A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.

BACKGROUND: Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. METHODS: We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). RESULTS: Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n=5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p<0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. CONCLUSION: Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

Prognostic determinants in patients with uterine and ovarian clear cell carcinoma: a SEER analysis.

INTRODUCTION: The purpose of this study is to analyze and compare the demographics, treatment, and survival rates in patients with uterine clear cell carcinoma (UCCC) and ovarian clear cell carcinoma (OCCC). METHODS: The Surveillance, Epidemiology and End Results (SEER) program data for all 18 registries from 1988 to 2010 was reviewed to identify women with OCCC and UCCC. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS: The final study group consisted of 5421 women with clear cell histopathology. 3631 (67%) had OCCC and 1790 (33%) had UCCC. The mean age at diagnosis was 56 (± 12) years for women with OCCC and 67.7 (± 12.0) years for UCCC (P<0.001). Patients with OCCC had a higher rate of late stage disease (38.9% vs. 21.2%; P<0.001). Over the entire study period, after adjusting for known variables, there was no significant difference in cancer specific mortality between UCCC and OCCC, HR 1.05 (0.92-1.19). In the subset analysis by staging, in women with localized disease there was an improved survival in UCCC compared to OCCC. In contrast, in women with distant disease there was an increased mortality in women with UCCC. CONCLUSION: In the entire population, there was no significant difference in cancer related mortality between the groups. However, in women with localized disease, UCCC had improved survival, but increased mortality in distant disease compared to OCCC.

Carcinosarcoma of the ovary compared to papillary serous ovarian carcinoma: a SEER analysis.

OBJECTIVE: The aims of this study are to determine if outcomes of patients with ovarian carcinosarcoma (OCS) differ from women with high grade papillary serous ovarian carcinoma when compared by stage as well as to identify any associated clinico-pathologic factors. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program data for all 18 registries from 1998 to 2009 was reviewed to identify women with OCS and high grade papillary serous carcinoma of the ovary. Demographic and clinical data were compared, and the impact of tumor histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazard model. RESULTS: The final study group consisted of 14,753 women. 1334 (9.04%) had OCS and 13,419 (90.96%) had high grade papillary serous carcinoma of the ovary. Overall, women with OCS had a worse five-year, disease specific survival rate, 28.2% vs. 38.4% (P<0.001). This difference persisted for each FIGO disease stages I-IV, with five year survival consistently worse for women with OCS compared with papillary serous carcinoma. Over the entire study period, after adjusting for histology, age, period of diagnosis, SEER registry, marital status, stage, surgery, radiotherapy, lymph node dissection, and history of secondary malignancy after the diagnosis of ovarian cancer, carcinosarcoma histology was associated with decreased cancer-specific survival. CONCLUSIONS: OCS is associated with a poor prognosis compared to high grade papillary serous carcinoma of the ovary. This difference was noted across all FIGO stages.

Primary debulking surgery versus neoadjuvant chemotherapy in stage IV ovarian cancer.

PURPOSE: Primary debulking surgery (PDS) has historically been the standard treatment for advanced ovarian cancer. Recent data appear to support a paradigm shift toward neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS). We hypothesized that stage IV ovarian cancer patients would likely benefit from NACT-IDS by achieving similar outcomes with less morbidity. METHODS: Patients with stage IV epithelial ovarian cancer who underwent primary treatment between January 1, 1995 and December 31, 2007, were identified. Data were retrospectively extracted. Each patient record was evaluated to subclassify stage IV disease according to the sites of tumor dissemination at the time of diagnosis. The Kaplan-Meier method was used to compare overall survival (OS) data. RESULTS: A total of 242 newly diagnosed stage IV epithelial ovarian cancer patients were included in the final analysis; 176 women (73%) underwent PDS, 45 (18%) NACT-IDS, and 21 (9%) chemotherapy only. The frequency of achieving complete resection to no residual disease was significantly higher in patients with NACT-IDS versus PDS (27% vs. 7.5%; P < 0.001). When compared to women treated with NACT-IDS, women with PDS had longer admissions (12 vs. 8 days; P = 0.01), more frequent intensive care unit admissions (12% vs. 0%; P = 0.01), and a trend toward a higher rate of postoperative complications (27% vs. 15%; P = 0.08). The patients who received only chemotherapy had a median OS of 23 months, compared to 33 months in the NACT-IDS group and 29 months in the PDS group (P = 0.1). CONCLUSIONS: NACT-IDS for stage IV ovarian cancer resulted in higher rates of complete resection to no residual disease, less morbidity, and equivalent OS compared to PDS.

Prognostic determinants in patients with uterine and ovarian clear carcinoma.

OBJECTIVE: The purpose of this study is to analyze and compare the demographics, treatment, recurrence, and survival rates in patients with uterine clear cell carcinoma (UCCC) and ovarian clear cell carcinoma (OCCC). METHODS: A retrospective review of the Cancer Registry database was performed. All patients with UCCC and OCCC who underwent surgical staging at the two participating institutions, between January, 1995 and December, 2007, were identified. Categorical variables were evaluated by Chi square test. Survival estimates were plotted utilizing the Kaplan-Meier method. RESULTS: Analysis of 41 women with UCCC and 121 with OCCC was performed. In patients with OCCC, 48.4% had localized disease, 18.9% had regional spread, 31.1% had distant metastasis, and in 1.6% spread is unknown; compared to UCCC, 41.5% had localized disease, 12.2% regional spread, and 46.3% distant metastasis (p=0.2). The median progression free survival was 31.4 months in women with UCCC, compared to 145 months in patients with OCCC (p=0.04). UCCC women had a median overall survival of 39.5 months, compared to 155.8 months in patients with OCCC (p=0.002). In the multivariate Cox regression model, age>55 years old, tumor extension, optimal cytoreduction, and platinum-based chemotherapy were identified as independent predictors of overall survival. UCCC vs. OCCC was not associated with decreased overall survival in multivariate analysis. CONCLUSION: OCCC and UCCC have the same rate of localized disease, regional spread and distant metastasis. After controlling for age, tumor extension, optimal cytoreduction, and platinum based chemotherapy, UCCC was not associated with decreased overall survival compared to OCCC.

