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To examine hysterectomies in the United States performed for gynecologic malignancies and identify factors associated with the use of minimally invasive techniques.This is a cross-sectional analysis of the 2012 National Inpatient Sample, the largest national all-payer database of hospital discharges. International Classification of Diseases, 9th Revision, Clinical Modification codes for any type of hysterectomy performed for gynecologic malignancy were used to abstract pertinent observations. Weighted multivariable logistic regression models were used to examine the associations between demographic and clinical factors and mode of hysterectomy by cancer diagnosis.In 2012, there were an estimated 46,450 hysterectomies for gynecologic malignancy in the United States. Of these, 28,285 (61%) were performed for uterine, 4,275 (9%) for cervical, 12,370 (27%) for ovarian cancer, and 1,520 (3%) for other gynecologic malignancies. Minimally invasive hysterectomy was used in 50% of uterine, 43% of cervical, and 8.5% of ovarian cancer cases. Black women had decreased odds of undergoing minimally invasive hysterectomy for uterine (adjusted odds ratio [OR] 0.50, 95% confidence interval [CI] 0.40-0.0.63, P.001) and cervical (adjusted OR 0.56, 95% CI 0.33-0.96, P=.03) cancers. Those without insurance or with Medicaid had decreased odds of undergoing minimally invasive hysterectomy (P.001) for uterine cancer. As compared with the Northeast, patients in the South (adjusted OR 0.72, 95% CI 0.53-0.98, P=.04) were less likely to undergo minimally invasive hysterectomy for uterine cancer, whereas those in the West more likely (adjusted OR 1.48, 95% CI 1.10-1.99, P=.009).Minimally invasive hysterectomy for gynecologic malignancies remained underused in 2012; there were striking racial disparities associated with use of minimally invasive hysterectomy for uterine and cervical cancers.III.

To analyze margin status and prognostic factors for complications in patients undergoing vulvectomy for invasive squamous cell cancer (iSCC) with and without plastic-assisted closure.Demographic and clinical data were collected on 94 patients with iSCC who underwent vulvectomy between 2004 and 2013. All pathology slides were re-reviewed by two gynecologic pathologists. Data were analyzed using XLSTAT-Pro v2014.2.02.Of 88 eligible patients, 15 (17%) had plastic-assisted vulvar closure and 73 (83%) did not. There were significantly more patients in the plastics group with recurrent disease (53% v 10%) and history radiation therapy prior to surgery (40% versus 5%). Plastic-assisted closure was associated with larger tumors (3.73 cm versus 2.03 cm, p0.01) and a higher frequency of adequate margins (53% versus 29%, p=0.06). For tumors≥3.0 cm, plastic-assisted closure was significantly associated with adequate margins (44% versus 6%, p=0.03). Prior radiation use was associated with plastic-assisted closure, larger tumors, older age, and recurrent disease. Complications occurred in 36 patients (41%) and significantly more occurred in those with plastic-assisted closure (67% versus 36%, p=0.04). On multivariate analysis including age, tumor size, recurrent disease, plastic-assisted closure, and history of radiation, only history of radiation therapy was a significant predictor of complications (OR=17, 95%CI 2.05-141.35; p=0.01).Plastic-assisted vulvectomy closure was more often utilized in cases involving past radiation therapy and larger tumors. Plastic-assisted closure significantly increased the frequency of adequate margins in tumors≥3 cm and did not impact complications.

Background Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors. Methods RNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors. Results Ovarian epithelial tumor cells showed concurrent up-regulation of miR-200, down-regulation of the four target genes (ZEB1, ZEB2, TGFβ1 and TGFβ2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection. Conclusions The activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high-grade serous ovarian carcinomas (HGSOC) usually express high levels of CA125, the induction of CA125 expression in FTE cells by miR-200 precursor transfection is consistent with the notion that HGSOC has an origin in the distal fallopian tube. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3417-z) contains supplementary material, which is available to authorized users.

Protein kinases (PKs) mediate the reversible conversion of substrate proteins to phosphorylated forms, a key process in controlling intracellular signaling transduction cascades. Pluripotency is, among others, characterized by specifically expressed PKs forming a highly interconnected regulatory network that culminates in a finely-balanced molecular switch. Current high-throughput phosphoproteomic approaches have shed light on the specific regulatory PKs and their function in controlling pluripotent states. Pluripotent cell-derived endothelial and hematopoietic developments represent an example of the importance of pluripotency in cancer therapeutics and organ regeneration. This review attempts to provide the hitherto known kinome profile and the individual characterization of PK-related pathways that regulate pluripotency. Elucidating the underlying intrinsic and extrinsic signals may improve our understanding of the different pluripotent states, the maintenance or induction of pluripotency, and the ability to tailor lineage differentiation, with a particular focus on endothelial cell differentiation for anti-cancer treatment, cell-based tissue engineering, and regenerative medicine strategies.

BACKGROUND Uterine leiomyosarcoma (ULMS) is identified in 0.1% to 0.2% of hysterectomy specimens of presumed leiomyoma. To date, there is no preoperative technique that reliably differentiates ULMS from uterine leiomyoma. Increasing use of minimally invasive approaches for the management of leiomyomas may result in inadvertently morcellated ULMS with resultant intraperitoneal dissemination of tumor. The objective of this study was to assess the impact of intraperitoneal morcellation on the outcomes of patients with ULMS. METHODS In this retrospective cohort study, all patients with ULMS who attended the authors' institutions from 2007 to 2012 were reviewed. Demographics and outcomes were compared between those who underwent morcellation or total abdominal hysterectomy (TAH) as their first surgery for uterus-limited ULMS. RESULTS In total, 58 patients were identified, including 39 who underwent TAH and 19 who underwent intraperitoneal morcellation. Intraperitoneal morcellation was associated with a significantly increased risk of abdominal/pelvic recurrences (P = .001) and with significantly shorter median recurrence-free survival (10.8 months vs 39.6 months; P = .002). A multivariate adjusted model demonstrated a >3 times increased risk of recurrence associated with morcellation (hazard ratio, 3.18; 95% confidence interval, 1.5-6.8; P = .003). CONCLUSIONS Intraperitoneal morcellation of presumed leiomyoma worsens the outcomes of women with ULMS. Because there are no reliable preoperative techniques to distinguish ULMS from benign leiomyoma, all efforts to minimize intraperitoneal uterine morcellation should be considered. [See editorial on pages 000-000, this issue.] Cancer 2014;120:3154–3158. © 2014 American Cancer Society.

