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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 EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 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.

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 chi-square 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/TFBR1 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 represents an emerging avenue of scientific exploration.

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.

Background: Chemotherapy-induced cognitive impairment (CICI), ‘chemo-brain,’ involves concentration and executive functioning difficulty and slowed processing speed and memory. Although cognitive changes in CICI can be subtle and difficult to quantify, CICI affects up to 75% of cancer survivors and impacts quality of life. Objectives: The objective of our study was to add to the definition of CICI by quantifying changes in specific cognitive domains before and after administration of platinum/taxane-based chemotherapy in gynecologic cancer patients using a tailored battery of neurocognitive tests. Methods: Following institutional review board approval, chemotherapy-naive gynecologic cancer patients scheduled to receive six cycles of intravenous platinum/taxane-based chemotherapy were identified. Baseline demographic, social, and clinical characteristics were obtained. Eleven neurocognitive assessments measured cognitive domains of interest (Table 1), including a brief cognitive screen, evaluation of fine motor skills, verbal fluency, working memory, information processing speed, visuospatial learning and memory, attention, mental flexibility, and abstract problem-solving skills. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and Psychiatric Diagnostic Screening Questionnaire assessed emotional functioning. The Functional Assessment of Cancer Therapy - Cognitive Function assessed self-perceived cognitive functioning. Testing was performed prior to the first and three to four weeks after the last cycle of chemotherapy. Descriptive statistics identified trends in individual indices of cognitive dysfunction and quality of life. Results: Fourteen patients enrolled and nine were eligible for complete analyses. The mean age was 60.6 years. The mean full scale intelligence quotient prior to therapy was 103.5. Most patients were White (8/9, 89%), had obtained at least a Bachelor's degree (5/9, 55.6%), and were diagnosed with high grade (6/9, 66.7%) stage III or IV disease (5/9, 55.6%). The majority of patients declined on cognitive screening performance (5/9, 55.6%) as well as worse scores on indices of attention (7/9, 77.8%), mental flexibility (5/8, 62.5%) verbal learning (5/9, 55.6%), and fine motor skills (5/9, 55.6%) after completion of chemotherapy. Most patients improved on indices of verbal memory (7/9, 77.8%), visuospatial learning (6/8, 75%), and verbal fluency (5/9, 55.6%). Despite changes in indices of cognitive function, most patients’ perceived quality of life improved (5/9, 55.6%) after chemotherapy. Download : Download high-res image (219KB) Download : Download full-size image Conclusions: Although gynecologic cancer patients complain of CICI, there is discrepancy regarding its incidence and affected cognitive domains. This pilot study highlights attention and mental flexibility as indices of cognitive dysfunction that may be at risk following receipt of chemotherapy in gynecologic cancer patients. Future research may focus on targeted assessment strategies.

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.

e24051 Background: Chemotherapy-induced cognitive impairment (CICI) is a common side effect of cancer therapy, affecting up to 75% of cancer patients. Oxidative stress is thought to play a key role in CICI and patients who have been treated with chemotherapy have demonstrated biochemical brain changes on magnetic resonance spectroscopy (MRS). Methods: Following institutional review board approval, chemotherapy-naïve gynecologic cancer patients scheduled to receive intravenous platinum/taxane-based chemotherapy were identified. The primary objective of this study was identification of chemotherapy-induced cognitive function changes using the Montreal Cognitive Assessment (MoCA) tool. This exploratory analysis evaluates correlations between changes in MoCA scores, oxidative analytes TNF-a, protein carbonyls (PC), and 4-hydroxynonenal (HNE) protein adducts, and MRS metabolic signals. Testing was performed at baseline and three weeks post-treatment. Simple linear regression was performed to evaluate the correlation between changes in MoCA scores and oxidative metabolites. Results: Fourteen patients were enrolled. Six patients had complete pre/post oxidative stress data, and four patients had complete pre/post MRS data. Five of six had decreased PC values (mean net change -15.17%, SD 0.15), half had increased HNE levels (mean net change +16.38%, SD 0.38), and four of six had decreased TNF-a values (mean net change -15.10%, SD 0.27) (Table). MoCA scores were positively correlated with serum PC levels ( r = 0.86, p = 0.03) and not significantly correlated with TNF-a or HNE levels. Of those with complete pre/post MRS data, all patients had a decrease in glycerophosphocholine + phosphocholine/creatinine ratio signals. MoCA raw score prior to and after completion of chemotherapy. A higher score indicates improved test performance. Positive percentage of oxidative stress markers (PC, HNE, TNF-a) indicates increased post-therapy levels compared to pre-therapy. Conclusions: In this study, we evaluated candidate oxidative stress serum markers and changes in MRS metabolite signals for CICI. Serum PC levels correlate with cognitive screening scores. For patients undergoing brain imaging, MRS evaluation for individual choline components, glycerophosphocholine and phosphocholine, may serve as an additional marker of oxidative damage. This pilot study highlights the potential value of serum PC levels and dedicated brain imaging for signs of oxidative stress, including MRS, to guide future CICI identification studies. Clinical trial information: NCT03324945. [Table: see text]

