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Objective: We aimed to study the association between obesity and survival in ovarian cancer (OC) patients, accounting for confounders as disease stage, histology, and comorbidities., Methods: Retrospective matched case-control study of consecutive patients, with epithelial OC. Obese (body mass index [BMI] ≥ 35 kg m -2 ) patients were matched in a 1:4 ratio with patients having lower BMIs (BMI < 35 kg m -2 ) based on disease stage, cytoreduction state, tumor histology and ASA score. We compared the 3-year and total recurrence-free survival and overall survival through Kaplan-Meier survival curves and Cox proportional hazards., Results: Overall, 153 consecutive patients were included, of whom 32 (20.9%) had a BMI ≥ 35. and 121 a BMI < 35. The median follow-up time was 39 months (interquartile range 18-67). Both study groups were similar in multiple prognostic factors, including American Society of Anesthesiologists physical status, completion of cytoreduction, histology and stage of disease (p = 0.981, p = 0.992, p = 0.740 and p = 0.984, respectively). Ninety-five (62.1%) patients underwent robotic surgery and conversion rate from robotic to laparotomy was similar in both groups 2 (6.3%) in obese group vs. 6 (5.0%) in lower BMI patients, p = 0.673. During the follow-up time, the rate of recurrence was similar in both groups; 21 (65.6%) in obese group vs. 68 (57.1%), p = 0.387 and the rate of death events was similar; 16 (50.0%) in obese group vs. 49 (40.5%), p = 0.333). The 3-year OS was higher in the obese group (log rank p = 0.042) but the 3-year RFS was similar in both groups (log rank p = 0.556). Median total OS was similar in both groups 62 months (95% confidence interval 25-98 months) in obese vs. 67 months (95% confidence interval 15-118) in the lower BMI group, log rank p = 0.822. Median RFS was similar in both groups; 61 months (95% confidence interval 47-74) in obese, vs. 54 (95% confidence interval 43-64), log rank p = 0.842. In Cox regression analysis for OS, including obesity, age, laparotomy and neoadjuvant treatment - only neoadjuvant treatment was independently associated with longer OS: odds ratio 1.82 (95% confidence interval 1.09-3.05) and longer RFS: odds ratio 2.16 (95% confidence interval 1.37-3.41)., Conclusions: In the present study on consecutive cases of ovarian cancer, obesity did not seem to be associated with outcome, except for an apparent improved 3-year survival that faded away thereafter., (© 2024. The Author(s).)

Background: Carriers of pathogenic variants in both BRCA1 and BRCA2 genes as a double mutation (BRCA1/2 DM) have been rarely reported in women with epithelial ovarian cancer (EOC)., Methods: We reviewed the English literature and interrogated three repositories reporting EOC patients carrying BRCA1/2 DM. The clinicopathological parameters of 36 EOC patients carrying germline BRCA1/2 DM were compared to high-grade serous EOC women of the COEUR cohort with known germline BRCA1/BRCA2 mutation carrier status (n = 376 non-carriers, n = 65 BRCA1 and n = 38 BRCA2). Clinicopathological parameters evaluated were age at diagnosis, stage of disease, loss of heterozygosity, type of mutation, immunohistochemistry profile, progression occurrence and survival., Results: Median age at diagnosis of BRCA1/2 DM patients was 51.9 years, similar to BRCA1 mutation carriers (49.7 years, p = .58) and younger than BRCA2 mutation carriers (58.1 years, p = .02). Most patients were diagnosed at advanced stage (III-IV; 82%) and were carriers of founder/frequent mutations (69%). Tissue immunostainings revealed no progesterone receptor expression and low intraepithelial inflammation. The 5-year survival rate (60%) was significantly lower than that of BRCA2 mutation carriers (76%, p = .03) but not of BRCA1 mutation carriers (51%, p = .37)., Conclusions: Our data suggests some co-dominant effect of both mutations but the outcome of these patients more closely resembled that of BRCA1 mutation carriers with poor prognosis factors., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: With the rapid uptake of robotic surgery in surgical oncology, its use in the treatment of epithelial ovarian cancers is being evaluated. Complete cytoreduction represents the goal of surgery either at primary cytoreduction or after neoadjuvant chemotherapy in the setting of interval cytoreduction. In selected patients, the extent of disease would enable minimally invasive surgery. The objective of this study was to evaluate the impact of introducing robotic surgery for interval cytoreduction of selected patients with stage III-IV ovarian cancer., Methods: All patients who underwent surgery from November 2008 to 2014 (concurrent time period when robotic and open surgery were used simultaneously) after receiving neoadjuvant chemotherapy for advanced ovarian cancer (stage III-IV) were compared with all consecutive patients who underwent cytoreductive surgery by laparotomy after neoadjuvant chemotherapy between January 2006 and November 2008. Inclusion criteria included an interval cytoreductive surgery by laparotomy or robotic assistance for stage III-IV non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Exclusion criteria included patients treated concurrently for a non-gynecologic cancer, as well as secondary cytoreductive surgeries and diagnostic surgeries without an attempt at tumor reduction. Overall survival, progression-free survival, and peri-operative outcomes were compared for the entire patient cohort with those with advanced ovarian cancer who received neoadjuvant chemotherapy immediately before and after the introduction of robotic surgery., Results: A total of 91 patients were selected to undergo interval cytoreduction either via robotic surgery (n=57) or laparotomy (n=34) after the administration of neoadjuvant chemotherapy. The median age of the cohort was 65 years (range 24-88), 78% had stage III disease, and the median follow-up time was 37 months (5.6-91.4 months). The median survival was 42.8±3.1 months in the period where both robotic surgery and laparotomy were offered compared with 37.9±9.8 months in the time period preceding when only laparotomy was performed (p=0.6). All patients selected to undergo interval robotic cytoreduction following neoadjuvant chemotherapy had a reduction of cancer antigen 125 by at least 80%, resolution of ascites, and CT findings suggesting the potential to achieve optimal interval cytoreduction. All these patients achieved optimal cytoreduction with <1 cm residual disease, including 82% with no residual disease. The median blood loss was 100 mL (mean 135 mL, range 10-1250 mL), and the median hospital stay was 1 day., Conclusion: Robotic interval cytoreductive surgery is feasible in well-selected patients. Future studies should aim to define ideal patients for minimally invasive cytoreductive surgery., Competing Interests: Competing interests: WG and SL obtained partial travel support for proctoring robotic surgery., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