Objectives To determine the toxicity and survival rates in a trial of concurrent bevacizumab and external beam radiation (EB) for patients with recurrent endometrial or ovarian cancer. Methods Nineteen women with recurrent endometrial ( n =15) or ovarian ( n =4) cancer with gross disease involving the vaginal cuff, and/or pelvic nodes and/or para-aortic nodes, cancer were enrolled between 2008 and 2010. All patients received bevacizumab during radiation. Toxicity was assessed at baseline, weekly during treatment and every 3months for at least 1year after treatment. Results All patients completed EB on schedule. For the 15 patients with recurrent endometrial cancer, the 1- and 3-year progression-free survival (PFS was) 80%/67% and overall survival (OS) was 93%/80%. Patients that had a vaginal cuff recurrence alone had a 1- and 3-year PFS of 75%/63% and OS of 100%/75%. Two patients with pelvic node involvement did not recur throughout the entire follow-up period. The 5 patients with para-aortic node involvement had a 1- and 3-year PFS of 80%/60% and OS of 80%/80%. Of the 4 ovarian cancer patients 3 relapsed with 1- and 3-year PFS of 80%/40% and OS of 100%/60%. Toxicities included thrombosis and 1 embolic event in the setting of metastastic disease. No gastrointestinal perforations were noted. Conclusions Delivering bevacizumab with concurrent radiation provides excellent local tumor control and survival for women with recurrent endometrioid endometrial cancer, particularly those with unresectable nodes. Caution must be used in those at highest risk of developing metastatic disease given the increased risk of thromboembolic events. This regimen may be considered for recurrent gynecologic malignancies in future trials.

Patients with High Grade Serous Ovarian Cancer (HGSC) have limited therapeutic options. Immuno-oncologic (IO) agents have had limited effect. DNA damage repair gene mutations that may confer repair defects have been identified in up to 50% of HGSCs, making therapies that target repair defects, like PARP, CHK1, and ATR inhibitors, additional options. We have no means of predicting which patients will respond to any of these therapies. A model system that allows for functional assays to assess for DNA damage repair defects, prediction of response to therapies targeting such defects, and assessment of the functionality of the tumor immune infiltrate and its response to IO agents is needed. Organoids are three-dimensional structures derived from human normal or tumor tissue cells that anatomically and functionally mimic the developed human organ. Organoids mimicking the parent tumor from which they were derived have aided in the study of multiple tumor types. They are inexpensive and easily manipulated and may be an ideal model system for studying ovarian cancer. We have devised a functional assay platform to profile the DNA damage repair capacity and immune targetability of short-term patient-derived HGSC organoids. The organoids mimic the tumors from which they were derived morphologically, molecularly, and genetically. We have tested 33 organoid cultures derived from 21 HGSC patients for homologous recombination (HR) and replication fork protection capacity and compared the functional results to the tumor genomic profile. Regardless of repair gene mutational status, an HR functional defect in the organoids correlated with PARP inhibitor sensitivity. A fork protection functional defect correlated with carboplatin, and ATR and CHK1 inhibitor sensitivity. Importantly, this work has led to the discovery of potential therapeutic combinations, such as a CHK1 inhibitor plus carboplatin or gemcitabine that may be useful in treating tumors otherwise resistant to most therapies. Drugs such as carboplatin or gemcitabine can synergize with a CHK1 inhibitor by enhancing replication stress and fork deprotection. In parallel, we have immune phenotyped the parent tumors and organoid cultures from 15 patients, and shown that the organoid cultures retain lymphocytes expressing relevant IO receptors in the short term. Upon treatment with carboplatin, olaparib, and pembrolizumab as single agents or in combination, we detect changes in IO receptor expression and production of different cytokines in the cultures, suggesting an immune response induced by these agents. We have detected receptor and cytokine alterations that would create an immune suppressive environment with specific drug combinations in tumors with specific repair defects, suggesting that these may be inappropriate combinations for harnessing the immune system in tumors with specific repair capacities. Continued combined immune and DNA damage repair phenotyping analyses of the organoids will lead to a better understanding of which mechanistic defects are needed to confer sensitivity to DNA damage repair agents, what functional properties and immune milieu lead to sensitivity to IO agents, and how best to combine such therapies. In addition, through further correlation with patient responses over time, HGSC organoids may become a useful tool for rapidly predicting patient response to therapeutic agents. Citation Format: Sarah J. Hill, Brennan Decker, Emma A. Roberts, Chunyu Yang, Neil S. Horowitz, Michael G. Muto, Michael J. Worley Jr., Colleen M. Feltmate, Marisa R. Nucci, Elizabeth M. Swisher, Ryuji Morizane, Bose Kochupurakkal, Khanh T. Do, Panagiotis Konstantinopoulos, Joyce F. Liu, Joseph V. Bonventre, Ursula A. Matulonis, Geoffrey I. Shapiro, Ross S. Berkowitz, Christopher P. Crum, and Alan D. D'Andrea. REAL-TIME ASSESSMENT OF HGSC DNA DAMAGE REPAIR DEFECTS AND DEFECT-INDUCED RESPONSE TO THERAPY IN OVARIAN CANCER ORGANOIDS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP10.

Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease.To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes.Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated.Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P.001).Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients.

Patients with high grade serous ovarian cancer (HGSC) have limited additional therapeutic options beyond traditional carboplatin and paclitaxel. Immuno-oncologic (IO) agents have had limited effect, and despite the fact that 50% of HGSCs have genomic alterations in DNA damage repair genes, we still have no means of predicting which of these tumors actually harbor repair defects and will respond to these agents. Using patient-derived organoids which contain patient immune cells, we have developed functional assays to test the DNA damage repair capacity, anti-tumor immune response, and therapeutic vulnerability of HGSCs. These assays include testing for defects in the two key DNA damage repair pathways, homologous recombination (HR) and stalled replication fork protection, testing for activity and specificity of the immune cells in the cultures against the tumor cells when exacerbated by specific therapeutic combinations, and testing for therapeutic sensitivity to targeted and traditional chemotherapy agents and IO agents either alone or in rational combinations. In parallel, many of the tumors and organoids have undergone genomic and RNA sequencing, searching for relevant alterations to explain detected defects. Flow cytometry analysis of the parent tumors and short term (7-10 day) organoids reveal that organoids contain an immune milieu with IO receptor expression levels similar to the parent tumors. Upon treatment with IO agents alone or in combination with chemotherapeutic agents, we have found that specific IO receptor expression is altered, certain combinations lead to induction of cytokine expression that may repress an anti-tumor response, and that some combinations do not induce the expected cytotoxicity. The DNA damage repair functional assays have revealed that in HGSC, stalled fork protection defects are more common than HR defects, regardless of the repair gene mutational status of the tumors. Importantly, there is a wider array of therapies available to target these defects. For instance, organoids with unstable replication forks are more sensitive to ATR and CHK1 inhibitors. Organoids with stable forks are more sensitive to combinations of drugs which confer replication stress, such as the combination of a CHK1 inhibitor plus gemcitabine. Overall, the repair assays will allow for a better understanding of the types and mechanisms of repair defects present in tumors and a more accurate prediction of sensitivity to targeted agents. The immune functional assays will allow for a better mechanistic understanding of what response specific agents actually induce in immune and tumor cells and allow for better rational therapeutic pairings. Through assessment of a larger number of patients, we hope to demonstrate that these functional assays can have a clinical impact in rapidly predicting patient response. Citation Format: Sarah J. Hill, Patrick Lizotte, Neil S. Horowitz, Michael G. Muto, Michael J. Worley, Colleen M. Feltmate, Bose Kochupurakkal, Khanh T. Do, Panagiotis Konstantinopoulos, Marisa R. Nucci, Joyce F. Liu, Ursula A. Matulonis, Geoffrey I. Shapiro, Ross S. Berkowitz, Christopher P. Crum, Alan D. D'Andrea. Functional assessment of DNA damage repair defects and the anti-tumor immune response in high grade serous ovarian cancers using patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 368A.

