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Background: The purpose of this study was to confirm whether black and white women with endometrial cancer are equally tolerant of chemotherapy and identify factors that impact survival.Methods: A retrospective review of 169 black women and 982 white women with the International Federation of Gynecologists and Obstetricians stage III, stage IV, or recurrent endometrial carcinoma was performed. All patients received doxorubicin combined with cisplatin. Chemotherapy parameters that were reviewed included relative dose, relative time, and relative dose intensity. Treatment cycles > or =7 were defined as treatment completion.Results: Although black patients were more likely to experience grades 3-4 anemia (20% vs 14%) and genitourinary (5% vs 1%) toxicity, and less likely to experience severe gastrointestinal toxicity (10% vs 17%), the overall incidence of grades 3-4 treatment-related chemotoxicity was the same between the 2 groups (82% vs 82%). There were no differences in the number of cycles received, relative dose (0.57 vs 0.58), relative time (0.77 vs 0.78), or relative dose intensity (0.76 vs 0.76) for black and white patients.Conclusions: Black patients with advanced stage or recurrent endometrial cancer, treated on 4 Gynecologic Oncology Group (GOG) protocols, had similar dose intensity and severe chemotherapy-related toxicity compared with white patients, suggesting that previously described racial disparities in survival among patients in GOG trials may have an novel etiology. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the deadliest of all gynecologic malignancies claiming the lives of nearly 14,000 women in the United States annually. Despite therapeutic advances, the ovarian cancer mortality rate has remained stagnant since the 1980's. The molecular heterogeneity of ovarian cancers suggest they may be more effectively treated via precision medicine. Current guidelines recommend germline and somatic testing for all new epithelial ovarian cancer diagnoses to assist providers in identifying candidates for targeted therapies. Next generation sequencing (NGS) identifies targetable, driver, and novel mutations used to guide treatment decisions. Performing NGS is standard of care in many other malignancies, but for ovarian cancer the use of NGS in daily practice is still emerging. This review discusses the targetable genetic mutations and role of NGS and molecular biomarker testing in the treatment of ovarian cancer.

The primary objective was to examine the role of pelvic fluid observed during transvaginal ultrasonography (TVS) in identifying ovarian malignancy. A single-institution, observational study was conducted within the University of Kentucky Ovarian Cancer Screening trial from January 1987 to September 2019. We analyzed true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) groups for the presence of pelvic fluid during screening encounters. Measured outcomes were the presence and duration of fluid over successive screening encounters. Of the 48,925 women surveyed, 2001 (4.1%) had pelvic fluid present during a TVS exam. The odds ratio (OR) of detecting fluid in the comparison group (TN screen; OR = 1) significantly differed from that of the FP cases (benign pathology; OR: 13.4; 95% confidence interval (CI): 9.1-19.8), the TP cases with a low malignant potential (LMP; OR: 28; 95% CI: 26.5-29.5), TP ovarian cancer cases (OR: 50.4; 95% CI: 27.2-93.2), and FN ovarian cancer cases (OR: 59.3; 95% CI: 19.7-178.1). The mean duration that pelvic fluid was present for women with TN screens was 2.2 ± 0.05 encounters, lasting 38.7 ± 1.3 months. In an asymptomatic screening population, free fluid identified in TVS exams was more associated with ovarian malignancy than in the control group or benign ovarian tumors. While pelvic free fluid may not solely discriminate malignancy from non-malignancy, it appears to be clinically relevant and warrants thoughtful consideration.

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC 50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC 50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects ( p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K-Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog ( MUTYH ) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian cancer by the failure of its well-known base excision repair mechanism or by failure to induce cell death. Biallelic germline MUTYH mutations confer a 14% risk of ovarian cancer by age 70. A monoallelic germline mutation in conjunction with a somatic MUTYH mutation may also contribute to the development of ovarian cancer. Resistance to platinum-based chemotherapeutic agents may be seen in tumors with monoallelic mutations, but platinum sensitivity in the biallelic setting. As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH -driven ovarian cancers.

Epithelial ovarian cancers (EOC) consist of several sub-types based on histology, clinical, molecular and epidemiological features that are termed "histo-types", which can be categorized into less aggressive Type I and more aggressive Type II malignancies. This investigation evaluated the disease-specific survival (DSS) of women with Type I and II EOC using histo-type, grade, and stage. A total of 200,658 EOC cases were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. Kaplan-Meier survival analyses, one-factor ANOVA and Chi-square analyses were performed on 10-year DSS survivals. DSS strongly supported a 2-tiered classification (grade 1 vs. grade 2 & 3) for serous EOC. DSS of early stage serous EOC for grade 2 was significantly different from grade 3 indicating that a 2-tier classification for serous EOC applied only to late stage. DSS of Type I EOC was much better than Type II. However, DSS was 46-58% lower with late stage Type I than with early stage Type I indicating that Type I ovarian cancers should not be considered indolent. Early stage Type II EOC had much better DSS than late stage Type II stressing that stage has a large role in survival of both Type I and II EOC., Competing Interests: Page: 10The authors declare no conflict of interest.

Purpose: This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women., Methods: Appalachian women's survey data and blood samples from the Community Awareness, Resources, and Education (CARE) CARE I and CARE II studies (n = 163 invasive cervical cancer cases, 842 controls) were used to assess gene-environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t tests and χ 2 tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics., Results: Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between "Appalachian self-identity" variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TGFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18., Conclusions: This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represent an emerging avenue of scientific exploration.

Background : Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy and is treated with a combination of cytoreductive surgery and platinum-based chemotherapy. Extended length of stay (LOS) after surgery can affect patient morbidity, overall costs, and hospital resource utilization. The primary objective of this study was to identify factors contributing to prolonged LOS for women undergoing surgery for ovarian cancer. Methods : The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify women from 2012-2016 who underwent hysterectomy for ovarian, fallopian tube and peritoneal cancer. The primary outcome was LOS >50th percentile. Preoperative and intraoperative variables were examined to determine which were associated with prolonged LOS. Results : From 2012-2016, 1771 women underwent elective abdominal surgery for OC and were entered in the ACS-NSQIP database. The mean and median LOS was 4.6 and 4.0 days (IQR 0-38), respectively. On multivariate analysis, factors associated with prolonged LOS included: American Society of Anesthesiologists (ASA) Classification III (aOR 1.71, 95% CI 1.38-2.13) or IV (aOR 1.88, 95% CI 1.44-2.46), presence of ascites (aOR 1.88, 95% CI 1.44-2.46), older age (aOR 1.23, 95% CI 1.13-1.35), platelet count >400,000/mm 3 (aOR 1.74, 95% CI 1.29-2.35), preoperative blood transfusion (aOR 11.00, 95% CI 1.28-94.77), disseminated cancer (aOR 1.28, 95% CI 1.03-1.60), increased length of operation (121-180 min, aOR 1.47, 95% CI 1.13-1.91; >180 min, aOR 2.78, 95% CI 2.13-3.64), and postoperative blood transfusion within 72 h of incision (aOR 2.04, 95% CI 1.59-2.62) ( p < 0.05 for all). Conclusions : Longer length of hospital stay following surgery for OC is associated with many patient, disease, and treatment-related factors. The extent of surgery, as evidenced by perioperative blood transfusion and length of surgical procedure, is a factor that can potentially be modified to shorten LOS, improve patient outcomes, and reduce hospital costs.