In studying the age dependence and chronology of ovarian tumors in follicle stimulating hormone receptor knockout mice, we identified a novel ovarian tumor associated gene-12 (OTAG-12), which is progressively downregulated and maps to Chr. 8B3.3. OTAG-12 protein overexpression in mouse ovarian and mammary tumor cells suggested powerful anti-proliferative effects. In human epithelial ovarian cancers (OCs) and OC cell lines, OTAG-12 mRNA expression is downregulated in comparison with normal ovaries. Cloning and identification revealed that human OTAG-12 mapping to gene-rich Chr. 19p13.12 is expressed in three spliced forms: hOTAG-12a, hOTAG-12b and hOTAG-12c, of which b is predominant in the normal ovary. Functionally active hOTAG-12b is a simple protein with no disulfide bonds and a nuclear localization signal is present in all variants. Transfection of OTAG-12 variants in OC and tumorigenic HEK293 cells confirmed nuclear localization. hOTAG-12b overexpression in OC and HEK293 cells effectively suppressed cell growth, anchorage-dependent and independent colony formation followed by apoptosis, whereas hOTAG-12a and hOTAG-12c had no such effects. Deletion mutants identified the critical importance of carboxyl terminus for hOTAG-12b function. Doxycycline-inducible growth inhibition of HEK293 cells by hOTAG-12a was associated with effects on G2 cell cycle arrest and apoptosis induction. hOTAG-12b expression rendered tumorigenic cells more sensitive to four apoptotic stimuli including etoposide-a topoisomerase-II inhibitor. Doxycycline-induced hOTAG-12b expression blocked xenograft tumor growth in nude mice, whereas hOTAG-12a was ineffective. Although p53-pathway-dependent apoptotic agents could upregulate endogenous hOTAG-12b and p53 in UCI-101/107 OC cells, hOTAG-12b could also induce apoptosis in p53-null and platinum-resistant SKOV3 OC cells and Doxycycline-induced hOTAG-12b did not alter p53. Further study showed that hOTAG-12b increases mRNAs of pro-apoptotic genes such as BAD, GADD45α and CIEDB, while inhibiting anti-apoptotic NAIP and Akt1 expression, suggesting that hOTAG-12b-induced apoptosis might be p53-independent. These results indicate that hOTAG-12b is a putative ovarian tumor suppressor gene warranting further studies.

Objective: This pilot study aimed to provide supportive evidence for the acceptability and usefulness of the Meaning-Making intervention (MMi) in patients newly diagnosed with Stage III or IV ovarian cancer, and to provide estimates of parameters needed to design a full-scale study., Methods: A randomized controlled trial with 24 patients (12 experimental and 12 control) was conducted. Existential well-being (primary outcome), overall quality of life, distress, anxiety, depression and self-efficacy were measured., Results: Compared to the control group, patients in the experimental group had a better sense of meaning in life at one and three months post-intervention., Conclusion: The MMi seems a promising intervention for advanced cancer patients, and a full randomized controlled trial is warranted to further investigate its efficacy.