• HVO focuses on the education, surgical training and development of research skills of surgical oncology residents.

Purpose Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1 , ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy. Methods Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1 , the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model. Results The C421A variant (CA+AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8months, p=0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR]=0.75, 95% confidence interval [CI]=0.59-0.96, p=0.022). The association between C421A and OS was not statistically significant (HR=0.88, 95% CI=0.67-1.15, p=0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS. Conclusion The C421A variant in ABCG2 , previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum+taxane-based chemotherapy. This finding requires further validation.

Objective This study evaluated common polymorphisms in excision repair cross-complementation group 1 (ERCC1) involved in repair of platinum-induced DNA damage in advanced-stage, epithelial ovarian/peritoneal/tubal cancer (EOC/PPC/FTC) patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. Methods Pyrosequencing was performed to examine single nucleotide polymorphisms (SNPs) in codon 118 and C8092A in ERCC1 in leukocyte DNA from the Gynecologic Oncology Group phase III protocol, GOG-182. Kaplan–Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphisms and progression-free survival (PFS) and overall survival (OS). Results The genotype distribution at codon 118 ( n =278) in ERCC1 for CC, CT, and TT was 23%, 45% and 32%, and the median OS was 32, 47 and 43months, respectively. Patients with the CT+TT versus CC genotype in codon 118 in ERCC1 were at a reduced risk of death (hazard ratio [HR]=0.68, 95% confidence interval [CI]=0.49–0.95, p=0.025). The genotype distribution for C8092A in ERCC1 ( N =280) was 50%, 42% and 8%, and the median OS was 45, 40 or 30months for CC, CA and AA, respectively. Women with the CA+AA versus CC genotype in C8092A in ERCC1 had a trend suggesting an increased risk of death (HR=1.29, 95% CI=0.97–1.72, p =0.077). Conclusions The polymorphism in codon 118 in the DNA repair gene ERCC1 was an independent predictor for better survival in EOC/PPC/FTC patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. The relationship between the C8092A polymorphisms in ERCC1 and survival was modest with an effect size that was not always statistically significant.

BackgroundThere 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.MethodsNine 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.ResultsOf 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.ConclusionsChemoFx 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.

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 ≥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. Cancer 2010. © 2010 American Cancer Society.

To explore associations between histology and outcome in advanced or recurrent endometrial cancer patients participating in Gynecologic Oncology Group chemotherapy trials.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).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%, p0.05). 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).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.

Objective The aim of this study was to evaluate the use of co-registered PET/CT using F-18 fluorodeoxyglucose (FDG) for surveillance and follow-up of ovarian cancer patients to detect recurrent disease. Material and methods A retrospective chart review was performed on 39 ovarian cancer patients who underwent a total of 59 FDG-PET/CT scans. The following information was obtained: clinical indication for FDG-PET/CT, the results of FDG-PET/CT particularly with regard to the additional diagnostic information, the localization of disease and subsequent clinical patient management. Results Twenty-four FDG-PET/CT were performed in 22 patients with previously negative or indeterminate CT scans but rising CA-125 levels providing a sensitivity of 90% for localizing disease. Nine FDG-PET/CT in 8 patients with clinical symptoms of recurrence but normal CA-125 levels detected all three patients who had recurrent disease confirmed within 6 months of follow-up. In addition, 4 FDG-PET/CT performed as routine follow-up with no clinical evidence of recurrent disease were true-negative in all cases. Fourteen FDG-PET/CT in 12 patients with recurrent disease already identified by conventional CT imaging were useful in guiding treatment decisions such as radiation therapy, surgery or chemotherapy by confirming the recurrence and more precisely localizing the site(s) of disease. Of note, FDG-PET/CT helped to avoid surgery in four patients who had additional disease detected in unresectable anatomic areas. A total of 51 FDG-PET/CT were performed in the patients described above with an overall sensitivity and specificity of 94.5% and 100%, respectively. Eight FDG-PET/CT scans in five patients performed for assessment of treatment response following chemotherapy or radiation were useful as the disease was not clearly visualized by conventional CT imaging at baseline. Conclusions In our experience, FDG-PET/CT has the greatest utility in settings of suspected ovarian cancer recurrence, particularly in patients with rising CA-125 levels and negative conventional imaging. FDG-PET/CT was specifically helpful in optimizing the selection of patients for site-specific treatment, including radiation treatment planning, and aided in the selection of optimal surgical candidates. The co-registered metabolic–anatomic information from combined FDG-PET/CT holds promise in replacing the single imaging procedures.