Background: There are a number of equally efficacious chemotherapy options for the treatment of women with endometrial cancer, all of which work in only a subset of those women with this disease. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. Such an assay should yield response rates similar to those found in treated patient populations. The purpose of this investigation was to determine whether the patterns of in vitro tumor response rates as determined by ChemoFx are consistent with expected population response rates., Methods: Nine hundred twenty-three tumor specimens from patients with high-risk early-stage, advanced stage, or recurrent endometrial cancer were sent for testing with the ChemoFx drug response marker from August 2, 2006, to August 31, 2009. Tumors were categorized as responsive (R), intermediately responsive (IR), or nonresponsive to each drug or combination tested. Response rates from clinical trials were identified and compared with the corresponding in vitro response rates., Results: Of the 923 specimens received, 759 (82%) were successfully tested by ChemoFx. Of these, 755 were tested for at least 1 of 5 National Comprehensive Cancer Network-recommended endometrial cancer drugs. The response rates (R+IR) for these drugs were as follows: 66% carboplatin-paclitaxel, 48% carboplatin, 37% cisplatin, 23% doxorubicin, and 36% paclitaxel. Moreover, 20% of tumors were pan-sensitive (R or IR) to all 5 regimens tested, 27% were pan-resistant (nonresponsive), and 53% showed different degrees of response to different drugs., Conclusions: ChemoFx in vitro response rates were consistent with published population response rates, and the ChemoFx drug response marker may provide clinically useful information to better optimize individual chemotherapy for treatment of women with endometrial cancer.

Objectives: Standard infusion of gemcitabine plus carboplatin showed improved efficacy compared to carboplatin alone in patients with platinum-sensitive (Pt-S) ovarian cancer (OC). Fixed-dose rate (FDR) administration of gemcitabine produces more efficient intracellular phosphorylation of gemcitabine to its active form. This study was designed to identify the maximum tolerated dose (MTD), toxicity profile, and response rate of FDR gemcitabine plus carboplatin in Pt-S OC., Methods: Patients with measurable OC relapsing > or =6 months after exposure to platinum (N=60) were assigned to one of three treatment cohorts, each with a different delivery schedule and escalating doses of both FDR gemcitabine (10 mg/m(2)/min) and standard infusion carboplatin (60 min). MTDs were determined using dose-limiting toxicities (DLTs). Measurable disease was assessed using modified RECIST criteria. CA-125 levels were evaluated using Rustin criteria. Toxicities were assessed using NCI Common Toxicity Criteria, version 2.0., Results: The MTD of Arm 1 was FDR gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin AUC 5 on day 1, every 21 days. The MTD of Arm 2 was FDR gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin AUC 2.5+AUC 2.5 on days 1 and 8, every 21 days. Patient accrual on Arm 3 consisting of bi-weekly FDR gemcitabine plus carboplatin was terminated because dose level 1 exceeded the MTD. Overall response rates were 38.1% (Arm 1), 58.8% (Arm 2), and 44.4% (Arm 3)., Conclusions: FDR gemcitabine+carboplatin on a 21-day schedule was active and produced no unusual safety signals in patients with Pt-S OC.

Background: For chemosensitivity and resistance assays to be clinically useful in predicting patient outcome, they should require small amounts of tissue and be highly reproducible and reliable., Patients and Methods: Expanded tumor cells from transcutaneous biopsies of breast lesions (n=62) were tested for chemoresponse using the cell-based ChemoFx assay. Pathologic complete response (pCR) was determined on a subset of patients (n=34). Assay score and pCR were determined independently in a blinded manner. Logistic regression models were used to select predictors for response., Results: Tumor cells were successfully isolated from 83.9% of patients. Chemoresponse profiles were robust and reproducible with coefficient of variance of <3%. In a limited initial patient outcome correlation, assay score of docetaxel/capecitabine significantly predicted pCR; the cross-validated model was 75% accurate., Conclusion: It is feasible to assess the chemoresponsiveness of small breast lesions using the ChemoFx assay to assist in choosing neoadjuvant chemotherapy for breast cancer patients.

Objective: Current firstline chemotherapy for ovarian cancer consists of carboplatin combined with either paclitaxel or docetaxel. Disposition of carboplatin is determined by renal clearance, while the taxanes are metabolized by cytochrome P450 (CYP450) enzymes. Although the majority of taxane metabolism occurs in the liver, recent data have shown that some solid tumors express CYP450 enzymes in the tumors themselves. The objective of this study was to determine whether ovarian tumors express genes regulating cellular efflux and subsequent metabolism, and whether any clinico-pathologic features correlated with expression., Methods: Gene expression of CYP2C8, CYP3A4/A5 and the ABC transporter ABCB1 was determined in 56 primary epithelial ovarian tumors. Cells were grown from seven different tumors and exposed ex vivo to paclitaxel (PAC) and docetaxel (DOC) for up to 24 h. PAC and DOC concentrations were measured in the media by an LC-MS assay., Results: Results from this analysis demonstrate that ovarian cancer cells do express functional taxane-metabolizing enzymes. Such expression appeared to enhance the ability of cancer cells to metabolize DOC. Specifically, the PK of DOC was correlated with the ratio of CYP4A5 to ABCB1 gene expression, thus representing a novel mechanism of chemotherapy resistance. There was no relationship between PAC PK parameters and gene expression., Conclusions: Knowledge of inter-individual variation in CYP450 enzyme and ABC transporter tumor expression and activity may influence the individualization of chemotherapy, by avoiding agents that are rapidly metabolized and selecting agents that are not.