To compare primary debulking surgery (PDS) vs. neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) among elderly patients with ovarian/fallopian tube/primary peritoneal carcinoma.Medical records of patients ≥70 years old with epithelial ovarian/fallopian tube/primary peritoneal carcinoma between January 2000 and December 2010 were reviewed. Patients were separated by PDS or NACT-IDS. Preoperative characteristics, surgical procedures and postoperative and oncologic outcomes were compared. Surgical procedures were given a complexity score based on a previously published method.Of 165 patients, 125 (75.8%) underwent PDS and 40 (24.2%) underwent NACT-IDS. Patients undergoing NACT-IDS were more likely to have a pleural effusion (without cytology) and stage 4 disease. Median CA-125 at diagnosis was greater for those undergoing NACT-IDS. The NACT-IDS group was associated with less intraoperative blood loss (250 vs. 400 mL, p=0.001), a greater chance of achieving no residual disease (40% vs. 16%, p=0.005) and a shorter hospital length of stay (LOS) (5 vs. 7 days, p0.001). PFS (17 vs. 15 months, p=0.708) and OS (29 vs. 33 months, p=0.827) were similar between the two groups. Readmission rates within 30 days of surgery were greater in those undergoing PDS (17.6% vs. 2.5%, p=0.016). After readmission, the median hospital LOS was 6 days (range: 1-41).Elderly patients undergoing PDS have similar oncologic outcomes when compared to patients undergoing NACT-IDS. The risk of readmission within 30 days of surgery is significantly greater among patients undergoing PDS.

Purpose To identify a combination of sonographic features that best predicts ovarian malignancy. Methods Subjects included 249 women who had a transvaginal sonogram for a pelvic mass at Brigham and Women's Hospital between December 2005 and February 2010. Subjects underwent surgery for removal of the mass and pathologic diagnosis was available. Images were reviewed retrospectively by one sonologist blinded to diagnosis and clinical information. Twelve sonographic features were scored for each mass. The dataset was divided into training (n = 149) and testing (n = 100) sets. Within the training set, a stepwise logistic regression was used to weigh each variable and combination of features to identify those associated with malignancies. Using the results from the logistic regression analyses, we created a three-level risk stratification that was applied to the sonograms of subjects in the testing set to assess its ability to distinguish benign lesions from invasive and borderline cancers. Results High risk lesions included all masses with internal vascularity. In our testing set, this feature was present in 9 out of 12 (75%) invasive cancers, 1 out of 6 (16.7%) borderline lesions, and 9 out of 82 (11%) benign masses. The intermediate risk level included lesions with a thick wall or thick septa without internal blood flow. This combination of features identified one additional invasive cancer and 5 out of 6 (83.3%) borderline tumors. Masses with low risk features had a 2/49 (4.0%) incidence of malignancy. Conclusions In the absence of high or intermediate risk sonographic features, the risk of malignancy is low. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound, 41:269–274, 2013

To describe the clinical characteristics of patients with endosalpingiosis (ES) and examine its association with endometriosis and gynecologic malignancies.We queried the medical record for patients who underwent gynecologic surgery (Gynecologic Surgery Cohort (GSC), n=58,161) from 1998 to 2013 at a single institution for the presence of "endosalpingiosis" (ES). Demographic and clinical characteristics were collected for patients with pathologically confirmed ES (n=838). Within GSC, we compared the frequency of endometriosis and gynecologic malignancies with and without ES. We estimated the expected distribution of ovarian cancer subtypes using cases from the New England Case Control Study (NECC). We used chi-square tests to test for significant differences in frequency distributions and unconditional logistic regression to calculate multivariate odds ratios for the association between ES and ovarian cancer subtypes.We observed concurrent endometriosis (p0.0001), uterine cancer (p0.0001), and ovarian cancer (p0.0001) more frequently in women with ES. Women from the GSC with ES and ovarian cancer were more likely to have serous borderline (OR=10.2, 95% CI=5.1-20.7), clear cell (OR=3.0, 95% CI=1.1-8.0), and invasive mucinous tumors (OR=5.0, 95% CI=1.5-16.6) as compared to ovarian cancer cases from the NECC without ES, after accounting for age, race, menopausal status, parity, tubal ligation, and endometriosis.Women with ES are more likely to also be diagnosed with endometriosis, uterine, and ovarian cancers. Further study is needed to understand these associations so we may appropriately counsel patients with ES diagnosed at time of gynecologic surgery.

We, as a group of international multi-disciplinary neurointerventional societies involved in the endovascular management of acute ischemic stroke, have put forth these training guidelines. We believe that a neuroscience background, dedicated neurointerventional training, and stringent peer review and quality assurance processes are critical to ensuring the best possible patient outcomes. Well-trained neurointerventionalists are a critical component of an organized and efficient team needed to deliver clinically effective mechanical thrombectomy for acute ischemic stroke patients.

Malignant ovarian neoplasms represent the leading cause of death in gynecological malignancies. Although the majority of ovarian neoplasms occur in women of advanced years, ovarian neoplasms can occur in women of the reproductive age group. Preservation of fertility balanced with treatment of disease is the goal of young patients diagnosed with ovarian neoplasms. A new discipline termed "oncofertility" has emerged; however, several informational gaps exist. Concern has centered on the safety of conservative treatment, the uncertain efficacy of fertility options, the detrimental effects of chemotherapy to remaining reproductive organs, and the timing and execution of fertility workup relative to disease requiring treatment. This study involved an evaluation of young premenopausal women who underwent fertility-sparing surgery for an ovarian neoplasm. Given the rarity of this disease in premenopausal women the objective was to assess the feasibility of this study as defined by the completion rate of the survey. The aim was to broaden our knowledge of patient needs to partner with our survivorship clinic thereby ensuring that patients may facilitate their options. Patients were asked to complete a questionnaire titled Ovarian Cancer or Borderline Malignancy of the Ovary: Fertility Sparing Survey and a previously published instrument termed The Sexual Activity Questionnaire, a 21-item scale that assessed the impact of treatment on sexual functioning. All participants completed the survey illustrating the feasibility of the study. The study revealed that the majority of patients (91%) discussed fertility options with their clinicians, yet only 16% engaged in measures to preserve fertility. Patient's sexual interest and activity was maintained in this cohort of patients. This underscores the importance of continued studies in this unique population to ensure optimal fertility counseling and to better delineate the sexual well-being of young women diagnosed with ovarian neoplasms.