Objectives: To evaluate the role of intraperitoneal (IP) chemotherapy as part of primary treatment in patients with advanced ovarian cancer and to develop standards of care within the context of current clinical practice., Methods: A multidisciplinary expert panel, convened to develop standards on the use of IP chemotherapy, searched the MEDLINE, EMBASE, and Cochrane Library databases up to December 2006 for randomized trials or published standards on the efficacy and/or delivery of IP chemotherapy., Results: Eight randomized trials comparing IP chemotherapy versus intravenous (IV) chemotherapy were identified. Three trials reported statistically significant improvements in median survival of 8.0, 11.0, and 15.9 months with cisplatin-based IP chemotherapy. In one trial, the 15.9-month improvement in median overall survival (RR=0.75, 95% CI=0.58-0.97) represented a 25% reduction in the risk of death with IP chemotherapy. Severe adverse events and catheter-related complications were often dose limiting with IP chemotherapy. Using a consensus-based approach with a nationally representative panel, multidisciplinary care standards were developed to review medical and surgical criteria, the practice setting, volume requirements, and the institutional criteria required to safely deliver IP chemotherapy., Conclusion: The survival benefits with cisplatin-based IP chemotherapy may represent a significant improvement in the outlook for select patients with advanced ovarian cancer. The delivery of IP chemotherapy is more challenging than the IV route; however, severe adverse events and catheter-related complications may be offset through research defining the optimum treatment regimen, and the standardization of care. System-wide standards for the delivery of IP chemotherapy in Canada for patients with optimally debulked stage III ovarian cancer are offered.

Aims: To investigate the diffusion and accumulation of doxorubicin metabolites in the ascites of patients with ovarian cancer following intravenous injection, as a model for intraperitoneal accumulation of drugs., Methods: The concentrations of doxorubicin and its metabolites [Doxorubicinol (Dox-ol), 7-deoxydoxorubicinolone (7d-Dox-ol-on) and 7-deoxydoxorubicinone (7d-Dox-on)] were measured using high-performance liquid chromatography in the serum and in the ascites of seven patients with recurrent ovarian carcinoma suffering from symptomatic ascites and treated with intravenous doxorubicin., Results: Doxorubicin metabolites accumulated in the peritoneal cavity. The concentrations of the doxorubicin metabolites were initially higher in the serum compared to the ascitic fluid, but following several hours the doxorubicin metabolites became higher in the ascites, and remained detectable in the ascites for up to 168h, long after disappearance from the serum., Conclusions: Doxorubicin metabolites accumulate in the ascites and are cleared more slowly from the peritoneal compartment than from the serum. Accumulation in the peritoneal cavity with prolonged half-life should be considered when administering medication in patients with ascites.

Purpose: To analyze the possible correlation between expression of the alphav and beta1 integrin chains and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome., Experimental Design: Sections from 56 primary ovarian carcinomas and metastatic lesions from 34 patients diagnosed with advanced-stage ovarian carcinoma (Fédération Internationale des Gynaecologistes et Obstetristes stages III-IV), divided into long-term (16) and short-term (18) survivors, were evaluated for expression of alphav and beta1 integrin chains using mRNA in situ hybridization. Protein expression was additionally studied in 52 specimens using immunohistochemistry., Results: The mean values for disease-free survival and overall survival were 115 and 132 months for long-term survivors, as compared with 4 and 23 months for short-term survivors, respectively. Expression of alphav integrin mRNA was observed in carcinoma (18 of 56; 32%) and stromal (17 of 56; 30%) cells. beta1 integrin mRNA was similarly detected in carcinoma (25 of 56; 47%) and stromal (19 of 56; 34%) cells. No significant differences were observed when primary and metastatic lesions were compared (P > 0.05). Alphav integrin mRNA was present more often in carcinoma cells in tumors of short-term survivors (P = 0.017 for carcinoma cells). In univariate survival analysis for all cases, alphav integrin mRNA expression in tumor cells correlated with poor survival (P = 0.012). This finding retained its predictive power in a multivariate survival analysis, in which all of the molecules studied previously in this patient cohort were included (P = 0.031). Immunohistochemistry confirmed the differences in alphav integrin expression in tumor cells of short-term as compared with long-term survivors, whereas beta1 integrin protein expression was comparable in the two groups., Conclusions: To our best knowledge, this is the first evidence associating integrin expression with poor survival in ovarian carcinoma. Alphav integrin is, thus, a novel prognostic marker in advanced-stage ovarian carcinoma.

Background: Young patients with ovarian tumors of low malignant potential usually undergo conservative surgery because of the excellent prognosis of these tumors. Patients wishing to conceive after diagnosis occasionally require ovulation induction, but data regarding the safety of assisted reproductive technologies in this situation remains anecdotal. The current study analyzes the outcome of a group of patients who received infertility treatment after the conservative management of borderline ovarian tumors., Methods: The clinical and pathologic records of 104 patients with a borderline tumor of the ovary who were treated and followed over a 20-year period (1979--1999) were reviewed. Forty-three patients who underwent conservative management were the subjects of the current study., Results: Follow-up was available for 95% of the patients, giving a total of 270 women-years of follow-up. Nine of the 43 patients developed a local recurrence, 8 of which occurred in patients with serous tumors. Five of these 9 patients underwent cystectomy only at the time of recurrence, and all were without evidence of disease at a mean follow-up of 75 months (range, 25--93 months). Nineteen patients delivered a total of 25 healthy children after diagnosis of a borderline ovarian tumor; 7 of these patients were treated with in vitro fertilization (IVF) after diagnosis. Four of these patients developed a recurrence, two patients before the IVF treatment and two patients after the IVF treatment. The latter two patients were without evidence of disease at the time of last follow-up (15 months and 26 months, respectively, after the recurrence)., Conclusions: The results of the current study suggest that ovulation induction may be considered after the diagnosis of a borderline ovarian tumor. Recurrences were observed in two of seven patients, all of which remained histologically borderline., (Copyright 2001 American Cancer Society.)