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. Cancer 2006. Published 2006 by the American Cancer Society

The study objective was to determine the effectiveness of a phenotypic chemoresponse assay in predicting response to chemotherapy measured by progression-free interval (PFI) in a retrospective series of ovarian cancer patients whose tumor specimens had been tested with the ChemoFx assay. A statistically significant correlation between assay prediction of response and PFI was observed in 256 cases with an exact or partial match between drug(s) assayed and received. In 135 cases with an exact match, the hazard ratio for progression of the resistant group was 2.9 (confidence interval [CI]: 1.4-6.3; P0.01) compared to the sensitive group and 1.7 (CI: 1.2-2.5) for the intermediate compared to the sensitive group. The median PFI for patients treated with drugs assayed as resistant was 9 months, 14 months for those with drugs assayed as intermediately sensitive, and PFI had not been achieved for those with drugs assayed as sensitive. These data indicate that the ChemoFx assay is predictive of PFI in ovarian cancer. As the majority of ovarian cancers display different degrees of response to different chemotherapy agents ex vivo, the incorporation of assay information into treatment selection has the potential to improve clinical outcomes in ovarian cancer patients.

Objectives To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen. Methods Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m 2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m 2 over 15 min followed by mesna 120 mg/m 2 IV bolus, then 1.5 g/m 2 /24 h as a continuous infusion. Initial doses (daily × 5 every 21 days × 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity. Results Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity. Conclusion Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.

Background: This study was performed to determine whether 24-h paclitaxel plus doxorubicin and filgrastim was superior to cisplatin plus doxorubicin in patients with endometrial cancer with respect to response, progression-free survival (PFS) and overall survival (OS). Patients and methods: Eligible chemotherapy-naive patients were randomly assigned to doxorubicin 60 mg/m2 intravenously (i.v.) followed by cisplatin 50 mg/m2 i.v. (arm 1, n=157) or doxorubicin 50 mg/m2 i.v. followed 4 h later by paclitaxel 150 mg/m2 i.v. over 24 h plus filgrastim 5 μg/kg on days 3–12 (arm 2, n=160). Starting doses were reduced for prior pelvic radiotherapy and age >65 years. Both regimens were to be repeated every 3 weeks for a maximum of seven cycles. Results: There was no significant difference in response rate (40% versus 43%), PFS (median 7.2 versus 6 months) or OS (median 12.6 versus 13.6 months) for arm 1 and arm 2, respectively. Toxicities were primarily hematological, with 54% (arm 1) and 50% (arm 2) of patients experiencing grade 4 granulocytopenia. Gastrointestinal toxicities were similar in both arms. Conclusions: Doxorubicin and 24-h paclitaxel plus filgrastim was not superior to doxorubicin and cisplatin in terms of response, PFS or survival in advanced endometrial cancer.

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 γ-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. © 2004 Wiley-Liss, Inc.