Objective. To establish short-term surgical outcomes of three-port laparoscopic risk-reducing salpingo-oophorectomy (RRSO) in women with hereditary breast-ovarian cancer syndrome (HBOC). Methods. The medical records of all HBOC women that underwent laparoscopic RRSO between January 2001 and December 2010 were retrospectively reviewed. Demographic data, operative details, and short-term surgical outcomes were obtained and subjected to SAS. Statistical univariate and multivariate analyses were performed. Results. 358 patients met study criteria with 277 (77.4%) carrying a documented BRCA mutation. The predominant technique utilized three ports (two 5 mm and one 10/12 mm), a 5 mm laparoscope and a 5 mm Ligasure pulsatile bipolar device. Mean operative time was 58.3 minutes (SD 22.6, 26.0–197.0), significantly affected by BMI greater than 30 (P<0.0001) and status of adhesions (P=0.001). Estimated blood loss (EBL) was negligible in 96.9% of cases. Seven patients required conversion to laparotomy. No major intraoperative complications were recorded. One-night hospital admission rate was less than 2.0% while postoperative complication rate was 3.1%. Malignancy was revealed in 14 patients (3.9%). Conclusion. In HBOC population, three-port laparoscopic RRSO is a simple, reproducible, and safe procedure with low conversion rate, short operative time, minimal EBL, low surgical morbidity, and rapid postoperative recovery.

The objective of our study was to compare clinical and pathologic outcomes of robot-assisted and open abdominal techniques for treatment of uterine cancer in obese patients. Institutional review board approval was obtained. Patient demographic data, pathological data, and surgical data were collected by retrospective chart review. Data were analyzed using SAS statistical software. One-hundred and eighty-nine consecutive cases of suspected uterine cancer were identified from October 2003 until January 2009. Of these, 116 patients (61%) had a body mass index (BMI) over 30. There were 66 completed robot-assisted hysterectomies (RAHs), 43 total abdominal hysterectomies (TAHs), and seven patients that were converted from RAH to open abdominal hysterectomy. There were no significant differences in preoperative patient demographics, including body mass index (BMI), medical co-morbidities, or preoperative cytology, except for parity. There were no differences in postoperative grade, stage, lymph vascular space invasion, positive pelvic washings, mean number of pelvic lymph nodes, or proportion of patients undergoing pelvic lymphadenectomy. Length of stay and estimated blood loss were lower for the robotic technique; RAHs had a significantly longer operative time, however. Postoperative blood transfusions and wound infections were more frequent in the TAH group. Of the RAH group there were seven conversions to TAH (10%). Differences in surgical times with and without lymphadenectomy were least in patients in the largest BMI category of >50. Length of time required for RAH was significantly longer then TAH in obese and morbidly obese patients, however benefits to patients of a minimally invasive approach included reduced incidence of wound infections, reduced transfusion rates, reduced blood loss, and shortened length of stay. These data also suggest the greatest advantage of robotic technology over laparotomy in patients with BMI over 50.

Disseminated peritoneal leiomyomatosis (DPL) is a rare condition characterized by scattered smooth muscle nodules over the peritoneal surfaces. The pathogenesis of DPL remains unclear. Herein, we report a case of DPL occurring 7 years after laparoscopic supracervical hysterectomy with morcellation for uterine leiomyomata (UL). We analyzed both the original UL and the subsequent DPL by molecular cytogenetics to assess the role of chromosomal abnormalities in DPL pathobiology. Interestingly, all of the chromosomal aberrations detected in this case of DPL, including r(1)(p34.3q41), del(3)(q23q26.33), and t(12;14)(q14.3;q24.1), are characteristic chromosomal abnormalities detected in UL. Fluorescence in situ hybridization analysis of the initial UL confirmed an interstitial deletion spanning at least 3q24 and 3q25.1, suggesting that functional alteration of a potential gene in this chromosomal region may play a role in DPL development from UL. With the increasing rate of hysterectomy through laparoscopic approach to UL, the unique complications of laparoscopy with morcellation, especially seeding and proliferation of tumor cells over abdominal organs and peritoneum, are becoming more significant and may necessitate review of current surgical protocols to prevent future seeding of the pelvic region with tumor particles.

Recent reports have described 'vascular pseudoinvasion' in total laparoscopic hysterectomies with endometrial carcinoma. To better understand this phenomenon, we compared pathologic findings in these laparoscopic and total abdominal hysterectomies performed for uterine endometrioid adenocarcinoma. Reports from 58 robotically assisted laparoscopic and 39 abdominal hysterectomies with grade 1 or 2 endometrioid endometrial adenocarcinomas were reviewed for stage, depth of invasion, vascular space involvement, uterine weight, and lymph node metastases. In addition, attention was given to possible procedural artifacts, including vertical endomyometrial clefts, and inflammatory debris, benign endometrial glands, and disaggregated tumor cells in vascular spaces. All foci with vascular involvement were reviewed by three gynecologic pathologists. Nine of the 58 (16%) laparoscopic and 3 of the 39 (7%) abdominal hysterectomies contained vascular space involvement based on the original pathology reports (P-value=0.0833). No one histologic feature consistently distinguished laparoscopic from abdominal cases on blind review of the available cases. Disaggregated intravascular tumor cells were significantly associated with reported vascular involvement in both procedures (P-values

Objective This study identified risk factors for ovarian granulosa cell tumors (GCT) through a case-control study comparing women with GCT to women with epithelial ovarian cancers (OC) and general population (GP) controls. Methods Women with GCT and OC were identified from our hospital tumor board and the Massachusetts and New Hampshire Statewide Cancer Registries between January, 1988 and November, 2008. Age, gender and county matched GP controls were identified through town books in Massachusetts and drivers' license lists in New Hampshire. Epidemiologic factors including age, race, obesity, pregnancy history, smoking, and family history were evaluated. Odds ratio (OR) was calculated and adjusted for race and age. Results Seventy-two women with GCT, 1578 GP controls, and 1511 OC controls were identified. Patients with GCT were significantly more likely to be non-white (OR 8.49; 4.07, 17.7), obese with a BMI >30 (OR 5.80; 3.01, 11.2), and have a family history of breast (OR 2.13; 1.19, 3.80) or ovarian cancer (OR 2.89; 1.08, 7.72) than GP controls. The risk of developing GCT was significantly decreased in women who smoked (OR 0.46; 0.27, 0.78), used oral contraceptive pills (OR 0.32; 0.17, 0.63) or were parous with 1–2 (OR 0.30; 0.16–0.56) or greater than 2 births (OR 0.50; 0.27, 0.94) when compared to GP controls. Conclusion These findings suggest an independent association between non-white race and obesity as a hyperestrogenic state in the development of GCT while parity and OCP use may be protective. An unknown familial predisposition for GCT may exist.