Objective: This study aimed to evaluate topoisomerase II compared to Ki-67 expression as a marker for tumor behavior and for prognosis of patients with ovarian cancer., Methods: In order to screen for potential prognostic markers, two groups of patients with advanced stage (FIGO stages III and IV) epithelial ovarian carcinoma were selected based on differences in survival (mean survival, 11 years versus 2 years). Pathology slides were reviewed, and immunohistochemistry using antibodies to topoisomerase II and Ki-67 was performed on the original cell blocks. No patients were lost to follow-up., Results: Detectable expression of topoisomerase II was present in 70.0 +/- 30.3% of cells in patients with rapidly progressing disease, compared to only 12.3 +/- 12.4% of cells in long-term survivors (P = 0.0001). Ki-67 expression was also more frequent in short-term survivors compared to long-term survivors, but the difference was less prominent than with topoisomerase II (P = 0.01). Specificity and sensitivity as prognostic factors reached 88.2 and 93.8% for topoisomerase II, compared to 55.6 and 88.2% for Ki-67., Conclusions: Topoisomerase II expression as detected by immunohistochemistry in tumor samples emerged as a promising clinically relevant biomarker for survival in advanced epithelial ovarian cancer., (Copyright 2001 Academic Press.)

Objective: The aim of this study was to analyze the correlation among the expression of caveolin-1, the protein constituent of caveolae, and disease outcome in advanced-stage ovarian carcinomas., Methods: Sections from 76 primary ovarian carcinomas and metastatic lesions from 45 patients diagnosed with advanced-stage ovarian carcinoma (FIGO stages III-IV) were evaluated for caveolin-1 expression using immunohistochemistry. Patients were divided into long-term survivors and short-term survivors based on disease outcome. Twenty nonneoplastic fallopian tubes and ovaries were additionally studied., Results: The mean follow-up period was 70 months. The mean values for disease-free survival and overall survival were 109 and 125 months for long-term survivors, compared to 3 and 21 months for short-term survivors, respectively. Caveolin-1 expression was localized to the cell membrane in 24/76 (32%) specimens and was detected in the cytoplasm in 52/76 (68%) cases. Both patterns were more often detected in metastases, when compared with primary tumors. In addition, membrane immunoreactivity was more often seen in tumor of short-term survivors. These differences did not reach statistical significance (P > 0.05). Combined membrane and cytoplasmic immunoreactivity was seen in 17/20 (85%) nonneoplastic lesions. Despite its role in tyrosine-kinase-mediated signal transduction in vitro studies, caveolin-1 expression in carcinomas showed no association with the protein expression of c-erbB-2 and epidermal growth factor receptor, evaluated in a previous study of this patient cohort., Conclusions: This study provides the first in vivo evidence of caveolin-1 membrane expression in human malignancies. Caveolin-1 is often expressed in advanced-stage ovarian carcinoma, but does not appear to be a powerful predictor of disease outcome in these tumors. The reduced expression level in carcinomas compared to nonneoplastic epithelium may point to a role for caveolin-1 as a tumor suppressor gene., (Copyright 2001 Academic Press.)

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.

Objective: The aim of this study was to analyze the correlation between expression of E-cadherin complex proteins, epidermal growth factor receptor (EGFR), and c-erbB-2 and disease outcome in advanced-stage ovarian carcinomas., Methods: Sections from 75 primary ovarian carcinomas (=37) and metastatic lesions (=38) from 45 patients diagnosed with advanced-stage ovarian carcinoma (FIGO stage III-IV) were immunostained and evaluated for staining pattern, extent, and intensity. Patients were divided in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cutoff of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively., Results: Comparison of all primary and metastatic lesions showed upregulation of gamma-catenin protein expression in the latter (P = 0.05). When segregated according to disease outcome, the expression of all studied proteins, with the exception of EGFR, was more diffuse in tumors of short-term survivors. The presence of cytoplasmic staining for c-erbB-2 was associated with poor survival in the entire cohort (P = 0.007), as well as in primary tumors alone (P = 0.003), in survival analysis. Similar results were seen in the evaluation of primary tumors for gamma-catenin (P = 0.002)., Conclusions: gamma-Catenin, and possibly c-erbB-2, are valid markers of poor survival in advanced-stage ovarian carcinoma., (Copyright 2000 Academic Press.)