Objectives. The aim of the study was to determine the prevalence of BRCA1 and BRCA2 germline mutations among ovarian cancer patients ascertained to have a family history of ovarian cancer. Methods. Ovarian cancer patients were eligible if they had a family history of cancer that met any one of the following criteria: (1) a first-degree relative with ovarian cancer; (2) a second-degree relative with ovarian cancer plus a first-degree relative with breast cancer (diagnosed younger than 50 years of age); or (3) a first- and a second-degree relative with breast cancer (diagnosed younger than 50 years of age). The entire coding sequence of BRCA1 and exon 11 of BRCA2 were screened for germline alterations by single-strand conformation polymorphism analysis. Results. Of 26 eligible patients screened for mutations, 12 had deleterious alterations, 8 in BRCA1 and 4 in BRCA2. A correlation was noted between the presence of a BRCA1 mutation and the strength of family history of breast ovarian cancer, with the likelihood of a mutation increasing with the number of affected relatives ( P = 0.0002). No association was detected between the location of mutations in BRCA1 and the ratio of ovarian cancer cases relative to breast cancer ( P = 0.28). Conclusions. Mutations in BRCA1 or BRCA2 are present in about 50% of ovarian cancer patients with at least one first-degree relative with disease, and in 70% of patients with two or more relatives with ovarian cancer.

Introduction: Invasive cancer of the uterine cervix (ICC) is a leading cause of cancer death in women worldwide. ICC incidence and mortality rates are especially high among women from Appalachia. In addition to lifestyle and social-behavioral factors and HPV infections, hereditary predispositions may mediate cervical cancer risk. Polymorphic alleles within the Transforming Growth Factor Beta (TGFB) signaling cascade, an important regulator of epithelial cell growth, have been implicated in modifying cancer susceptibility. The contributions of these factors within a gene-environment model have not been well characterized in Appalachian ICC patients. Hypothesis: High-risk genomic variants of TGFB signaling pathway components will be overrepresented in Appalachian women diagnosed with ICC compared to their healthy Appalachian counterparts. Methods: A case-control study was conducted with 163 cases, women diagnosed with ICC, and 842 controls, women with normal Pap tests from Appalachia Ohio, West Virginia, and Kentucky. Inclusion criteria were (i) women residing in Appalachian counties who were ≥18 years, (ii) spoke English, (ii) not cognitively impaired, (iii) able to provide informed consent. Three distinct groups were considered, representing (i) prevalent invasive cervical cancer cases, (ii) newly diagnosed invasive cervical cancer cases, and (iii) healthy controls. Targeted genomic variance analysis of 9 SNPs (rs1800469, rs1800470, rs3917200, rs7034462, rs11568785, rs868, rs1042522, rs750749, rs1800566) and a polymorphic repeat variant was conducted on blood DNA. Behavioral and environmental factors were collected using a comprehensive, self-administered questionnaire completed at the time of enrollment. Characteristics between cases and controls were compared by a two sample t-test, assuming unequal variance for continuous variables and by Fisher's exact test for categorical variables. Associations between disease status, polymorphism and behavioral or environmental characteristics were estimated via multivariable logistic regression. Results: Never smokers with TGFB1 rs1800469 overdominant allele types A/A-G/G had 0.4 (95% CI: 0.22-0.73, p=0.003) times the odds of cervical cancer compared to never smokers with A/G genotype. This effect was not observed in ever smokers (interaction p=0.02). While there was a suggestion of an increased risk of cervical cancer for never smokers with TGFB1 rs1800469 recessive A/G-A/A genotypes compared to G/G non9A genotype CD83 dominant T/T compared to C/C-C/T, or overdominant C/C -T/T compared to C/T alleles, there were no strong interaction effects identified. The effect of dominant TP53 rs1042522 allele type (C/C C/G versus G/G) differed by smoking status. There was a significant 3-fold increase in the odds of cervical cancer (aOR: 3.1, 95% CI: 1.1-8.5, p=0.03) for never smokers with TP53 rs1042522 G/G compared to never smokers with C/C-C/G genotypes. A similar increase was not observed in ever-smokers (smoking status by genotype interaction effect p=0.02). In codominant types, there was a similar increased adjusted odds (aOR: 3.65, 95% CI: 1.21-11.0, p=0.021) of cervical cancer for never smokers with G/G genotypes compared to never smokers with C/G genotypes. This effect was not observed in ever smokers (interaction effect p=0.06). Conclusions: Genetic susceptibility may contribute to the overall cervical cancer risk associated with the Appalachian population, especially among non-smokers. Inclusion of additional demographic and social-behavioral features, as well as other genetic events, may further define this evolving cervical cancer risk model. Citation Format: Thomas J. Knobloch, Steve Oghumu, Marta Sears, Zhaoxia Zhang, Blessing Ogbemudia, Joe Perrault, David Cohn, Cecilia R. DeGraffinreid, Bo Lu, Juan Peng, Erinn M. Hade, Michael A. Schiano, Byron C. Calhoun, William McBee, Jr., Jamie Lesnock, Holly Gallion, Jondavid Pollock, Mack T. Ruffin, IV, Christopher M. Weghorst, Electra D. Paskett. Inherited alterations of Transforming Growth Factor Beta signaling components in Appalachian Cervical Cancers. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B57.

