ovarian cancer
patient population, patients who have also been diagnosed with breast
cancer or have family history of breast or breast and ovarian cancer
could benefit from referral to genetic counselling and mutation testing.
16
UI - 21426823
AU - Chiari S; Rota S; Zanetta G; Vecchione F; Caspani G
TI -
Early-stage epithelial ovarian cancer: an overview.
SO - Forum (Genova) 2000 Oct-Dec;10(4):298-307
AD - Universita degli Studi di Milano, Bicocca, Facolt di Medicina e Chirugia
e Ospedale San Gerardo, Clinica Ostetrica e Ginecologica, Monza, Italy.
The clinical treatment of malignant epithelial ovarian cancer limited to
the gonad(s) involves many problems that have given rise to analyses in
recent literature and to different approaches: i. intensive
anatomo-radio-surgical staging, evaluation and clinical incidence of
prognostic risk factors; ii. re-staging of patients after inadequate and
incomplete surgery; iii. indications, role and topicality of second-look
surgery; iv. conservative surgery in patients of a fertile age wishing
to have children and retain activity of the gonads; v. laparoscopic
surgery for treatment, staging, re-staging and surveillance; vi. the
lymph node issue; vii. adjuvant therapy: indications, options, type of
drugs, doses and length; viii. quality and frequency of surveillance;
ix. malignant epithelial ovarian cancer limited to the gonads in
pregnancy. The clinical handling of these tumours entails many complex
problems causing emotional involvement since it is most frequent at a
fertile age.
17
UI - 21426829
AU - von Schlippe M; Rustin GJ
TI -
Circulating tumour markers in ovarian tumours.
SO - Forum (Genova) 2000 Oct-Dec;10(4):383-92
AD - Department of Medical Oncology, Mount Vernon Centre for Cancer
Treatment, Northwood, Middlesex, UK.
Many circulating tumour markers are in clinical or experimental use for
the management of ovarian tumours. The only marker to have an
established role in the diagnosis, monitoring treatment, and detection
of relapse of epithelial ovarian cancer (OC) is cancer antigen-125
(CA-125). The place of markers in predicting prognosis, in follow-up,
and in screening for OC, is less well defined. This review concentrates
on epithelial cancer of the ovary, and on CA-125, the most commonly-used
OC marker. Other markers in epithelial OC are also discussed, as well as
markers used in the management of germ cell tumours of the ovary, mixed
Mullerian tumours, and stromal ovarian tumours.
18
UI - 21443289
AU - Syed V; Ulinski G; Mok SC; Yiu GK; Ho SM
TI -
Expression of gonadotropin receptor and growth responses to key
reproductive hormones in normal and malignant human ovarian surface
epithelial cells.
SO - Cancer Res 2001 Sep 15;61(18):6768-76
AD - Department of Surgery, Division of Urology, University of Massachusetts
Medical School, Worcester, Massachusetts 01655, USA.
Epidemiological data have implicated reproductive hormones as probable
risk factors for ovarian cancer (OCa) development. Although pituitary
and sex hormones have been reported to regulate OCa cell growth, no
information is available regarding whether and how they influence normal
ovarian surface epithelial (OSE) cell proliferation. To fill this data
gap, this study has compared cell growth responses to gonadotropins and
sex steroids in primary cultures of human OSE (HOSE) cells with those
observed in immortalized, nontumorigenic HOSE cells and in OCa cell
lines. Both malignant and normal cell lines/cultures responded equally
well to the stimulatory actions of luteinizing hormone and
follicle-stimulating hormone and to 17beta-estradiol and estrone,
although the latter estrogen has a much lower affinity for estrogen
receptor than does the former estrogen. In normal HOSE cell
cultures/lines, 5alpha-dihydrotestosterone was found to be more
effective than testosterone in stimulating cell growth, but in OCa cell
lines, 5alpha-dihydrotestosterone and testosterone are equally potent.
One OCa cell line, OVCA 433, was found to be nonresponsive to androgen
stimulation. In general, primary cultures of normal HOSE cells exhibited
the greatest hormone-stimulated growth responses (>10-fold enhancement),
followed by immortalized HOSE cell lines (4-5-fold enhancement) and by
OCa cell lines (2-4-fold enhancement). Interestingly, progesterone (P4),
at low concentrations (10(-11) to 10(-10) M), was stimulatory to HOSE
and OCa cell growth, but at high doses (10(-8) to 10(-6) M), P4 exerted
marked inhibitory effects. In all cases, cotreatment of a cell
culture/line with a hormone and its specific antagonist blocked the
effect of the hormone, confirming specificity of the hormonal action.