Many ovarian carcinomas are presumed to arise within ovarian cortical inclusion cysts (CICs). This study examined the frequency of ovarian CICs in relation to epidemiologic risk factors in women with BRCA1 and BRCA2 (BRCA+) mutations.BRCA+ women who underwent risk-reducing bilateral salpingo-oophorectomy were studied (n=74). Fifteen demographic variables (e.g., age at time of surgery, age at first birth, age at menopause, body mass index (BMI), gravidity) from a review of the medical records and three pathologic variables (cystic and atretic follicles, corpora lutea) were recorded. Statistical associations were made using T-test or Chi Square analysis and logistic regression analysis for p-trend.Women whose ovaries contained 7 for more CICs were older at first birth (p=0.034), surgery (p=0.059), menopause (p=0.046) and had a higher BMI (p=0.034) than those with7 CICs. Regression analysis revealed a significant association between CICs and increasing BMI (p=0.01).CICs correlate with greater body mass index, similar to low-grade serous and endometrioid tumors and in contrast to high-grade serous carcinoma and its putative precursor in the fallopian tube. A model is presented for ovarian and tubal pathways to pelvic cancer that are linked to different microscopic precursors with distinct epidemiologic correlates.

To compare the short-term surgical outcome of patients undergoing robotic radical hysterectomy (RRH) versus open radical hysterectomy (ORH) for the treatment of early stage cervical cancer.IRB approval was obtained for a retrospective chart review of all radical hysterectomies (RHs) for Stage I and II cervical cancer performed at Brigham and Women's Hospital between August 1, 2004 and August 1, 2007. Prior to August 1, 2006 all procedures were ORHs. After this date, all procedures were RRHs. Demographic data, operative data and short-term outcomes were compared. Statistical analysis using t-tests and Fisher's Exact test were performed with SAS software.A total of 48 RHs were identified, including 16 RRHs and 32 ORHs. The groups did not differ significantly in age, body mass index, stage, or histology. Mean operative time was significantly longer for RRH than ORH (4:50 vs 3:39 h, p=0.0002). The mean estimated blood loss was significantly less for RRH than ORH (81.9 vs 665.6 mL, p0.0001). The mean number of lymph nodes resected did not differ between RRHs and ORHs (15.6 vs 17.1, p=0.532). There were no intra-operative complications in the RRH group and one ureteral transection in the ORH group. Three RRH patients (18.8%) suffered post-operative complications which included a vaginal cuff infected hematoma, a transient ureterovaginal fistula, and a pelvic lymphocele, in comparison to seven in the ORH group (21.9%) which included 3 wound infections, two patients with pulmonary emboli, a partial small bowel obstruction with a mesenteric abscess, and a post-operative ileus (p=0.999). Mean length of stay was significantly shorter for the RRH group (1.7 vs. 4.9 days, p0.0001).RRH results in lower blood loss and shorter length of stay, compared to ORH. Intra-operative and post-operative complication rates are comparable. RRH is a promising new surgical technique that deserves further study.

Pelvic (ovarian) serous carcinomas frequently contain p53 mutations. Recently, a candidate serous cancer precursor (the p53 signature) with p53 mutations and other features in common with serous cancer has been discovered in distal fallopian tube mucosa. This study examined the relationship of putative ovarian cancer risk factors with the presence of p53 signatures in women with BRCA mutations (BRCA+).Fallopian tubes from 75 BRCA+ women were immunostained for p53 signatures and correlated with age at first childbirth, parity, oral contraceptive use, body mass index (BMI), and BRCA subtype (1 or 2). Statistical analysis was performed with the T-test or Chi-square analysis and logistic regression adjusting for age and parity.Thirty-eight percent of the tubes contained p53 signatures, which were significantly associated with older age at first childbirth (mean 30.8 vs. 28.4 years; p=0.04) and lower parity (mean 1.4 vs. 2.2; p=0.01) in univariate analyses. The unadjusted odds ratios were 3.8 (p-trend=0.04) for first childbirth/=30 years versus30 and 0.2 (p-trend=0.01) for parity/= 3 versus nulliparous women. After adjusting for age and parity, the trend for age at first childbirth became non-significant (adjusted odds ratio 3.5; p-trend=0.15), while that for parity remained significant (adjusted odds ratio 0.2; p-trend 0.02).The p53 signature is significantly associated with lower parity and possibly higher age at first childbirth, further linking this entity to serous cancer via risk factors associated with ovulation. The p53 signature merits consideration as a surrogate marker for serous cancer risk.

Purpose A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women. Patients and Methods Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review. Result Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up. Conclusion The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.

Background. Vulvar synovial cell sarcomas are rare, with only four previously published cases in the literature. Traditionally, the primary management for these tumors has been surgery alone. Case. We report a case of a large vulvar synovial cell sarcoma in a 50-year-old woman treated with comprehensive combined multimodality management, including preoperative intensity-modulated radiation therapy, radical hemivulvectomy, flap reconstruction, interstitial low-dose-rate brachytherapy boost, and adjuvant chemotherapy. Conclusion. Based on this case and the limited data in the literature, multimodality treatment of advanced soft tissue sarcoma of the vulva may optimize local control and minimize toxicity while preserving sexual function.

Objective: Lower extremity lymphedema adversely affects quality of life by causing discomfort, impaired mobility and increased risk of infection. The goal of this study is to investigate factors that influence the likelihood of lymphedema in patients with endometrial cancer who undergo adjuvant radiation with or without chemotherapy. Methods: A retrospective chart review identified all stage I–III endometrial cancer patients who had a hysterectomy with or without complete staging lymphadenectomy and adjuvant radiation therapy between January 2006 and February 2013. Patients with new-onset lymphedema after treatment were identified. Logistic regression was used to find factors that influenced lymphedema risk. Results: Of 212 patients who met inclusion criteria, 15 patients (7.1%) developed new-onset lymphedema. Lymphedema was associated with lymph-node dissection (odds ratio [OR], 5.6; 95% CI, 1.01 to 105.5; p=0.048) and with the presence of pathologically positive lymph nodes (OR, 4.1; 95% CI, 1.4 to 12.3; p=0.01). Multivariate logistic regression confirmed the association with lymph-node positivity (OR, 3.2; 95% CI, 1.0007 to 10.7; p=0.0499) when controlled for lymph-node dissection. Median time to lymphedema onset was 8 months (range, 1 to 58 months) with resolution or improvement in eight patients (53.3%) after a median of 10 months. Conclusion: Lymph-node positivity was associated with an increased risk of lymphedema in endometrial cancer patients who received adjuvant radiation. Future studies are needed to explore whether node-positive patients may benefit from early lymphedema-controlling interventions.