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.

Objective. The goal of this work was to develop a combination chemotherapy regimen consisting of ifosfamide and paclitaxel to be evaluated in the management of gynecologic malignancies. Methods. The Gynecologic Oncology Group conducted a Phase I trial of the regimen, initially with paclitaxel (24-h infusion) delivered on Day 1 and ifosfamide (1 h) administered (with Mesna) over the subsequent 4 days. All patients received granulocyte colony-stimulating factor (G-CSF) starting 24 h after the Day 5 chemotherapy. Treatment was repeated on a 28-day schedule. A cohort of patients also received the alternate sequence of ifosfamide (4 days) followed by paclitaxel. Results. Twenty-two patients were evaluated. Even at the lowest dose level tested (paclitaxel 135 mg/m 2 followed by ifosfamide 1 g/m 2 /day × 4 days) grade 4 neutropenia was almost universal, despite the routine use of G-CSF. The alternate drug administration sequence resulted in marrow suppression of similar severity. Conclusion. The combination of 24-h infusional paclitaxel with ifosfamide delivered over 4 days results in severe neutropenia, despite the administration of G-CSF, and is not recommended for further evaluation. In view of the known activity of the two agents in several malignancies, including cervix cancer, it would be reasonable to investigate the delivery of the agents employing alternative treatment schedules predicted to result in less severe marrow suppression (e.g., 3-h infusional paclitaxel).

Objective. The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix. Methods. The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m 2 /day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions. Results. Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used. Conclusions. The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare.

BACKGROUND Cytologic sampling is performed routinely after radiotherapy for cervical carcinoma. The prognostic significance of postirradiation dysplastic and atypical cells is uncertain because of difficulties in distinguishing preneoplastic and cancerous changes from benign radiation changes. DNA cytometry studies may provide a more objective method of identifying significant lesions. METHODS Postirradiation cervical carcinoma patients with cervical/vaginal smears containing atypical or dysplastic cells were identified prospectively. Papanicolaou smears were destained, restained with a Feulgen stain, and evaluated for DNA content using image cytometry. Pathologic and clinical records were monitored on each patient for evidence of recurrence or biopsy-proven dysplasia. RESULTS Of 46 patients, 14 had been diagnosed on cytology as having atypical squamous cells, 4 as having atypical/suspicious cells, 12 with low grade squamous intraepithelial lesions (SIL), 3 with high grade SIL, and 13 with ungraded SIL. DNA histograms were classified as follows: 14 diploid, 19 polyploid, and 13 aneuploid. Cytologic diagnosis and histogram type were correlated significantly and both correlated with clinical outcome. The probability of either postirradiation dysplasia or recurrence was as follows: SIL, 82%; suspicious, 100%; polyploid, 79%; and aneuploid, 92%. Patients with atypical squamous cells of undetermined significance or diploidy most frequently had negative follow-up (57% each). All patients with both SIL and aneuploidy developed either dysplasia or recurrence. The stage of disease did not correlate with outcome or histogram pattern. CONCLUSIONS DNA analysis of postirradiation cytologic smears demonstrating atypia or dysplasia may provide useful ancillary information. The presence of aneuploidy usually signifies either recurrence or dysplasia. Polyploidy most frequently occurs in dysplastic processes, whereas diploid histograms usually denote a benign disease course. Cancer (Cancer Cytopathol) 1998;84:11-6. © 1998 American Cancer Society.