Our objective was to evaluate the preoperative clinical, laboratory, and sonographic characteristics of struma ovarii in comparison to ovarian dermoid cysts. A retrospective review of gynecologic patients operated on for mature cystic teratoma over a 10 year period identified 12 cases of struma ovarii. These cases, combined with 4 additional cases from an earlier report, were the subject of this study. Results were compared to 32 cases of ovarian dermoid cysts. Ovarian struma ovarii occurred in 12 (4.8%) of 251 cases of ovarian dermoid cysts. Most patients were premenopausal, and the mean lesion diameter was 57.3 mm (range, 30-95 mm). Struma ovarii occurred more frequently (68.8%) in the right adnexa and was seen with a normal CA-125 level. Blood flow, assessed by Doppler ultrasonography, was located in the center of the lesion in all cases of struma ovarii. Rare cases were seen with elevated tumor markers and low resistance blood flow. With regard to dermoid cysts, blood flow had a higher resistive index. In addition, no blood flow could be detected from the center of the echoic lesion in dermoid cysts (P < 0.0001). In summary, it is difficult to distinguish between struma ovarii and dermoid cysts on the basis of their sonographic appearance. Nevertheless, Doppler flow may aid in the preoperative diagnosis of struma ovarii. Blood flow signals, detected from the center of the echoic lesion, and low resistance to flow may be more common in struma ovarii.

Objectives: Our goal was to perform an analysis of ultrasonographic characteristics and CA 125 levels in ovarian tumors of borderline malignancy., Study Design: We performed a retrospective analysis of CA 125 levels and ultrasonographic parameters in 91 patients with borderline tumors., Results: Serous tumors of borderline malignancy were associated with elevated CA 125 levels in 75% of patients before surgery (mean, 156 IU/mL) compared with 30% of mucinous tumors (mean, 28 IU/mL; P =.004). CA 125 was elevated in 35% of stage IA serous tumors (mean, 67 IU/mL) compared with 89% of tumors with spread beyond the ovary (mean, 259 IU/mL; P =.001). Mucinous tumors tended to be bigger (13.1 +/- 7 cm) on ultrasonography than serous tumors (9.3 +/- 6.2 cm, P =.016). Mucinous tumors were multilocular in half the patients and contained papillations in 40% of the patients. Serous tumors were multilocular in 30% of the patients but presented with solid or papillary patterns in 78% of the patients (P =.001). A resistance index of <0.4 was found in 36% of mucinous tumors and half the cases of serous tumors. In 13% of patients, ultrasonographic characteristics were compatible with a simple cyst only, including 1 patient with microinvasion and 1 patient with stage IIIB disease. Sensitivity of gray-scale ultrasonography was 87%, that of CA 125 measurement was 62%, and that of flow was 55%. At least 1 diagnostic test result was abnormal in 93% of patients, 2 were abnormal in 69% of patients, and all 3 were abnormal in 21% of patients., Conclusions: A high proportion of borderline tumors of the ovary, particularly of the serous type, were associated with elevated CA 125 levels and abnormal ultrasonographic characteristics, although some tumors presented as simple cysts.

To gain an understanding of the molecular mechanisms of ovarian cancer, we analyzed 16 ovarian tumors from Jewish Israeli patients by comparative genomic hybridization: 12 invasive epithelial tumors (including three BRCA1 and one BRCA2 mutation carriers), 2 primary peritoneal carcinomatosis, 1 pseudomyxoma peritoneii tumor, and 1 sertoli cell tumor. We similarly analyzed 1 normal ovary from a BRCA1 mutation carrier, and 3 metastases. The most common abnormalities in epithelial tumors were amplification of 8q22.1-ter (8/12, 66.6%), 1q22-32.1 (5/12, 41.6%), 3q, 10p (4/12, 33.3% for each), and deletions of 9q (5/12, 41.6%) and 16q21-24 (4/12, 33.3%). All 3 BRCA1 mutation carriers and 2 of 8 sporadic cases displayed 9q deletion, and 2 of 3 BRCA1 mutation carriers, but none of the sporadic cases, had deletion of chromosome 19. The range of genetic changes in primary peritoneal tumors and epithelial ovarian cancers was similar, though the mean number of alterations in the former was less (3.5/tumor versus 8/tumor). Our preliminary results may indicate that inherited predisposition to ovarian cancer possibly entails preferential somatic deletions of chromosomes 9 and 19.