To determine factors that can identify a population at increased risk for uterine leiomyosarcoma.Retrospective case-control study (Canadian Task Force classification II-2).University teaching hospitals.Seventy-two women who underwent minimally invasive gynecologic surgery for presumed leiomyoma. Patients diagnosed with leiomyosarcoma (cases) were matched with up to 4 controls on age, year of surgery, and surgeon specialty.Cases were identified through the pathology database, and the diagnosis of leiomyosarcoma or leiomyoma was confirmed by gynecologic pathologists. The cumulative risk of leiomyosarcoma was calculated, and factors predictive of elevated risk for leiomyosarcoma were investigated using conditional logistic regression.Fifteen patients with the diagnosis of inadvertently morcellated leiomyosarcoma were identified and matched with 57 controls. The cumulative risk of diagnosing uterine leiomyosarcoma on pathology after performing minimally invasive gynecologic surgery with morcellation was 0.19% (95% confidence interval [CI], 0.06%-0.56%). The presence of a hematocrit value 30% (adjusted odds ratio [aOR], 20; 95% CI, 1.08-100; p = .05) was independently associated with the diagnosis of uterine leiomyosarcoma on multivariate analysis. Increased myoma size (aOR, 9.73; 95% CI, 0.75-1.26; p = .08) and presence of a solitary myoma (aOR, 3.85; 95% CI, 0.65-25; p = .14) were associated with a greater risk of uterine leiomyosarcoma; however, the difference was not statistically significant.Anemia and myoma size7 cm may be associated with occult leiomyosarcoma; however, these criteria are not sufficiently discriminatory to allow for preoperative identification of patients with uterine sarcoma. Future large multicenter studies are needed to further investigate these findings and the discovery of innovative ways to detect uterine leiomyosarcoma are urgently needed.

A 45-year-old woman noted a mass in her lower abdomen that was intermittently painful. An examination disclosed a slightly tender mass, 4 cm in diameter, on the right side of the lower abdomen. Imaging studies showed a solid mass in the right lower abdominal wall. A diagnostic procedure was performed.

Unlike many other human solid tumors, ovarian tumors express many epithelial markers at a high level for cell growth and local invasion. The phosphoprotein Pinin plays a key role in epithelial cell identity. We showed that clinical ovarian tumors and ovarian cancer cell lines express a high level of Pinin when compared with normal ovarian tissues and immortalized normal ovarian surface epithelial cell lines. Pinin co-localized and physically interacted with transcriptional corepressor C-terminal binding proteins, CtBP1 and CtBP2, in the nuclei of cancer cells. Knockdown of Pinin in ovarian cancer cells resulted in specific reduction of CtBP1 protein expression, cell adhesion, anchorage-independent growth, and increased drug sensitivity. Whole transcriptomic comparison of next-generation RNA sequencing data between control ovarian cancer cell lines and cancer cell lines with respective knockdown of Pinin, CtBP1, and CtBP2 expression also showed reduced expression of CtBP1 mRNA in the Pinin knockdown cell lines. The Pinin knockdown cell lines shared significant overlap of differentially expressed genes and RNA splicing aberrations with CtBP1 knockdown and in a lesser degree with CtBP2 knockdown cancer cells. Hence, Pinin and CtBP are oncotargets that closely interact with each other to regulate transcription and pre-mRNA alternative splicing and promote cell adhesion and other epithelial characteristics of ovarian cancer cells.

Objective To evaluate whether the presence of mucinous differentiation influences histopathologic findings, stage distribution, or rate of recurrence among women with grade 1, endometrioid type, endometrial carcinoma. Methods This was a retrospective cohort study of all patients with grade 1, endometrioid type, endometrial carcinoma between January 2005 and December 2012. Patients were separated by the presence or absence of mucinous differentiation and then compared. Results Of 655 patients, mucinous differentiation was present in 137 (20.9%) and absent in 518 (79.1%) patients. Compared to the group without mucinous differentiation, the group containing mucinous differentiation was older at diagnosis (mean: 61.1 vs. 58.5years, OR, 95% CI; 1.03, 1.01–1.05) and more likely to have myometrial invasion (61.3% vs. 51.5%, OR, 95% CI; 1.49, 1.01–2.19). Additional histopathologic findings including: tumor size, cervical stromal invasion, adnexal involvement, LVI and/or the presence of positive lymph nodes were similar between groups. Mucinous differentiation did not affect stage distribution, as most patients were stage 1A (85.4% vs. 86.3%). The median PFS for the entire group has yet to be reached. The mean PFS for the entire study sample was 94.7months. There was no difference in mean PFS when comparing the group with mucinous differentiation to the group without mucinous differentiation (98 vs. 93.4months, p =0.07). Conclusions In the setting of grade 1, endometrioid type, endometrial carcinoma, mucinous differentiation is more common in older patients and is associated with an increased likelihood of myometrial invasion. However, stage distribution and risk of recurrence are not affected.

BACKGROUND: Phytoestrogens are increasingly used by patients as “natural” alternatives to hormone replacement. Attention in scientific and lay literature has focused on their potential to prevent menopausal symptoms, bone loss, heart disease, or breast cancer. Less is known about effects on the endometrium, specifically, whether prolonged exposure to phytoestrogens could promote hyperplasia or neoplasia, as does unopposed estrogen. CASE: We report the case of a woman diagnosed with grade 1 endometrioid adenocarcinoma of the endometrium whose history was notable for extensive use of supplemental phytoestrogens. CONCLUSION: The effects of phytoestrogens on endometrial tissue are not known. Given their increasing popularity and availability in concentrated form as dietary supplements, additional research is warranted before we can counsel our patients regarding the safety of such supplements.