Objective: To determine if percent surface area involvement (SAI) of tumor in endometrial cancer is predictive of lymph node metastasis., Methods: A retrospective study was performed of all patients diagnosed with endometrial cancer at Magee Women's Hospital between January 1990 and December of 1995. Papillary serous and clear cell histologic subtypes were excluded. Pathology reports were reviewed for percent SAI, myometrial invasion, grade, histologic subtype, lymphovascular space invasion, and lymph node metastasis. Percent SAI was categorized into three groups: <35%, 35-80%, and >80%. The primary outcome variables were pelvic or periaortic lymph node metastasis. Univariate and multivariate analysis logistic regression models were used to determine predictors of nodal metastasis., Results: Of 558 patient records reviewed, 319 had lymph node dissections performed and 42 (13%) of those patients had positive lymph nodes. Two of 79 (3%) patients with <35% SAI had lymph node metastasis, 17 of 165 (10%) patients with 35-80% SAI had lymph node metastasis, and 23 of 75 (31%) patients with >80% SAI had lymph node metastasis. The percent SAI was significantly associated with lymph node metastasis (p<0.001). Multivariate logistic regression indicated that for patients with >80% SAI, the odds of having lymph node metastasis were 10.8 times (CI 1.3-90.4) that for patients with similar tumor histology, grade, and invasion, but <35% SAI (p=0.03). A subset analysis of patients with superficial myometrial invasion was performed and 16% of patients with <50% myometrial invasion and >80% SAI had positive lymph nodes, while only 1.4% of patients with <50% myometrial invasion and <35% SAI had positive lymph nodes (p=0.02)., Conclusion: Our analysis indicates that percent SAI is an independent risk factor for lymph node metastasis. Furthermore, assessing SAI with myometrial invasion gives a more accurate prediction of lymph node metastasis than myometrial invasion alone. This becomes clinically relevant when assessing risk factors for lymph node metastasis intraoperatively.

Objectives: To explore associations between histology and outcome in advanced or recurrent endometrial cancer patients participating in Gynecologic Oncology Group chemotherapy trials., Methods: Age, race, performance status, histologic type (serous=S; clear cell=CC; endometrioid=E), disease stage, and prior radiation were evaluated using various analytic methods to evaluate the probability of response and identify independent predictors of progression-free survival (PFS) and overall survival (OS)., Results: Single agent or combination chemotherapy regimens including doxorubicin (A) (12%), doxorubicin/cisplatin (AP) (63%), doxorubicin/paclitaxel (AT) (13%), and paclitaxel/doxorubicin/cisplatin (TAP) (11%) were used among 1203 patients treated on 4 randomized clinical trials. Breakdown of disease stage was 7.8% stage III, 22.8% stage IV, and 69.4% recurrent disease. Histologic distribution was 18% S, 3.7% CC, 8.5% mixed, 51.7% E and 18.1% other. More S/CC patients enrolled on trials with advanced stage (III-IV) disease (as opposed to recurrent disease) compared to E patients (45% vs. 24%, p<0.05). Overall response rate was 42% (E=44%, S=44%, CC=32%). Histologic type was not an independent predictor of response. Independent predictors of PFS included race, performance status, disease stage, and CC histology. Histology was also an independent predictor of OS; the relative hazard ratio for S histology was 1.2 (1.02-1.4; p=0.03), and for CC was 1.51 (1.1-2.07; p=0.01)., Conclusion: In patients with advanced/recurrent endometrial cancer treated with A, P and/or T, response was not associated with histology. This exploratory analysis does not support exclusion of S tumors in future trials. Poorer PFS and OS were observed in CC compared to other types, but a lack of benefit from chemotherapy was not shown, and as this histology represents such a small fraction, it does not seem feasible to have separate chemotherapy trials for CC.

Objectives: To evaluate the association between body mass index (BMI) and outcomes in women with advanced or recurrent endometrial cancer treated with doxorubicin/cisplatin., Methods: Data from patients treated on five Gynecologic Oncology Group trials were retrospectively reviewed. BMI was categorized as normal (< 25), overweight (> or = 25 to < 30), obese (> or = 30 to < 40), and morbidly obese (> or = 40). BMI was analyzed for associations with demographics, clinical characteristics, toxicity, progression-free survival (PFS), and overall survival (OS)., Results: Among 949 patients, 533 (56%) had recurrent disease, 227 (23.9%) had Stage IV disease, and 189 (19.9%) had Stage III disease. Mean BMI was 29.8; 29.6%, 27.0%, 33.2% and 10.2% of patients, respectively, were categorized as normal, overweight, obese, and morbidly obese. The mean BMI was significantly different when compared by age group (p<0.001), stage (p=0.047), histologic type (p=0.024), and tumor grade (p=0.014). Older patients and those with clear cell, poorly differentiated tumors, or stage IV disease had a lower BMI. No significant associations between PFS and BMI were detected. Increasing BMI was significantly associated with an increased risk of death in Stage III/IV (HR=1.86, 95% CI 1.16-2.99 for BMI > or = 40 vs. BMI < 25) but not recurrent patients. Higher BMI patients had less Grade 3/4 toxicities than normal patients (p<0.001) but this difference disappeared for obese patients receiving > or = 95% of the calculated dose., Conclusions: BMI was not predictive of PFS in this endometrial cancer population although morbidly obese patients had decreased OS in primary Stage III/IV patients. Toxicities decreased with increasing BMI, perhaps secondary to capped dosing.

Background: Previous studies have reported shorter survival of black women compared with white women who had advanced/recurrent endometrial cancer. It has been suggested that this may reflect racially based differences in treatment., Methods: The authors retrospectively reviewed data from 169 black women and 982 white women with International Federation of Gynecologic Oncology (FIGO) Stage III, Stage IV, or recurrent endometrial carcinoma who were participants in 1 of 4 Gynecologic Oncology Group randomized treatment trials of doxorubicin alone or combined with paclitaxel and/or cisplatin. Demographic, histologic, treatment, and outcome data were analyzed to estimate survival, and between-group comparisons were performed., Results: The pooled data revealed that black women were more likely to have papillary serous histology (P < .001), Stage IV disease (P < .001), and higher tumor grade (P < .001) compared with white women, and survival was worse among black women than among white women (median survival, 10.6 months vs. 12.2 months, respectively; P < .001). A Cox proportional hazards regression analysis that was adjusted for performance status, disease stage, tumor histology, tumor grade, and treatment demonstrated worse survival for black women (hazards ratio, 1.26, 95% confidence interval, 1.06-1.51; P = .010)., Conclusions: The data from a large group of women with advanced/recurrent endometrial cancer suggested that a racial disparity in survival persists, despite the finding that black women and white women received similar treatment. Although the causes of racial disparity in endometrial cancer remain to be elucidated, socioeconomic, biologic, and cultural factors should be investigated to identify the etiologic origins of this multifactorial healthcare problem.