Objective: To investigate whether polymorphic p53 and WAF1 alleles are associated with clinical, demographic and histopathological features and BRCA mutation in women with ovarian cancer., Design: A cross-sectional study., Population: Two hundred and twenty-one nonselected Israeli women with epithelial ovarian cancer., Methods: DNA was analysed for known polymorphisms in intron 3 (a 16 nucleotide single repeat) and intron 6 (a G to A change at nucleotide 13,494) of the p53 gene, the S31R polymorphism in the WAF1 gene, and for three predominant Jewish mutations in the BRCA genes (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2)., Main Outcome Measure: The rate of polymorphic p53 and WAF1 alleles and their association with BRCA mutation, ethnic origin, age and stage at diagnosis, and family history of cancer., Results: Of the tested women, 72 (32.6%) were either BRCA1 (n = 57) or BRCA2 (n = 15) mutation carriers. Sixty-eight of 213 (31.9%) were heterozygous for intron 3 polymorphism, 67/193 (34.7%) for intron 6 polymorphism, and 22/154 (14.3%) for S31R of the WAF1 gene. The p53 and WAF1 polymorphism rate did not differ between BRCA mutation carriers and noncarriers. No significant association between specific p53 or WAF1 genotypes, and clinical, histopathological or demographic variables was observed., Conclusion: In Jewish-Israeli women with sporadic and familial ovarian cancer, p53 or WAF1 polymorphisms do not seem to affect the phenotype.

Ovarian cancer usually remains clinically silent until it is far advanced, and is associated with significant morbidity and mortality. In view of the modest impact of adjuvant treatments on survival, much effort is devoted to early detection programs and prevention strategies. However, the usefulness of early detection programs remains to be established, with only one randomized study indicating improved median survival in screened individuals. At present, oral contraceptives and prophylactic oophorectomy are the only options for prevention of ovarian cancer. Indications for prophylactic oophorectomy either as a primary procedure, or secondary to abdominal surgery, will vary according to the estimated risk, and to the individual's perception of that risk. Genetic screening allows better identification of pre-symptomatic individuals who would benefit the most from prophylactic oophorectomy. Data concerning the benefit of prophylactic surgery, and the safety of established or innovative hormone replacement therapies in individuals at risk, are encouraging., (Copyright 2000 Wiley-Liss, Inc.)

A single germ line mutation in BRCA1, (185delAG) is detected in a substantial portion of Jewish Israeli patients with ovarian cancer. Whether disease phenotypes differ in BRCA1 mutation carriers and sporadic cases is presently a subject for debate. To gain insight into this issue, we analysed tumours from 65 Jewish women with ovarian cancer, 29 (45%) were 185delAG BRCA1 mutation carriers, and 36 (55%) were non-carriers of any of the predominant Jewish mutations in BRCA1 or BRCA2 (sporadic). In 19/29 mutation carriers (66%) diagnosis was made prior to age 60 years, compared with 14/36 (39%) of the non-carriers (P=0.03; Yates corrected P=0.06). Low malignant potential ('borderline') tumours were detected less frequently among carriers (2/29; 7%) than non-carriers (9/36; 25%) (P=0.03; one tail P=0.05). Immunohistochemical analysis in invasive carcinoma (n=54) showed that 17/27 carriers (63%) and 18/27 non-carriers (67%) had positive nuclear staining with a p53 antibody. In 4/27 carriers (15%) and 3/25 non-carriers (12%), 25% or more of the tumour cells stained positive for Ki-67, an insignificant difference. Results were not altered by including borderline tumours (n=11) in these analyses. We conclude that the rate of TP53 inactivation and proliferative index in ovarian cancer, are similar for 185delAG BRCA1 mutation carriers and sporadic cases.

Objective: Up-regulated expression or loss of expression of various carbohydrate antigens on the surface of cancer cells has been associated with a metastatic phenotype and poor survival in epithelial malignancies of different origins. The object of this study was to investigate the expression of carbohydrate antigens in two groups of patients diagnosed with advanced-stage ovarian carcinoma-one with an extremely favorable outcome and the other with a uniformly poor survival., Methods: Sections from 76 paraffin-embedded blocks (primary ovarian carcinomas and metastatic lesions) from 45 patients diagnosed with advanced-stage ovarian carcinomas (FIGO stages III-IV) were immunohistochemically stained using five monoclonal antibodies for Lewis(y) (Le(y))(two antibodies), Sialyl Lewis(x) (Slex), Tn, and Sialyl Tn (STn) antigens. Patients were divided in two groups based on outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Staining results for primary tumors and metastases were analyzed separately., Results: Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors and 3 and 25 months for short-term survivors. Staining for all four antigens was seen in the majority of cases (range = 72-96%) and tended to be comparable in primary tumors and their metastases. However, absence of immunoreactivity for STn was seen in 9/38 (24%) metastatic lesions and only 1/38 (3%) primary tumors. This finding did not reach statistical significance (P > 0.05). A combined pattern of membranous and cytoplasmic staining was predominant in the majority of cases. Enhanced staining for Le(y) and STn was detected in the invasive front of some tumors, while Slex and Tn immunoreactivity did not relate to cell location. Primary tumors and metastatic lesions of long-term survivors displayed immunoreactivity patterns that were comparable to those of short-term survivors. In the evaluation of survival curves, more diffuse staining for Slex showed marginal correlation with poor survival (P = 0.05), while a trend toward poorer survival was seen in tumors that were more extensively stained for Le(y) and Tn (P > 0.05)., Conclusions: Le(y), Slex, STn, and Tn antigens are widely expressed in primary ovarian carcinomas and their metastases. Altered expression of Sialyl Tn is observed with tumor progression in a fraction of ovarian carcinomas. Expression of membrane carbohydrate residues is prevalent in tumors of both long-term and short-term survivors and does not appear to be a strong predictor of disease outcome. However, larger studies are needed to further elucidate the role of these molecules in ovarian carcinogenesis., (Copyright 2000 Academic Press.)