BACKGROUND Screening biomarkers for ovarian cancer are needed because of its late stage at diagnosis and poor survival. We used microarray technology to identify overexpressed genes for secretory proteins as potential serum biomarkers and selected prostasin, a serine protease normally secreted by the prostate gland, for further study. METHODS RNA was isolated and pooled from three ovarian cancer cell lines and from three normal human ovarian surface epithelial (HOSE) cell lines. Complementary DNA generated from these pools was hybridized to a microarray slide, and genes overexpressed in the cancer cells were identified. Real-time quantitative polymerase chain reaction was used to examine prostasin gene expression in ovarian cancer and HOSE cell lines. Anti-prostasin antibodies were used to examine prostasin expression and to measure serum prostasin by an enzyme-linked immunosorbent assay in 64 case patients with ovarian cancer and in 137 control subjects. Previously determined levels of CA 125, an ovarian cancer marker, were available from about 70% of all subjects. All statistical tests were two-sided. RESULTS Prostasin was detected by immunostaining more strongly in cancerous ovarian epithelial cells and stroma than in normal ovarian tissue. The mean level of serum prostasin was 13.7 microg/mL (95% confidence interval [CI] = 10.5 to 16.9 microg/mL) in 64 case patients with ovarian cancer and 7.5 microg/mL (95% CI = 6.6 to 8.3 microg/mL) in 137 control subjects (P

Background. Few studies have addressed in detail the genetic alterations that occur in vulvar squamous carcinomas (VSCC) and their precursor lesions. In a previous study, we determined the most common chromosomal loci for allelic imbalance (AI) in HPV-positive and -negative VSCCs. The present study was designed to determine whether AI and the microsatellite instability phenotype (MIN) were present in epithelial lesions known to be associated with VSCC. Design. Fifty-seven epithelial loci were analyzed, including HPV-positive (classic) and -negative (differentiated) vulvar intraepithelial neoplasms (VINs), lichen sclerosus (LS), and nonatypical hyperplasias. Thirty-one epithelial loci (55%) were obtained from patients with associated invasive vulvar carcinoma. HPV status was determined by polymerase chain reaction analysis. AI and MIN were determined by comparisons of microdissected target tissues with stromal controls, targeting 11 chromosomal loci. Results. AI was identified in all epithelial categories, involving at least one chromosomal locus in 67, 53, 50, and 43% of classic VIN, differentiated VIN, hyperplasia, and LS. MIN was infrequent (10–13%), but confined to HPV-negative epithelial changes. HPV-positive lesions generally scored for AI more frequently, but certain loci scored nearly equally in both HPV-positive and -negative lesions, including 8p, 11q, and 17p. There were no differences in frequency of AI between epithelia with and without associated invasive carcinoma. Conclusions. The presence of allelic imbalance in vulvar hyperplasia and LS supports the hypothesis that these alterations are at greater risk for neoplasia despite the absence of conspicuous cellular atypia. A model is proposed in which these changes represent monoclonal expansion and are at empirically greater risk for subsequent "critical events" leading to morphologic atypia (VIN). The possibility that these early genetic changes influence both HPV-positive and -negative pathways merits further study.

Microsatellite instability is a frequent (13%-24%) finding in sporadic endometrial adenocarcinoma and its precursor lesions, but most studies are limited to patients who already have malignant or premalignant endometrial disease. We performed retrospective testing for microsatellite instability in women in whom cancers showing microsatellite instability developed later and prospective testing in randomly selected normal and anovular endometrial biopsy specimens. Microsatellite instability in cancer-bearing biopsy specimens accurately reflected that seen in matched malignant tissues obtained at hysterectomy. In 1 patient, microsatellite instability developed in a scanty sample of fragmented endometrial tissues 7 years before the onset of endometrial cancer. Prospective testing for microsatellite instability in the endometria of women unselected for subsequent appearance of endometrial cancer showed a very low rate of microsatellite instability. Only 1 endometrial specimen showing microsatellite instability was found among 75 anovulatory endometrial specimens, and none were found in 377 normal endometrial specimens and 46 polyps examined. Microsatellite instability may precede the onset of histologically diagnosed carcinoma but is rare in randomly sampled histologically normal endometrial tissues.

Objective. The ras genes are a well-studied family of proto-oncogenes whose involvement in many cancers has been delineated. However, K- ras mutations have not previously been examined in papillary serous carcinoma of the peritoneum (PSCP), a tumor which resembles serous epithelial ovarian carcinoma (SEOC) both in histology and epidemiology. In this study we examine the role of the K- ras oncogene in PSCP compared to SEOC. Methods. Using single-strand conformational polymorphism analysis and cycle sequencing protocols, we evaluated our collection of 51 cases of PSCP for K- ras mutations and compared these findings with the experience in SEOC. We then examined 5 cases of PSCP for activation of ras proteins and MAP kinase to evaluate the potential involvement of the ras pathway in PSCP tumorigenesis. Results. We found only one K- ras mutation in our 51 cases (2%) of PSCP compared to three mutations in 46 cases (6.5%) of high-grade, late-stage SEOC. This was not significantly different ( P > 0.10). In the single PSCP case with a K- ras mutation, the mutation was found in only one of five tumor sites tested. All four mutations involved a single nucleotide alteration in codon 12 (GGT to GTT, Gly to Val). To evaluate the ras pathway in PSCP, we used the known activated ras binding domain on Raf-1 to perform an assay to test for activated ras. We identified ras activation in 4 of 5 PSCP cases tested and, to confirm that the activation was functional, we tested and found similar activation of MAP kinase, a downstream mediator for K- ras expression. Conclusions. K- ras mutations occur at low rates in both PSCP and high-grade, late-stage SEOC, and therefore K- ras mutations are not involved in the development of these two diseases. Finding the mutation in only one of multiple tumor sites in the PSCP case supports growing evidence for a multifocal origin of PSCP. Our findings of ras activation in four of five cases of PSCP suggest that ras activation by mechanisms other than genetic mutation is important for PSCP tumorigenesis.

A client's emotional experiences and reactions to those experiences are influenced by his/her family of origin and direct or indirect interactions with various family members. Contextual therapists propose that a client's satisfaction with a relationship depends on the equity of his/her emotional interactions with family members. When relationships are inequitable, trust between individuals disintegrates. In order to reestablish trust in a relationship, a balance of interests must be restored. If not, imbalances may be passed down to future generations. A case of a woman with a family history of ovarian cancer is reviewed with the principles of contextual therapy in mind. In her family, several legacies have resulted in unbalanced relationships between family members that lead to difficulty in establishing trust within the genetic counseling session.

Objective: To compare BRCA1 mutations in papillary serous carcinoma of the peritoneum and papillary serous ovarian carcinoma. Methods: Germline DNA from 17 consecutive patients with peritoneal carcinoma was screened for mutations in the BRCA1 gene using single-strand conformation polymorphism analysis. Shifted DNA bands were sequenced. Patients with germline BRCA1 mutations were screened for allelic loss in tumor DNA at the BRCA1 locus. Results: Two of the 17 patients (11%, 95% confidence interval 0.07, 0.37) exhibited the 185 delAG germline BRCA1 mutation described in the Ashkenazi Jewish population. The family history of one patient was notable for a mother and five aunts with breast or ovarian cancer. The other patient had a personal history of breast cancer. Both patients exhibited allelic loss of the normal BRCA1 allele in their tumor. A third patient was found to have a previously undescribed exon 11 single base pair substitution at nucleotide 1239 (CAG to CAC) resulting in a missense mutation (Gln to His). The patient had no family or personal history of breast or ovarian cancer, and her tumor did not exhibit loss of heterozygosity. Conclusion: Germline BRCA1 mutations occur in papillary serous carcinoma of the peritoneum with a frequency comparable to the BRCA1 mutation rate in ovarian cancer. Although the penetrance is unknown, peritoneal carcinoma should be considered a malignancy expressed in the familial breast ovarian cancer syndrome.