Taken together, these data support the hypothesis that reproductive
states associated with rising levels of gonadotropins, estrogen, and/or
androgen promote cell proliferation in the normal OSE, which favors
neoplastic transformation. Conversely, those states attended by high
levels of circulating P4, such as that seen during pregnancy, induce OSE
cell loss and offer protection against ovarian carcinogenesis.
19
UI - 20487065
AU - Piver MS
TI -
Insurance policies for prophylactic mastectomy: to cover or not to
cover?
SO - Ann Surg Oncol 2000 Oct;7(9):714
20
UI - 21203582
AU - Choi KC; Kang SK; Nathwani PS; Cheng KW; Auersperg N; Leung PC
TI -
Differential expression of activin/inhibin subunit and activin receptor
mRNAs in normal and neoplastic ovarian surface epithelium (OSE).
SO - Mol Cell Endocrinol 2001 Mar 28;174(1-2):99-110
AD - Department of Obstetrics and Gynaecology, BC Women's Hospital,
University of British Columbia, 2H-30, 4490 Oak Street, Vancouver,
British Columbia, V6H 3V5, Canada.
Ovarian surface epithelium (OSE) is the tissue of origin for the
majority of ovarian cancers. The mechanism underlying the neoplastic
transformation of OSE to ovarian cancer is poorly understood. Activin, a
member of the transforming growth factor-beta superfamily, has been
shown to increase cell proliferation in ovarian cancer cells. The
present study was carried out to investigate the expression and
regulation of activin/inhibin subunits and activin receptors in normal
and neoplastic OSE. Using reverse transcriptase-polymerase chain
reaction and Southern blot analysis, the mRNA levels of alpha, betaA and
betaB subunits and activin receptor type IIA and IIB were analyzed in
normal OSE and the ovarian cancer cell line, OVCAR-3 cells. The alpha
and betaA subunits were highly expressed in normal OSE when compared to
OVCAR-3 cells. By contrast, betaB subunit was highly expressed in
OVCAR-3 cells, when compared to normal OSE cells. Interestingly, activin
receptor IIB mRNA levels were significantly higher in OVCAR-3 when
compared to normal OSE cells, whereas activin receptor IIA mRNA levels
were the same in both cell types. To characterize the growth modulatory
role of activin during neoplastic progression, normal OSE and OVCAR-3
cells were treated with recombinant human activin A (rh-activin A). At
concentrations of 1,10 and 100 ng/ml, rh-activin A stimulated the growth
of OVCAR-3 cells, but not of normal OSE. Treatment with follistatin,
binding protein of activin, attenuates the stimulatory effect of
activin. To determine whether the growth stimulatory action of activin
in the neoplastic OSE is mediated via an autocrine regulatory mechanism,
OVCAR-3 cells were treated with rh-activin A in a dose- and
time-dependent manner and the expression levels of activin/inhibin
subunits and activin receptors were investigated. Treatments with
activin increased the alpha and betaA subunit mRNA levels in a dose- and
time-dependent manner. However, no difference was observed in levels of
betaB subunit, or in activin receptor type IIA and IIB mRNAs following
activin treatments in OVCAR-3 cells. Taken together, these results
suggest that different levels of activin/inhibin and activin receptor
isoforms are expressed in normal and neoplastic OSE cells. In addition,
the altered expression of the activin/inhibin subunits, as well as the
cell proliferative effect of activin observed in OVCAR-3 but not in
normal OSE cells, indicate that activin may act as an autocrine
regulator of neoplastic OSE progression.
21
UI - 21348621
AU - Fleckenstein G; Sattler B; Hinney B; Wuttke W; Osmers R; Emons G
TI -
Androblastoma of the ovary: clinical, diagnostic and histopathologic
features.
SO - Onkologie 2001 Jun;24(3):286-91
AD - Abteilung Gynakologie und Geburtshilfe, Universitats-Frauenklinik
Gottingen, Robert-Koch-Strasse 40, D-37075 Gottingen, Germany.
mhanne_1@med.uni-goettingen.de
Androblastomas of Sertoli-Leydig cell tumors of the ovaries are
classified into the group of sex cord stromal tumors and represent an
extremely rare form of tumor (0.2% of all ovarian tumors) in women.