Angiogenic factors play a role in tumor growth and spread. The object of this study was to analyze the correlation between mRNA expression of angiogenesis-related genes and disease outcome in advanced-stage ovarian carcinomas. Sections from 66 primary ovarian carcinomas and metastatic lesions from 41 patients diagnosed with advanced stage ovarian carcinoma (FIGO stages III-IV) were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA In Situ Hybridization (ISH). Patients were divided in two groups based on disease outcome. Long-term survivors (17 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 116 and 133 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Expression of bFGF mRNA, most often intense, was detected in tumor and stromal cells in the majority of cases. Weak expression of IL-8 mRNA was detected in both cell compartments, while VEGF mRNA expression was limited to few cases. Primary tumors displayed higher bFGF and IL-8 mRNA expression. However, these differences did not reach statistical significance (P > 0.05). bFGF, IL-8 and VEGF mRNA expression in both tumor and stromal cells was comparable in tumors of long-term and short-term survivors, and showed no correlation with disease outcome in survival analysis (P > 0.05). bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma.

The object of this study was to analyze the potential association between the expression of MMP-2, MMP-9, MT1-MMP and TIMP-2, and disease outcome in advanced-stage ovarian carcinomas. Sections from 70 paraffin-embedded blocks (36 primary ovarian carcinomas and 34 metastatic lesions) from 45 patients diagnosed with advanced stage ovarian carcinomas (FIGO stages III-IV) were studied using mRNA in situ hybridization (ISH) technique. Patients were divided retrospectively in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period for patients that were diagnosed with advanced-stage carcinoma was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Intense mRNA signals were detected more frequently in tumor cells of short-term survivors with use of all four probes. Comparable findings were observed in peritumoral stromal cells with ISH for MMP-2, MMP-9 and TIMP-2 mRNA. Notably, primary tumors with intense mRNA signal for TIMP-2 (No = 14) were uniformly associated with a fatal outcome. In univariate analysis of primary tumors, mRNA levels of TIMP-2 in stromal cells (P = 0.0002), as well as for MMP-9 (P = 0.012) and TIMP-2 (P = 0.02) in tumor cells, correlated with poor outcome. In univariate analysis of metastatic lesions, mRNA levels of TIMP-2 in stromal cells (P = 0.031), as well as for MMP-2 (P = 0.027) and MT1-MMP (P = 0.008) in tumor cells, correlated with poor outcome. Interestingly, the presence of MT1-MMP in stromal cells correlated with longer survival (P = 0.025). In a multivariate analysis of ISH results for primary tumors, TIMP-2 levels in stromal cells (P = 0.006) and MMP-9 levels in tumor cells (P = 0.011) retained their predictive value. We conclude that MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.

Objective: The present study was designed to prospectively evaluate the intraperitoneal pressure, as well as clinical and hemodynamic effects of total paracentesis, as palliation of symptomatic ascites in ovarian cancer patients., Methods: Prospective study of 35 sequential total paracenteses was performed using a Veres cannula on patients with advanced recurrent ovarian cancer with symptomatic tense ascites. Relevant clinical symptoms and patient well-being were evaluated. Vital signs, abdominal parameters, and hydrostatic intraperitoneal pressure were recorded before, during, and after the procedure., Results: Intraperitoneal pressure dropped from 30 +/- 7 cmH2O before paracentesis to 13 +/- 6 cmH2O after the procedure (P < 0.0001). Marked symptomatic improvement was observed in all patients (89% complete relief, 11% partial relief), while all the patients tolerated the procedure well without any complications. The mean volume of ascitic fluid removed was 4800 ml. Mean respiratory rate and mean heart rate were both significantly decreased following the procedure (29.3 to 21.4 respirations per min and 101.5 to 93.6 beats per min, respectively). Mean systolic blood pressure mildly decreased (6.6 mmHg), while the mean diastolic blood pressure did not significantly change. None of the patients presented signs or symptoms of hypovolemia during or after the total paracentesis., Conclusions: Measurement of intraperitoneal pressures during total paracentesis for tense ascites in ovarian cancer patients indicated that the severity of symptoms correlated with the intraperitoneal pressure prior to paracentesis, but not with the volume of ascites. Intraperitoneal pressures measured following total paracentesis in patients with ovarian cancer were similar to the baseline intraperitoneal pressure measured in patients undergoing peritoneal dialysis., (Copyright 1998 Academic Press.)