Ovarian carcinoma accounts for greater than 50% of the gynecologic cancer deaths in the United States each year. One of the central reasons for this dismal outcome is that many patients present with advanced disease. In this series, a retrospective review of 130 patients with stage III and IV invasive epithelial ovarian carcinoma was performed to determine the prognostic significance of ascites. Patients were divided into two study groups based upon the presence or absence of ascites. Survival for the entire study group was 15%, but differed markedly when separated for the presence of ascites. In these patients, ascites was associated with a statistically decreased 5-year survival of 5% versus 45% without ascites ( P = 0.0001). Individuals were found to be similar in each group when examined for age, height, weight, cell type, grade, and surgical and chemotherapeutic treatment modalities. More patients proportionately with stage IIIC disease had ascites than those without ascites ( P = 0.0015). More of the individuals without ascites underwent second-look laparotomies and achieved a negative result than those with ascites ( P = 0.04; P = 0.0038). We conclude that ascites in the presence of stage III and IV disease produces an almost uniformly fatal outcome.

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. (AM J OBSTET GYNECOL 1996;174:1102-8.)

The Human Genome Project is a large scale international effort to create physical, genetic, and nucleotide sequence maps of the entire human genome. This initiative, which was begun in 1990, is expected to achieve its goal of sequencing the entire human genome by the year 2005. Undoubtedly, this massive resource will substantially enhance our ability to diagnose predisposition to disease at the genetic level and will provide us with important biologic information that can be used in the treatment and prevention of disease.

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 cm 3 in premenopausal women and greater than or equal to 10 cm 3 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 endometroid ovarian carcinoma may indicate transition to a more aggressive tumor. Cancer 1995; 76:650–7.

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.

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.

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. © 1994 Wiley-Liss, Inc.

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.

The objective of this study was to review severe complication frequency in a protocol study using a defined prescribed dose combined with fractionated whole pelvis radiotherapy to 40-45 Gy. The method used a dose of Cf neutrons to 35 Gy equivalents (relative biological effectiveness or RBE adjusted) to a total tumor dose of 80 Gy-eq in one to four implant sessions. Compliance was excellent, and most patients received two implants to 35 (0.4) (SE) Gy-eq in two sessions plus external radiation to a total point A or paracervical region dose of 80 (0.3) Gy-eqs. In patients who received delayed implants, the severe complication rate (pelvic necrosis, fistulas) was significantly greater (40% versus 3%). We postulate that neutron brachytherapy caused tumors to regress rapidly and completely, which allowed the neutron dose to adjacent radiosensitive organs (bladder, rectum, sigmoid colon, and bowel) to become excessive. The delayed Cf implant apparently contributed to the greater risk for normal tissue complications.

From 1981-1991, 15 patients with primary fallopian tube carcinomas were treated at the University of Kentucky Medical Center. Immunohistochemical staining for CA-125 was performed on tumor specimens from all cases. Thirteen tumors (87%) stained positively for CA-125. Antigen staining was most intense in the apical portions of carcinoma cells. Serum CA-125 levels were measured in 5 patients and were elevated in 4 (80%). There was a positive correlation between tumor and serum antigen expression in these cases. Serum CA-125 levels accurately reflected disease status in the patients studied. These data suggest that CA-125 is a useful marker in patients with fallopian tube carcinoma. Immunohistochemical localization of CA-125 in tumor tissue should predict which patients will benefit most from serial antigen determinations.

Histologic material from 42 patients with endometrioid carcinomas of the ovary was reviewed. Ovarian endometriosis was present in 11 cases (26%) and 8 of these patients were postmenopausal. The exact site of transition from benign to malignant epithelium was observed in 4 cases. The clinical characteristics of patients with associated endometriosis were not significantly different from those without this finding except that endometriosis was present only in patients with Grade 1 or Grade 2 carcinomas. These data suggest that ovarian endometriosis in the postmenopausal patient has the potential to undergo malignant transformation and, when detected, should be removed surgically.

The slides of all patients with ovarian cystadenocarcinoma treated at the University of Kentucky Medical Center from 1966–1990 were reviewed. Fifty-four serous tumors and 42 mucinous neoplasms were identified for further study. Benign epithelium adjacent to an area of borderline or malignant epithelium was observed in 74 tumors (79%) and a site of epithelial transition was noted in 38 cases (40%). The presence of associated benign epithelium was more common in borderline or well-differentiated lesions and in patients with early-stage disease. These findings are consistent with epidemiologic and molecular genetic data and suggest that certain benign serous or mucinous ovarian tumors have the potential for malignant transformation. Removal of these tumors, particularly in postmenopausal women, should result in a subsequent reduction in the frequency of ovarian cancer.