Background Papillary serous carcinoma of the peritoneum (PSCP) diffusely involves peritoneal surfaces, while it spares or only superficially involves the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. The molecular pathogenesis of PSCP remains unresolved, although preliminary data suggest a multifocal origin in some cases. Patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. The purpose of this study was to utilize the androgen receptor (AR) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP. Methods Specimens of normal and tumor tissues from 22 women with PSCP were obtained, and DNA was extracted. The AR gene locus was evaluated for patterns of loss of heterozygosity (LOH) and X-chromosome inactivation. The methylation-sensitive Hpa II restriction enzyme was used to differentiate the active and inactive X chromosomes. Germline BRCA1 mutation status of the patients was determined previously. Results Genetic analysis of tumor specimens indicated that five (23%) of 22 case subjects had patterns of selective LOH at the AR locus, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease (two-sided Fisher's exact test, P = .01). Conclusions Our results show that PSCP has a multifocal origin in at least some cases. Furthermore, patients with germline BRCA1 mutations are more likely to develop multifocal PSCP than are patients without BRCA1 mutations.

BACKGROUND Ifosfamide and paclitaxel are antineoplastic agents with broad activity and with different mechanisms of action. A Phase I trial was conducted to determine the maximum tolerated dose and associated toxicities of these agents when used in combination. METHODS Patients with refractory, incurable solid tumors were entered on a 5-step Phase I trial of ifosfamide, given in doses of 2-3 g/m2 intravenous (i.v.) bolus for 3 days with mesna support, and paclitaxel, given in doses of 135-190 g/m2 i.v. by continuous infusion over 24 hours. Paclitaxel was given after the first dose of ifosfamide on Day 1. RESULTS Twenty-three patients were treated, and the maximum tolerated dose was the highest planned dose level of the trial: ifosfamide, 3 g/m2/day i.v. for 3 days, and paclitaxel, 190 mg/m2 i.v. over 24 hours. Hematologic toxicity was not dose-limiting, and although neutropenia occurred, it was brief (median, 2-4 days) and resulted in hospitalization for neutropenia and fever in only 7 of 111 courses of therapy. For patients treated at the highest dose level, only 1 of 50 courses of therapy resulted in hospitalization for neutropenia and fever. Nonhematologic toxicity also was not severe and no significant neuropathy occurred. Although patients entered into the study were heavily pretreated, responses were observed, particularly in patients with breast or ovarian carcinoma. CONCLUSIONS Ifosfamide and paclitaxel can be administered safely in the doses used in this study and there are indications of significant antitumor effect. Further studies are necessary to explore the antineoplastic activity of this regimen, particularly for patients with breast and ovarian carcinoma. Cancer 1998;82:561-6. © 1998 American Cancer Society.

Objective This study computed the risk of clinically silent adnexal neoplasia in women with germ-line BRCA1 or BRCA2 mutations (BRCA m+ ) and determined recurrence risk. Methods We analyzed risk reduction salpingo-oophorectomies (RRSOs) from 349 BRCA m+ women processed by the SEE-FIM protocol and addressed recurrence rates for 29 neoplasms from three institutions. Results Nineteen neoplasms (5.4%) were identified at one institution, 9.2% of BRCA1 and 3.4% of BRCA2 mutation-positive women. Fourteen had a high-grade tubal intraepithelial neoplasm (HGTIN, 74%). Mean age (54.4) was higher than the BRCA m+ cohort without neoplasia (47.8) and frequency increased with age ( p m+ patients with neoplasia from three institutions were followed for a median of 5years (1–8years.). One of 11 with HGTIN alone (9%) recurred at 4years, in contrast to 3 of 18 with invasion or involvement of other sites (16.7%). All but two are currently alive. Among the 29 patients in the three institution cohort, mean ages for HGTIN and advanced disease were 49.2 and 57.7 ( p =0.027). Conclusions Adnexal neoplasia is present in 5–6% of RRSOs, is more common in women with BRCA1 mutations, and recurs in 9% of women with HGTIN alone. The lag in time from diagnosis of the HGTIN to pelvic recurrence (4years) and differences in mean age between HGTIN and advanced disease (8.5years) suggest an interval of several years from the onset of HGTIN until pelvic cancer develops. However, some neoplasms occur in the absence of HGTIN.

Objective To describe the role of immediate re-exploration in patients with inadvertently morcellated uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP). Methods All patients with ULMS/STUMP who were managed or referred to the participating institutions from January 2005 to January 2012 following minimally invasive gynecology surgery with morcellation were detected through the pathology database. The diagnosis was confirmed by gynecologic-pathologists following post-surgery pathology review. Results Twenty-one patients with the diagnosis of ULMS (N=15) and STUMP (N=6) after morcellation were identified. The median age of occurrence was 46years (range, 25–58years). Median follow-up duration was 27months (range, 1.8–93.1months). None of the 21 patients had documented evidence of extra-uterine disease at the time of original surgery. Ultimately 12 patients were immediately re-explored to complete staging. The median time to the staging surgery was 33days (range 15–118days). Two (28.5%) out of seven patients with presumed stage I ULMS and one (25%) out of four patients with presumed stage I STUMP had significant findings of disseminated intraperitoneal disease detected at immediate surgical re-exploration. One of the 8 patients with confined early ULMS and STUMP at the second surgery had intraperitoneal recurrence, while the remaining 7 patients have had no recurrence and remain disease free. Conclusion Surgical re-exploration is likely to show findings of disseminated peritoneal sarcomatosis in a significant number of patients diagnosed with ULMS after a morcellation procedure. Findings from re-exploration can contribute to the knowledge of natural history of morcellated ULMS/STUMP and allow for accurate prognostication.

We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers.We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers.We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P0.001).As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

Conventional therapy for epithelial ovarian cancer, including aggressive cytoreductive surgery followed by combination chemotherapy regimens, has failed to reduce the number of deaths caused by this disease, which remains the most lethal of gynecologic malignancies. Monoclonal antibodies, which offer the promise of high selectivity for detection and therapy, may be targeted to tumor-associated antigens, growth factors, receptors, or oncogenes. They may be used alone as immunotherapeutic agents or conjugated to chemotherapeutic drugs, toxins, or radionuclides. Radioimmunoconjugates may also be used for preoperative or intraoperative tumor localization. The authors focused on the clinical utility, technical limitations, and potential of monoclonal antibodies in the detection and treatment of epithelial ovarian cancer with emphasis on radioimmunodetection and radioimmunotherapy.