BRCA1 is a tumor suppressor gene that, when mutated, is associated with the development of hereditary ovarian cancer. A role for BRCA1 in the pathoetiology of sporadic ovarian epithelial cancer (OEC) development has been suggested, although spontaneous mutations of the BRCA1 gene in this disease are uncommon. Loss of gene function by epigenetic alteration is observed more commonly, while other means of gene inactivation have not been intensively investigated. We examined expression and localization of the BRCA1 gene product by immunohistochemistry and sought to clarify the relationship between protein expression and tumor stage, grade, histopathologic subtype, and outcome. Among 230 spontaneous OEC tumors, we found a statistically significant decrease in BRCA1 protein expression with advancing stages of OEC. There was no relationship between expression and tumor grade. There was a statistically significant relationship between the pathologic subtypes of OEC and BRCA1 expression. Minimal BRCA1 expression was protective for survival. These findings confirm a high rate of loss of BRCA1 protein expression in sporadic OEC and suggest a role of BRCA1 in the progression of sporadic ovarian carcinoma.

Both hereditary and sporadic ovarian tumors frequently have decreased BRCA1 expression. One mechanism of downregulating BRCA1 expression is hypermethylation of the BRCA1 promoter. Studies have shown that the BRCA1 promoter is aberrantly hypermethylated in a subset of ovarian tumors, although the proportion varies widely between reports. High-resolution analysis of the BRCA1 promoter in ovarian cancer may provide information regarding the extent and heterogeneity of methylation and guide future studies using methylation-specific polymerase chain reaction (MS-PCR). We screened 50 primary epithelial ovarian tumors for BRCA1 promoter hypermethylation using MS-PCR. The BRCA1 promoter was hypermethylated in 16% (8 of 50) of the tumors, including two stage IA tumors. Sequence analysis of the promoter revealed that methylation of the CpG island is both extensive and mosaic in the methylated samples. Two CpG dinucleotides in the BRCA1 promoter, within and adjacent to a Myb consensus binding site, were most frequently methylated in ovarian tumors. BRCA1 expression was significantly lower in methylated than in unmethylated samples. Our analysis of the BRCA1 promoter revealed preferential methylation of specific CpG sites in ovarian tumors. This finding could be exploited in the design of highly sensitive MS-PCR assays for direct assessment of tumor DNA and potentially for early detection of ovarian cancer in body fluids.

Centrosome abnormalities have been found in various cancer types and are thought to be involved in early development of cancer and/or progression. The contribution of centrosome abnormalities to ovarian tumorigenesis has not been previously evaluated. We sought to determine whether centrosome dysfunction occurs in ovarian tumorigenesis, and whether it could be used as an indicator of early neoplastic changes in ovarian surface epithelium (OSE). Primary cultures of normal OSE and ovarian tumors, as well as paraffin-embedded normal ovaries and ovarian tumors of different stages, were used for immunostaining with a gamma-tubulin antibody. Centrosomes were considered abnormal if there were more than 2 per cell, if their sizes were greater than 2-fold of a normal centrosome, and/or if they were abnormal in shape. Centrosomes in normal tissue were uniform in size, whereas centrosomes in ovarian tumors tended to be abnormal in size, number and shape. On average, 4.7% of cells in 5 primary normal OSE cultures had more than 2 centrosomes, whereas 14.1% of primary cells from 5 ovarian tumors displayed centrosome abnormalities (p = 0.008). Centrosome abnormalities were present in 60.9% of stage I (n = 23), 83.3% of stage II (n = 30) and all stage III (n = 10) paraffin-embedded ovarian tumor samples examined, but not in normal tissues. In addition, centrosome abnormalities occurred more frequently in ovarian tumors with higher grade and aggressive serous subtype. This is the first demonstration that centrosome abnormalities occur in ovarian tumors. Centrosome dysfunction may be an early event in ovarian carcinogenesis and involved in ovarian tumor progression., ((c) 2004 Wiley-Liss, Inc.)

Objectives: A deletion variant in the CHEK2 gene (del1100C) has been implicated as a low-penetrance risk factor for breast cancer. We sought to determine contribution of CHEK2 mutations to the etiology of ovarian cancer (OvCa)., Methods: We used cases ascertained from the United States through Gynecologic Oncology Group (GOG) protocols 172, 182, and 144, the University of Hawaii Cancer Research Center, and Creighton University. Control women were recruited from Pittsburgh and Hawaii. Denaturing high-performance liquid chromatography, sequence analysis, and single nucleotide polymorphism genotyping by Pyrosequencing were employed to analyze the CHEK2 gene., Results: Mutation screening of the CHEK2 gene in 48 cases who had a first-degree relative with OvCa uncovered only del1100C and A252G variants. Altogether, the del1100C variant was detected in none of 751 unselected cases, in 1 of 52 (1.9%) cases who had a first-degree relative with OvCa, and in 3 of 521 (0.6%) unselected controls. The frequencies of del1100C and A252G variants did not show statistically significant differences between the cases and the controls., Conclusions: These results suggest that variations in CHEK2 do not make a significant contribution to the pathogenesis of OvCa in the U.S. population.

Objective: The objective of this study was to evaluate the effectiveness and degree of toxicity of paclitaxel and carboplatin (PC) combination chemotherapy in patients with recurrent or persistent cervical carcinoma., Methods: Fifteen patients who received PC chemotherapy for recurrent or persistent carcinoma of the cervix at the Magee-Womens Hospital from 1994-1998 were studied retrospectively. Demographic data, pathology, radiation treatment response, site of recurrence, chemotherapy response, survival rates, and toxicities were reviewed. Months of survival were calculated by the method of Kaplan-Meier from the date after initiation of chemotherapy to death or the last date of follow-up., Results: Fifteen patients received PC for recurrence or persistence of disease with a median of six courses of PC (range, four to 26). Fourteen patients (93.3%) had received prior radiation, and one patient had received surgery as the primary therapy. Four (26.7%) of 15 patients had complete response and five (33.3%) had partial response for an overall clinical response rate of 60%. The median survival of all 15 patients treated with PC was 17 months (range, four to 39). Four patients demonstrated progression of disease while two patients had stable disease. Grade 3 or 4 neutropenia occurred in four patients (26.7%) while one patient (6.7%) suffered from sepsis. Three patients (20%) suffered from Grade 2 anemia and four patients (26.7%) patients developed Grade 2 or Grade 3 neuropathy. There was no incidence of nephrotoxicity., Conclusions: Paclitaxel/carboplatin chemotherapy appears to have promising activity in recurrent or persistent carcinoma of the cervix with an acceptable toxicity profile. Due to patient convenience and tolerance, consideration should be given to carboplatin as an alternative regimen to cisplatin in combination with paclitaxel.