Their malignant potential is lower than that of epithelial ovarian
cancer. They cause signs of virilization, although these are not
obligatory. In many cases secondary amenorrhea is the only symptom of
the disease. This leads to an intensive search for the source of the
disorder. Frequently only the elevated production of androgens gives a
preoperative clue to the tumor type. The recommendation to include the
measurement of androgen levels in the routine diagnosis of secondary
amenorrhea must therefore be endorsed. The tumors are usually
sonographically identifiable; in differential diagnosis,
hyperandrogenemia of other origins (e.g., Cushing's disease, adrenal
hyperplasia, pituitary adenoma, other causes of ovarian and adrenal
androgen hypersecretion, intersexuality, medically induced
androgenization) have to be ruled out. In view of the good prognosis,
the therapy of choice consists simply in adnexectomy of the affected
side. With regular measurement of serum androgen levels an effective
control of the course of the disorder is possible. A conclusive
pathological diagnosis is difficult as heterologous tumors and mixed
tumors exist and, furthermore, other tumor types are capable of
imitating Sertoli-Leydig cell tumors. Copyright 2001 S. Karger GmbH,
Freiburg
22
UI - 21381734
AU - Dong Y; Kaushal A; Bui L; Chu S; Fuller PJ; Nicklin J; Samaratunga H;
TI -
Clements JA
Human kallikrein 4 (KLK4) is highly expressed in serous ovarian
carcinomas.
SO - Clin Cancer Res 2001 Aug;7(8):2363-71
AD - Centre of Molecular Biotechnology, School of Life Sciences, Queensland
University of Technology, Brisbane, Queensland 4001, Australia.
Previous studies indicated that a new member of the human kallikrein
(KLK) gene family, KLK4, was expressed in prostate, breast, and
endometrial carcinoma cell lines and may have potential as a tumor
marker. The aim of this study was to examine the expression of KLK4 in
the normal ovary and ovarian tumors of different histology, stage, and
differentiation and to determine its association with ovarian tumor
progression. Using reverse transcription-PCR, Southern blot, and
densitometry analyses, we found the level of KLK4 expression was higher
in late stage serous (SER) epithelial-derived ovarian carcinomas than in
normal ovaries, mucinous epithelial tumors, and granulosa cell tumors.
KLK4 was highly expressed in all of the SER ovarian carcinoma cell lines
(eight of eight), SER epithelial carcinomas (11 of 11), and two
adenomas, whereas it was expressed at a lower level (or not at all) in
normal ovaries (four of six), mucinous epithelial tumors (three of
four), endometrioid carcinomas (four of five), clear cell carcinomas
(two of three), or granulosa cell tumors (three of six). Of particular
interest, KLK4 mRNA variants were detected in SER ovarian carcinoma cell
lines and primary cultured ovarian tumor cells, but they were not
present in normal ovaries. In situ hybridization analysis showed that
KLK4 mRNA transcripts are localized to adenocarcinoma cells of ovarian
tumor tissues. Similarly, immunohistochemical staining of ovarian
carcinoma sections showed immunoreactivity to KLK4 protein product (hK4)
antipeptide antibodies. In addition, intracellular hK4 levels, as
detected on Western blot analysis, were induced by 100 nM estrogen
treatment of the estrogen receptor positive ovarian carcinoma cell line
OVCAR-3, >8-24 h. Our results show that the level of KLK4 expression and
expression of KLK4 mRNA variants are associated with progression of
ovarian cancer, particularly late stage SER adenocarcinomas. Moreover,
hK4 may be a candidate marker for the diagnosis and/or monitoring of
ovarian epithelial carcinomas.
23
UI - 21381735
AU - Luo LY; Katsaros D; Scorilas A; Fracchioli S; Piccinno R; Rigault de la
TI -
Longrais IA; Howarth DJ; Diamandis EP
Prognostic value of human kallikrein 10 expression in epithelial ovarian
carcinoma.
SO - Clin Cancer Res 2001 Aug;7(8):2372-9
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,
Toronto, Ontario, M5G 1X5 Canada.
PURPOSE: Human kallikrein 10 (hK10; also known as the normal epithelial
cell-specific 1 gene and protein) is a secreted serine protease, which
belongs to the human kallikrein family. It has been reported that hK10
is down-regulated in breast and prostate cancer cell lines and that it
may function as a tumor suppressor. Recently, we developed a highly
sensitive and specific immunoassay for hK10 and found that this protein
is abundantly expressed in ovarian tissue. In this study, we measured
quantitatively hK10 levels in ovarian cancer cytosolic extracts and
evaluated the prognostic value of this biomarker in ovarian cancer.
EXPERIMENTAL DESIGN: Specimens from eight normal ovarian tissues, eight
ovarian tissues with benign disease, and 182 ovarian tumors were
investigated. RESULTS: hK10 concentration in ovarian tumor cytosols
ranged from 0 to 84 ng/mg of total protein, with a median of 2.6. This
median was highly elevated in comparison with normal and benign ovarian
tissues (P < 0.001). A cutoff of 1.35 ng/mg was selected to categorize
tumors as hK10 high and hK10 low. With chi(2) test and Fisher's exact
test, high concentration hK10 was found to be associated with advanced
disease stage, serous histological type, suboptimal debulking, and large
residual tumor (>1 cm; all P < 0.05). hK10 status was additionally
correlated with clinical outcome, including progression-free (PFS) and
overall survival (OS) using the Cox model. In univariate analysis, we
found that patients with hK10 high tumors were more likely to die and
relapse, in comparison with patients with hK10 low tumors (hazards
ratios for PFS and OS were 1.93 and 2.42, respectively; P < 0.05).