Background: Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCA1 and 6174delT-BRCA2, have been detected in a substantial proportion (20%-60%) of unselected Ashkenazi Jewish patients--i.e., Jewish patients of Eastern/Northern European descent--with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174delT-BRCA2 mutations in patients with borderline ovarian tumors., Methods: Analysis of 185delAG-BRCA1 and 6174delT-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insC-BRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer., Results: One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCA1 mutation, and no patients were found to carry the 6174delT-BRCA2 mutation. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations; 17 carried 185delAG-BRCA1 and two carried 6174delT-BRCA2 (chi2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCA1 were found to carry the mutation. In one high-risk family that included 185delAG-BRCA1 carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation., Conclusions: Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis.

Background: Ovarian tumors of borderline malignancy have a less aggressive behavior and tend to occur at a younger age than their invasive counterparts. The role and extent of fertility-sparing conservative treatments is under continuous evaluation., Methods: The current study was a retrospective review of 82 patients with confirmed borderline tumors diagnosed over a 25-year period, with special focus on fertility-associated issues., Results: Follow-up was available for 96% of the patients, for a total of 357 women-years of follow-up. Thirty-nine patients underwent conservative management. Of these, only three patients had a contralateral recurrence. Two of the three again opted for conservative management and were without evidence of disease at last follow-up. Seventeen patients did benefit from contralateral ovarian dissection either by cystectomy or oophorectomy because of contralateral benign or borderline disease. Eleven patients had received or were scheduled to receive ovulation induction. Five patients were diagnosed during the evaluation, and another two were diagnosed so soon after the initiation of ovulation induction that a causative relationship appeared to be unlikely. Six patients were diagnosed during ongoing pregnancies. Twenty-two pregnancies were achieved in 15 patients after conservative treatment. No influence of the disease or its treatment on the pregnancy (or vice versa) was observed during a mean follow-up of 69 months., Conclusions: Data are accumulating that indicate conservative fertility-sparing disease management is adequate treatment for patients with borderline tumors. Available data indicate that in these patients fertility, pregnancy outcome, and survival remain excellent.

This review discusses recent insights into the roles of the p53 tumor-suppressor gene and growth factors in the development of ovarian cancer and describes the genes implicated in familial ovarian cancer syndromes related to the MSH2 (Lynch II) and BRCA1 (breast and ovarian cancer) genes. Evidence of the monoclonality of ovarian cancer, which contrasts with data supporting the polyclonal origin of primary peritoneal carcinoma, is presented. Finally, the roles of the human papillomavirus and the HIV virus in the etiology of cervical cancer are analyzed in view of the growing importance of this HIV-associated cancer and the poor outcome in these patients.

Objective: Our purpose was to determine the effect of tumor necrosis factor-alpha on anti-oncogene expression and to investigate the relationship between the up-regulation of the p53 tumor suppressor gene and tumor necrosis factor-alpha-mediated apoptosis in epithelial ovarian cancer cell lines., Study Design: By means of Northern blot techniques p53 messenger ribonucleic acid expression was assayed in ovarian cancer cells. Tumor cells explanted from patients into Balb/c nude mice were exposed to supernatants from activated monocytes, activated T cells, or the recombinant cytokines interleukin-6 and tumor necrosis factor-alpha. Time- and dose-dependence of p53 up-regulation was measured. Induction of programmed cell death (apoptosis) by tumor necrosis factor-alpha was quantitated by means of a deoxyribonucleic acid fragmentation assay., Results: Detectable levels of messenger ribonucleic acid for p53 were seen in ovarian cancer cells. Tumor necrosis factor-alpha induced a significant up-regulation of p53 messenger ribonucleic acid levels in ovarian cancer cells grown in nude mice and in vitro, whereas interleukin-6 did not. The maximum level of induction was 8 hours, and the up-regulation of p53 was dose dependent. In addition, tumor necrosis factor-alpha induced a dose-dependent increase in deoxyribonucleic acid fragmentation., Conclusion: Tumor necrosis factor-alpha induced up-regulation of p53 tumor suppressor gene expression in epithelial ovarian cancer cell lines, together with the induction of cell death by apoptosis.

Typically, ovarian cancer remains restricted to the peritoneal cavity. Because of this unique localization, the study of ovarian cancer is particularly suitable for immune analysis and for the development of immunotherapy. Here we report that peritoneal fluid from patients with ovarian or other intra-abdominal cancers contained significantly elevated levels of interleukin 10 (IL-10) (542 +/- 77 pg/ml, N = 35), compared with peritoneal fluid from patients with benign gynecological conditions (34.2 +/- 7.5 pg/ml, N = 63) (P < 0.001). Peritoneal fluid IL-10 levels did not correlate with histology, tumor stage, grade, or prognosis. IL-10 levels were also elevated in the serum of patients with intra-abdominal cancer (1353 +/- 906, N = 8). Established ovarian cancer cell lines (N = 5) did not produce any detectable IL-10. Investigation of the cell surface phenotype of the cells in the peritoneal cavity indicated the presence of significant amounts of activated immune cells. The presence of cytokines such as IL-10 in the peritoneal cavity of ovarian cancer bearing patients could be important in the growth and development of cancer, more specifically, in relation to host immune responsiveness.