Purpose: To determine if circadian timed (CT) chemotherapy results in improved response, progression-free survival (PFS), overall survival (OS), and lower toxicity, when compared with standard timed (ST) chemotherapy., Materials and Methods: Eligibility criteria were stage III, IV, or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery; measurable disease; and no prior chemotherapy. Therapy was randomized to schedules of ST doxorubicin 60 mg/m2 plus cisplatin 60 mg/m2, or CT doxorubicin 60 mg/m2 at 6:00 am plus cisplatin 60 mg/m2 at 6:00 pm. Cycles were repeated every 3 weeks to a maximum of eight cycles., Results: The ST arm included 169 patients, and the CT arm included 173 patients. The objective response rate (complete responses plus partial responses) was 46% in the ST group compared with 49% in the CT group (P =.26, one tail). Median PFS and OS were 6.5 and 11.2 months, respectively, in the ST group; and 5.9 and 13.2 months, respectively, in the CT group (PFS: P =.31; OS: P =.21, one tail). Median total doses were 209 mg/m2 doxorubicin and 349 mg/m2 cisplatin in the ST group, versus 246 mg/m2 doxorubicin and 354 mg/m2 cisplatin in the CT group. Grade 3 or 4 leukopenia occurred in 73% of patients in the ST arm and in 63% of patients in the CT arm. There were eight treatment-related deaths., Conclusion: In this trial, no significant benefit in terms of response rate, PFS or OS, or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma.

Objective: The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer., Method: Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis., Results: Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk., Conclusion: In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing., ((c)2001 Elsevier Science.)

Objective: The goal of this study was to determine the relationship of ovarian volume to age, height, and weight in women undergoing transvaginal sonography., Methods: Thirteen thousand nine hundred sixty-three women 25-91 years of age undergoing annual transvaginal sonography as part of the University of Kentucky Ovarian Cancer Screening Program were the subjects for this investigation. Each ovary was measured in three dimensions, and ovarian volume was calculated using the prolate ellipsoid formula (L x H x W x 0.523). Mean ovarian volume according to age was calculated for each decade of life., Results: Data were obtained from 58,673 observations of ovarian volume. Mean ovarian volume was 6.6 +/- 0.19 cm(3) in women less than 30 years of age; 6.1 +/- 0.06 cm(3) in women 30-39; 4.8 +/- 0.03 cm(3) in women 40-49; 2.6 +/- 0.01 cm(3) in women 50-59; 2. 1 +/- 0.01 cm(3) in women 60-69; and 1.8 +/- 0.08 cm(3) in women >/=70. Mean ovarian volume was 4.9 +/- 0.03 cm(3) in premenopausal women and 2.2 +/- 0.01 cm(3) in postmenopausal women (P < 0.001). The use of exogenous estrogens was associated with a significant reduction in ovarian volume in women 40-59 years of age, but not in women >/= 60. Ovarian volume was unrelated to patient weight but was greater in tall women (>68 in.) than in short women (<58 in.)., Conclusion: There is a statistically significant decrease in ovarian volume with each decade of life from age 30 to age 70. Mean ovarian volume in premenopausal women is significantly greater than that in postmenopausal women. The upper limit of normal for ovarian volume is 20 cm(3) in premenopausal women and 10 cm(3) in postmenopausal women., (Copyright 2000 Academic Press.)

Objective: The purpose of this study was to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer., Methods: Annual TVS screening was performed on 14, 469 asymptomatic women from 1987 to 1999. Eligibility criteria included (1) all women >/= 50 years of age and (2) women >/= 25 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm(3) in postmenopausal women or >20 cm(3) in premenopausal women or (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with a persistently abnormal second screen had a serum CA-125 determination, tumor morphology indexing, and Doppler flow sonography, and were advised to have surgical tumor removal., Results: One hundred eighty patients with persisting TVS abnormalities underwent exploratory laparoscopy or laparotomy. Seventeen ovarian cancers were detected: 11 Stage I, 3 Stage II, and 3 Stage III. Only three patients with Stage I cancers had a palpable ovarian mass on clinical examination. All patients with Stage I and II ovarian cancer are alive without recurrence 1.8-9.8 years (median, 4.5 years) after diagnosis. Two of the three Stage III patients have died of disease: one at 4.3 years and one at 7.7 years after detection. Four patients developed ovarian cancer within 12 months of a negative scan (FN): 2 Stage II, 2 Stage III. Three of these patients are alive with no evidence of disease 0.4, 1.9, and 5.5 years after diagnosis, and 1 patient has died of disease 0.7 years after diagnosis. Four patients developed ovarian cancer more than 12 months following a normal screen. All 4 presented clinically with Stage III disease. Two of these patients have died of disease and two patients are alive 1.5 and 2.1 years after diagnosis. TVS screening was associated with the following statistical variables: sensitivity, 81%; specificity, 98.9%; positive predictive value (PPV), 9.4%; and negative predictive value (NPV), 99.97%. After 46, 113 screening years, there have been 3 ovarian cancer deaths in the annually screened population and 2 ovarian cancer deaths in women receiving less than annual screening. The survival of ovarian cancer patients in the annually screened population was 95.0 +/- 4.9% at 2 years and 88.2 +/- 8.0% at 5 years. Excluding all cases of nonepithelial or borderline epithelial malignancies, the survival of patients with ovarian cancer in the annually screened population was 92.9 +/- 6.9% at 2 years and 83.6 +/- 10.8% at 5 years., Conclusions: (1) TVS screening, when performed annually, is associated with a decrease in stage at detection and a decrease in case-specific ovarian cancer mortality. (2) TVS screening does not appear to be effective in detecting ovarian cancer in which ovarian volume is normal., (Copyright 2000 Academic Press.)

Objective: The aim of this study was to present a family with both BRCA1-related and sporadic ovarian cancer and address current difficulties in genetic testing., Methods: BRCA1 mutation detection was performed on a family having four confirmed cases of ovarian cancer, two cases of breast cancer, and one case each of colon, stomach, and prostate cancer. The incidence and types of cancer were consistent with a BRCA1 mutation although previous linkage analysis had excluded this family as being due to BRCA1., Results: A protein-truncating mutation in BRCA1, denoted 2799delAA, was identified in the germline DNA of each of the women affected with breast and ovarian cancer in this family except the proband, who was diagnosed with ovarian cancer at age 65., Conclusions: In an earlier study, which sought to determine the proportion of site-specific ovarian cancer due to BRCA1, the family described in this report was wrongly identified as not being due to BRCA1 when, in fact, all but one of the breast and ovarian cancer cases carry a deleterious BRCA1 mutation. Our analysis suggests that the proband, who was the first of the women in this family to seek genetic counseling, developed ovarian cancer by chance and not as the result of an inherited mutation. We describe the results of our analysis in light of current issues that face clinicians who may be involved in genetic testing for breast and ovarian cancer predisposition., (Copyright 1999 Academic Press.)