Although this correlation disappeared after the entire patient
population was subjected to multivariate analysis, it remained
significant in the subgroup of patients with stage III/IV ovarian cancer
(hazards ratios for PFS and OS were 1.98 and 2.12, respectively; P <
0.05). CONCLUSIONS: Our results indicate that hK10 is a new,
independent, unfavorable prognostic marker, especially for late-stage
ovarian cancer.
24
UI - 21381736
AU - Obiezu CV; Scorilas A; Katsaros D; Massobrio M; Yousef GM; Fracchioli S;
TI -
Rigault de la Longrais IA; Arisio R; Diamandis EP
Higher human kallikrein gene 4 (KLK4) expression indicates poor
prognosis of ovarian cancer patients.
SO - Clin Cancer Res 2001 Aug;7(8):2380-6
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,
Toronto, Ontario, M5G 1X5 Canada.
PURPOSE: Kallikrein gene 4 (KLK4, also known as prostase/KLK-L1),
located on chromosome 19q13.4, is one of the newly discovered members of
the human KLK-like gene family. This gene is up-regulated by androgens
in the LNCaP prostatic carcinoma cell line and by androgens and
progestins in the BT-474 breast cancer cell line. On the basis of its
apparent association with hormonally regulated tissues, we have
undertaken to examine the prognostic value of KLK4 expression in 147
malignant ovarian tissues. EXPERIMENTAL DESIGN: Tumors were pulverized,
total RNA was extracted, and cDNA was prepared by reverse transcription.
KLK4 was amplified by PCR using gene-specific primers, and its identity
was verified by sequencing. Ovarian tissues were then classified as
KLK4-positive or -negative, based on ethidium bromide visualization of
the PCR product on agarose gels. RESULTS: KLK4 was found to be expressed
in 69 (55%) of 147 of ovarian cancer samples. We found a strong positive
association between KLK4 expression and tumor grade (P = 0.02) and
clinical stage (P < 0.001). Univariate survival analysis revealed that
patients with ovarian tumors positive for KLK4 expression had an
increased risk for relapse and death (P = 0.003 and 0.001,
respectively). Whereas knowledge of KLK4 status did not significantly
increase the prognostic power of the multivariate models, additional
analyses did determine that KLK4 was an independent unfavorable
prognostic factor in patients with grade 1 and 2 tumors. CONCLUSIONS:
Our findings indicate that KLK4 expression is associated with more
aggressive forms of ovarian cancer.
25
UI - 21381738
AU - Schmalfeldt B; Prechtel D; Harting K; Spathe K; Rutke S; Konik E;
TI -
Fridman R; Berger U; Schmitt M; Kuhn W; Lengyel E
Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and
the urokinase-type plasminogen activator is associated with progression
from benign to advanced ovarian cancer.
SO - Clin Cancer Res 2001 Aug;7(8):2396-404
AD - Department of Obstetrics and Gynecology, Technische Universitat Munchen,
Klinikum rechts der Isar, 81675 Munich, Germany.
Proteases are linked to the malignant phenotype of different solid
tumors. Therefore, the expression of the matrix metalloproteinase
(MMP)-2 and MMP-9 and of the serine protease urokinase-type plasminogen
activator (uPA) and its inhibitor plasminogen activator inhibitor type 1
(PAI-1) in the progression of ovarian cancer was investigated.
Gelatinolytic activity and protein expression of MMP-2 and MMP-9 were
analyzed in tissue extracts of 19 cystadenomas and 18 low malignant
potential (LMP) tumors, as well as 41 primary tumors of advanced ovarian
cancer stage International Federation of Gynecology and Obstetrics
IIIc/IV and their corresponding omentum metastases by quantitative
gelatin zymography and Western blot. In the same tissue extracts,
antigen levels of uPA and its inhibitor PAI-1 were determined by ELISA.
Protein expression of pro-MMP-2 (72 kDa) and pro-MMP-9 (92 kDa as well
as antigen levels of uPA and PAI-1 were low in benign ovarian tumors but
increased significantly from LMP tumors to advanced ovarian cancers. The
highest values of all of the proteolytic factors were detected in
omentum metastases. Active MMP-2 enzyme (62 kDa) was detected only in
ovarian cancer (66%) and corresponding metastases (93%) but never in
benign or LMP tumors. The activation rate of MMP-2 to its active isoform
was higher in the metastases. Comparing both proteolytic systems, higher
PAI-1 concentrations were c
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