Objective: The aim of this study was to determine the risk of malignancy in cystic ovarian tumors < 10 cm in diameter in asymptomatic postmenopausal women or women >or =50 years of age., Methods: All cystic ovarian tumors detected by transvaginal sonography screening in asymptomatic postmenopausal women or women > or =50 years of age were evaluated with respect to size and morphology. Histology was recorded on all tumors removed surgically. Follow-up data were available both on patients undergoing surgery and on those who elected to be followed without operative intervention., Results: Unilocular cystic tumors were detected in 256 of 7705 patients (3.3%). All tumors were < 10 cm in diameter and 90% were < 5 cm in diameter. One hundred twenty-five of these cysts (49%) resolved spontaneously within 60 days and 131 (51%) persisted. Forty-five patients with persisting ovarian cysts underwent operative removal of these tumors. Thirty-two patients had ovarian serous cystadenomas, and the remainder had a variety of benign lesions. There were no cases of ovarian carcinoma in this group. Eighty-six patients with unilocular cystic ovarian tumors were followed at 3- to 6-month intervals without surgery, and none have developed ovarian cancer. Complex cystic ovarian tumors were detected in 250 patients (3.2%). All tumors were < 10 cm in diameter and 89% were < 5 cm in diameter. One hundred thirty-five (55%) resolved spontaneously within 60 days, and 115 (45%) persisted. One hundred fourteen of these patients underwent operative tumor removal. Seven patients had ovarian carcinoma, 1 had primary peritoneal cancer, and 1 had metastatic breast cancer to the ovary., Conclusion: Unilocular ovarian cysts < 10 cm in diameter in asymptomatic postmenopausal women or women > or =50 years of age are associated with minimal risk for ovarian cancer. In contrast, complex ovarian cysts with wall abnormalities or solid areas are associated with a significant risk for malignancy. These data are important in determining optimal strategies for operative intervention in these patients.

From December 1987 to December 1993, 6470 women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Two groups of women were eligible to participate in this investigation: (i) asymptomatic postmenopausal patients or patients >50 years of age, and (ii) asymptomatic women >30 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm3 in postmenopausal women or >20 cm3 in premenopausal women, and (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with persistently abnormal scans had a serum CA-125 determination, tumor morphology indexing, and color Doppler sonography. Ninety patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy or laparoscopy for tumor removal. Thirty-seven patients had serous cystadenomas and six had primary ovarian cancers. Five patients had Stage IA ovarian cancer and one patient had Stage IIIB disease. Only one of the ovarian cancer patients had a palpable abnormality on pelvic examination, and none had an elevated (>35 u/ml) serum CA-125. All these patients are presently alive and well 1-5 years after conventional therapy. There was one false negative in this study, a 38-year-old white female who was noted to have a small ovarian cancer at the time of laparoscopic prophylactic oophorectomy 11 months after a normal scan. Over 17,000 screening years have been accrued and there have been no deaths from primary ovarian cancer in the screened population. A cost analysis of TVS screening is presented.

Ninety-four patients with squamous cell carcinoma invading the cervical stroma to a depth of >3.0-5.0 mm with 7 mm or less in horizontal spread (FIGO Stage IA2) were evaluated. Depth and lateral extent of stromal invasion were verified using an ocular micrometer. Cell type and lymph vascular space invasion (LVSI) were recorded in each case. Patients were treated primarily by radical hysterectomy with pelvic lymphadenectomy, and those with lymph node metastases were offered postoperative radiation. Following treatment, patients were seen at 3-month intervals for 2 years, and every 6 months thereafter. The mean duration of follow-up was 6.9 years (range 0.4-23.5 years). Seven of 94 patients (7.4%) had lymph node metastases. Five patients had 1 positive node, 1 patient had 2 positive nodes, and 1 patient had 3 positive nodes. Five patients developed recurrent cancer and 4 died of disease. LVSI was present in 31 cases (33%). Tumor recurrence was significantly increased in patients with positive LVSI (9.7% vs 3.2%). The 5-year survival rate of patients with LVSI was 89% vs 98% in patients without this finding (P = 0.058). The 5-year survival rate of all Stage IA2 cervical cancer patients was 95%. Patients with Stage IA2 cervical cancer have a significant risk of lymph node metastases and should be treated by radical hysterectomy with pelvic lymphadenectomy. LVSI is an important prognostic variable in these patients and should be recorded in all cases.

Purpose: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma., Patients and Methods: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity., Results: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months., Conclusion: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Objective: The purpose of this investigation was to determine the pattern of loss of heterozygosity in multiple tumor sites from familial ovarian cancer cases. If ovarian cancer arises focally in one ovary and then metastasizes to other sites, a similar pattern should be seen in all tumor sites. However, if ovarian cancer arises multifocally throughout the peritoneal cavity, a different pattern of loss would be expected among the different sites., Study Design: The presence or absence of loss of specific alleles for 9 loci on chromosomes 1, 6, 11, 13, 16, and 17 was determined in multiple tumor sites from 12 familial ovarian cancer cases., Results: The frequency of loss of heterozygosity was as follows: chromosome 17 (100%), chromosome 13 (82%), chromosome 6 (80%), chromosome 16 (73%), chromosome 1 (57%), and chromosome 11 (22%). In every case an identical pattern was present for at least one locus. In four cases loss of the same allele was present in tumor from the ovary and all metastatic sites for all informative loci. In the remaining eight cases loss of the same allele for one to five (mean three) loci was detected., Conclusions: The pattern of loss of heterozygosity in the 12 familial ovarian cancers included in this investigation favors a unifocal origin of disease. A dual primary origin could not be absolutely excluded in 3 cases. High frequencies on chromosomes 17q and 13 suggest that loss of whole or part of these chromosomes is important in ovarian carcinogenesis.

Seventy-four sporadic ovarian tumors were studied for loss of heterozygosity (LOH) and microsatellite instability (MI) with 20 polymorphic markers on chromosome 17 and at least I marker on every other chromosome. Additionally, activation of the K-ras oncogene was examined through mutation analysis of codon 12. A majority of the tumors analyzed were low grade and/or of the mucinous histologic type. A negative correlation between LOH on chromosome 17 and K-ras activation was observed, with the former alteration present in the majority of high grade serous and endometrioid tumors and the latter most commonly found in the mucinous and low malignant potential (LMP) tumors. In 60% of cases where LOH on chromosome 17 was present, it was observed at all informative markers, indicating chromosome loss. In these cases, frequent events of LOH were observed on the other chromosomes. When confined events of LOH were observed on chromosome 17, fewer events of LOH were observed on the other chromosomes. In the absence of LOH on chromosome 17, LOH on other chromosomes was rare. K-ras activation was most commonly observed in tumors with no LOH events. Two endometrioid tumors and 2 mucinous tumors demonstrated MI. Our data support the involvement of different molecular pathways in the development of different types of ovarian tumors.

Background: Molecular genetic studies of ovarian cancer have been limited by the inaccessible location of the ovary, the advanced stage of tumors available for analysis, and the lack of a well-defined precursor lesion. However, genetic alterations important in ovarian tumorigenesis have been identified recently., Methods: Molecular genetic evaluation of ovarian cancer primarily has utilized mutation analysis, immunohistochemical techniques, and loss of heterozygosity (LOH) studies., Results: Overexpression of the HER-2/neu oncogene is present in approximately one third of ovarian cancers and is associated with poor prognosis. Mutations of the K-ras oncogene have been identified in a similar proportion of mucinous ovarian tumors, including borderline tumors. The study authors as well as others have frequently detected LOH on chromosome 17, including the p53 and BRCA1 loci, and at 17p3.3 and 1717q22-23. Genetic linkage analysis indicates that the majority of inherited ovarian cancers are caused by mutations in the BRCA1 gene. Mutations in mismatch repair genes have been identified in ovarian cancers that occur as part of the hereditary nonpolyposis colon cancer syndrome., Conclusions: Sporadic ovarian tumors are the end result of a complex pathway involving multiple oncogenes and tumor suppressor genes, including HER-2/neu, K-ras, p53, BRCA1, and additional tumor suppressor genes on chromosome 17. The majority of inherited ovarian cancers are due to mutations in the BRCA1 gene, which appears to be a tumor suppressor gene. It is hoped that an increased understanding of the molecular basis of ovarian cancer will lead to advances in prevention, diagnosis, and treatment.

Background: The three most extensively evaluated screening methods for ovarian cancer are pelvic examination, serum CA 125, and transvaginal sonography (TVS). The lack of sensitivity of pelvic examination and serum CA 125 has limited their use in ovarian cancer screening. Currently, the most effective screening method for ovarian cancer is TVS., Methods: Transvaginal sonography was performed with a standard ultrasound unit and a 5.0 MHz vaginal transducer. Each ovary was measured in three dimensions and ovarian volume was calculated using the prolate ellipsoid formula (L x H x W x 0.523). An ovarian volume greater than or equal to 20 cm3 in premenopausal women and greater than or equal to 10 cm3 in postmenopausal women was considered abnormal. Also, any internal papillary projection from the tumor wall was considered abnormal. A patient with an abnormal screen had a repeat TVS in 4-6 weeks. Women with a persisting abnormality on TVS underwent pelvic examination, serum CA 125 determination, Doppler flow sonography, and tumor morphologic indexing before operative tumor removal., Results: Eighty-five hundred asymptomatic women underwent TVS screening. One hundred twenty-one of these women had a persisting abnormality and underwent tumor removal. Fifty-seven patients had serous cystadenomas and eight had primary ovarian cancers. Six patients had Stage IA ovarian cancer, one had Stage IIC ovarian cancer, and one had Stage IIIB ovarian cancer. Only one of these patients had palpable ovarian enlargement on clinical examination and one had an elevated serum CA 125. All patients are alive and well 4-61 months after conventional therapy. The direct cost of TVS screening was highest during the initial years of the program and fell progressively to $30/screen during the 4th year of the study. Worldwide, more than 14,000 women have been screened using ultrasonography, and 19 ovarian cancers have been detected. More than 20,000 patient-screening-years have been accrued, and there have been no deaths from primary ovarian cancer in the screened population., Conclusions: Transvaginal sonography screening causes a decrease in stage at detection and a decrease in case-specific mortality. Further study is needed to determine if annual TVS screening will significantly reduce ovarian cancer mortality. The cost for TVS screening is reasonable and is well within the range of that reported for other screening tests.

Background: The unknown etiology of endometrioid carcinomas of the ovary and the relatively high frequency of a concomitant carcinoma of the endometrium in these patients warrants study of such tumors. The aim of this study was to identify the genetic alterations involved in endometrioid ovarian cancer development, and to determine whether primary tumors of the endometrium and synchronous primary endometrioid tumors of the ovary could be distinguished based on differing patterns of genetic alterations. The distinction of metastatic carcinoma of the ovary from other synchronous primary tumors is often difficult but has important therapeutic and prognostic implications., Methods: This study examined the genetic alterations at 28 polymorphic DNA markers in the DNA of tumors of 17 patients with endometrioid carcinoma of the ovary, including 5 nonmetastatic ovarian tumors, 5 ovarian tumors metastatic to the uterus, and 7 endometrioid ovarian tumors with a synchronous primary endometrial tumor., Results: Chromosomes 17 and 22 were found to be the most common sites of loss of heterozygosity (LOH) in the 17 patients studied. Loss of heterozygosity on chromosome 17 was associated with advanced stage ovarian tumors. In 96% of LOH events in the metastatic tumors, LOH was observed in the primary tumor and in the metastatic site. Conversely, in four of seven synchronous tumors in which LOH was observed, LOH was confined to the ovarian tumor. Genomic instability was identified in two of seven patients with synchronously occurring tumors that did not demonstrate LOH. A positive family history was noted for these two patients., Conclusions: A lack of shared genetic alterations and in synchronously occurring endometrial and endometrioid ovarian tumors indicates independent developmental pathways for these tumors. Loss of heterozygosity on chromosome 17 in endometrioid ovarian carcinoma may indicate transition to a more aggressive tumor.

Epithelial tumors of the ovary are the most common ovarian tumors of adult women. They exist in several different histological patterns and exhibit varying degrees of aggressiveness. Molecular genetic studies in epithelial ovarian cancer have shown that loss of heterozygosity (LOH) for regions of chromosome 17 is a common event, probably reflecting the inactivation of one or more tumor suppressor genes present on this chromosome. We examined 87 sporadic epithelial ovarian tumors of different grade and histological type at 16 loci on this chromosome and found that 35% of them showed LOH for chromosome 17. Of these, 84% showed LOH for all informative markers, suggesting that loss of the entire chromosome 17 homologue may have occurred. Interestingly, chromosome 17 loss was observed frequently in serous tumors (49%), was less common in endometrioid tumors (15%), and was rare in mucinous tumors (4%) (P = .01 and P = .0002, respectively). Our findings support the concept that the histological subtypes of epithelial ovarian cancer may be the result of different molecular genetic events.

Alterations of normal DNA methylation patterns have been reported in various types of human tumors. These alterations are represented by genome wide hypomethylation and by region specific hypermethylation. One commonly hypermethylated region is 17p13.3 (D17S5), the putative site of a tumor suppressor gene. In this study we report that hypermethylation at this locus occurs frequently (33%) in ovarian tumors. We reported previously that loss of chromosome 17 is a common event in serous epithelial ovarian tumors. A correlation of the methylation event and chromosome 17 loss suggests that hypermethylation at D17S5 precedes chromosome 17 loss.

In a study of nine families with "site-specific" ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age < 50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .32-1.0). If predisposition to both breast and ovarian cancer is assumed, the proportion linked is 1.0 (95% confidence interval .46-1.0). The linkage of familial site-specific ovarian cancer to BRCA1 indicates the possibility of predictive testing in such families; however, this is only appropriate in families where the evidence for linkage to BRCA1 is conclusive.

From 1963 to 1993, 157 patients with primary squamous cell carcinoma of the vulva were treated by radical surgery at the University of Kentucky Medical Center. There were 84 unilateral lesions confined to the labium majus or labium minus. Thirty-seven patients had T1 lesions, median diameter 1.5 cm (range 0.5-2.0 cm), and 47 patients had T2 lesions, median diameter 3.4 cm (range 2.2-9.0 cm). Radical vulvectomy with bilateral inguinal lymphadenectomy was performed in 56 patients and radical hemivulvectomy with selective inguinal lymphadenectomy in 28 patients. An average of 8 nodes was removed with superficial inguinal lymphadenectomy and 13 nodes with superficial and deep inguinal lymphadenectomy. Deep inguinal lymph node metastases occurred only in patients with positive superficial inguinal lymph nodes. There were no contralateral inguinal lymph node metastases in any lateral T1 or T2 lesion. Following surgery, patients were followed 1-15 years (mean 5.0 years) and none have been lost to follow-up. Nine patients developed ipsilateral recurrences, but no contralateral recurrences were noted. Seven of these patients developed local recurrences to the ipsilateral vulvar skin and were cured by reexcision. Two patients (2.4%), both of whom had positive ipsilateral superficial and deep inguinal lymph node metastases at the time of initial surgery, developed distant metastases and died of disease 10 and 11 months after treatment. These data suggest that deep inguinal lymph nodal metastases occurred only in patients with superficial inguinal node involvement. Contralateral inguinal lymph nodal metastases are extremely rare in lateral T1 and T2 vulvar squamous cell carcinomas. Radical hemivulvectomy is as effective as radical vulvectomy in the treatment of lateral T1 and T2 vulvar squamous cell cancers.

From 1970 to 1992, 136 patients with a histologic diagnosis of endometrial hyperplasia underwent total abdominal hysterectomy at the University of Kentucky Medical Center. Slides of the curettage or biopsy specimens were reviewed and classified according to the International Society of Gynecologic Pathologists System as simple or complex endometrial hyperplasia with or without cytologic atypia. Slides of the hysterectomy specimens were likewise reviewed independently and classified according to the same system. Eighty-two patients had a preoperative diagnosis of simple or complex endometrial hyperplasia without atypia. There were no cases of occult endometrial carcinoma in the hysterectomy specimens of these patients. Simple or complex hyperplasia with atypia was present in 54 patients and endometrial adenocarcinoma was observed in 19 of these cases (35%). The International Federation of Gynecology and Obstetrics stage and histologic grade of these patients was as follows: Stage IA grade 1--5; Stage IB grade 1--10; Stage IB grade 2--1; Stage IC grade 1--1; Stage IC grade 2--1; and Stage IIIA grade 2--1. The risk of associated endometrial cancer in patients with atypical hyperplasia was independent of age, diabetes mellitus, hypertension, or the use of exogenous estrogens. All patients with endometrial cancer have been followed for 1-12 years (mean 3.0 years) after therapy and no patient has experienced tumor recurrence. These data suggest that there is a significant risk of endometrial cancer in patients with histologic evidence of atypical endometrial hyperplasia on curettage or biopsy. At the time of surgery, patients with atypical endometrial hyperplasia should have careful inspection of the uterine specimen. Any endometrial tissue suspicious for malignancy should be examined histologically, and if cancer is confirmed, complete surgical staging should be performed.

Ovarian cancer is the leading cause of death from gynecologic cancer in the United States. Although the etiology of ovarian cancer is unknown, a number of factors including advancing age, nulliparity and environmental factors have traditionally been related to risk. More recently, genetic predisposition has been recognized as a strong risk factor for ovarian cancer. Three distinct hereditary syndromes have been identified: (1) breast-ovarian cancer syndrome, (2) hereditary nonpolyposis colon cancer, and (3) site-specific ovarian cancer. The mode of inheritance in these families is autosomal dominant with transmission occurring through either the maternal or paternal line. The breast-ovarian and site-specific ovarian cancer family syndrome have been linked to a gene on chromosome 17q that is called BRCA1. However, no simple genetic test can identify women at high risk of the disease. For this reason, genetic counseling, education and surveillance with currently available screening techniques should be made available to women at high risk of ovarian cancer by virtue of their family history. In selected individuals, prophylactic oophorectomy may be warranted.

Purpose: To evaluate the feasibility and toxicity of 252Cf neutron brachytherapy combined with hyperaccelerated chemoradiotherapy for Stage III and IV cervical cancers., Methods and Materials: Eleven patients with advanced Stage IIIB-IVA cervical cancers were treated with 252Cf neutron brachytherapy in an up-front schedule followed by cisplatin (CDDP; 50 mg/m2) chemotherapy and hyperfractionated accelerated (1.2 Gy bid) radiotherapy given concurrently with intravenous infusion of 5-Fluorouracil (5-FU) (1000 mg/m2/day x 4 days) in weeks 1 and 4 with conventional radiation (weeks 2, 3, 5, and 6). Total dose at a paracervical point A isodose surface was 80-85 Gy-eq by external and intracavitary therapy and 60 Gy at the pelvic sidewalls., Results: Patients tolerated the protocol well. There was 91% compliance with the chemotherapy and full compliance with the 252Cf brachytherapy and the external beam radiotherapy. There were no problems with acute chemo or radiation toxicity. One patient developed a rectovaginal fistula (Grade 3-4 RTOG criteria) but no other patients developed significant late cystitis, proctitis or enteritis. There was complete response (CR) observed in all cases. With mean follow-up to 26 months, local control has been achieved with 90% actuarial 3-year survival with no evidence of disease (NED)., Conclusion: 252Cf neutrons can be combined with cisplatin and 5-FU infusion chemotherapy plus hyperaccelerated chemoradiotherapy without unusual side effects or toxicity and with a high local response and tumor control rate. Further study of 252Cf neutron-chemoradiotherapy for advanced and bulky cervical cancer are indicated. We found chemotherapy was more effective with the improved local tumor control.

A breast-ovarian cancer susceptibility gene, BRCA1, which is responsible for disease in approximately 45% of breast cancer families and most families that contain breast and ovarian cancer, has been assigned by genetic linkage to 17q12-21. Here, we report the analysis of three marker-disease recombinants in families that contain breast and ovarian cancer, two of which strongly suggest a location for BRCA1 telomeric to D17S702, a microsatellite polymorphism, and a third which suggests a location centromeric to EDH17B, the gene encoding estradiol-17B dehydrogenase. If the interpretation of these recombinants is correct, the results localise BRCA1 to an interval of < or = 1 cM.