Carcinosarcoma of the ovary: a case-control study.

INTRODUCTION: Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. Chemotherapy for these tumors is chosen according to guidelines established for epithelial ovarian cancer (EOC). The purpose of this study is to compare response to chemotherapy and survival in patients with advanced stage carcinosarcoma of the ovary. METHODS: We identified women with advanced carcinosarcoma of the ovary who underwent first-line platinum and taxane-based chemotherapy. Each case was matched to two women with serous EOC. Cases and controls were matched by age, stage, and year of diagnosis. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS: Fifty women treated with first line platinum and taxane-based chemotherapy had advanced carcinosarcoma of the ovary and were selected as cases. The response rates to chemotherapy for cases and controls were 62% and 83% (P=0.03), respectively. Median progression-free survival was 11 months (95% CI, 8 to 14 months) versus 16 months (95% CI, 12 to 21 months; P=0.02) and median overall survival was 24 months (95% CI, 18 to 29 months) versus 41 months (95% CI, 33 to 49 months; P=0.002) for cases and controls, respectively. CONCLUSION: Patients with advanced carcinosarcoma of the ovary have a poorer response to platinum and taxane-based first-line chemotherapy and worse survival, compared to patients with serous EOC. Aggressive surgical treatment may play an important role. However, other alternative systemic therapeutic approaches should be sought for patients with carcinosarcoma of the ovary.

Prognostic determinants in patients with stage IIIC and IV uterine papillary serous carcinoma.

OBJECTIVE: The aim of this study was to evaluate the survival impact of cytoreductive surgery and other prognostic determinants in patients with stage IIIC and IV uterine papillary serous carcinoma (UPSC). METHODS: All patients with FIGO stage IIIC and IV UPSC who underwent surgical staging at the two participating institutions, between January 1, 1995 and December 31, 2007, were identified from the tumor registry database. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox regression analysis. RESULTS: Analysis of 79 patients with stage IIIC-IV disease was performed. Optimal cytoreduction was associated with a median survival of 36 months, compared with 12 months for patients who underwent a suboptimal surgical effort (p=0.001), and a disease-free survival (DFS) of 21 months vs. 10 months (p=0.001), respectively. Regression analysis identified stage (HR=2.4, p=0.03), absence of visible residual disease (HR=0.5, p=0.03), and chemotherapy (HR=0.1, p<0.001) as independent predictors of OS. CONCLUSIONS: Cytoreduction to no gross residual disease and the use of platinum therapy are associated with a significant survival benefit for patients with stage IIIC-IV UPSC. Recommended management for this group of patients should consist of maximal surgical cytoreduction followed by platinum-based chemotherapy, preferably in combination with paclitaxel. Adjuvant radiation therapy should also be considered.

Impact of bowel obstruction at the time of initial presentation in women with ovarian cancer.

OBJECTIVE: To determine whether the presence of bowel obstruction at the time of initial presentation has any prognostic significance in these women. DESIGN: Retrospective cohort study. SETTING: Dedicated gynaecological oncology service of a large tertiary institution. POPULATION: Women who had a bowel obstruction as part of their initial presentation of ovarian cancer were identified between 1995 and 2007. Each woman was matched with four control women (with disease but no obstruction). METHODS: Women with disease were compared with controls to determine the impact, if any, of bowel obstruction at presentation. Several prognostic variables including bowel obstruction were also evaluated in a Cox proportional hazard model. MAIN OUTCOME MEASURES: Progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-eight women with disease and 192 controls were identified during the study period. The median follow-up period was 19 months among women with disease versus 20 months in controls. No differences were seen in demographics and clinical characteristics of the women. Optimal cytoreduction rate was similar between the two groups (75% versus 78%, P = 0.7). Patients with bowel obstruction had a shorter PFS and OS compared with controls [19 months versus 21 months (P = 0.01) and 22 versus 35 months (P = 0.008)], respectively. Bowel obstruction at presentation was an independent prognostic variable with a hazard ratio of 1.5 (P = 0.009). Other prognostic variables were age, stage and extent of surgical cytoreduction. CONCLUSIONS: Bowel obstruction at the time of initial presentation is an adverse prognostic factor in women with ovarian cancer.

A challenging case of twin pregnancy with complete hydatidiform mole and co-existing normal live fetus - A case report and review of the literature.

Hydatidiform mole coexisting with a normal live fetus in a twin pregnancy is extremely rare. Management of these cases is challenging due to the risk of severe antepartum and post-partum complications. Herein, we report the case of a 24-year-old gravida 2 para 1 who presented at 28 weeks gestation with severe preeclampsia, vulvar edema and a serum ß-HCG of 285,000 IU/mL. Ultrasonography demonstrated a single live intra-uterine pregnancy with concurrent hydatidiform mole. Conservative management with magnesium sulfate and anti-hypertensive medications was initiated however the patient developed HELLP syndrome and required urgent delivery at 33 weeks. Copious molar tissue was removed from the uterus during delivery. Four weeks post-partum, her ß-HCG had dropped to 14,000 IU/ml and continued to decline at 6 weeks (2900 IU/ml). However, at eight weeks, it increased to 3500 IU/ml and the patient was treated with nine cycles of intramuscular methotrexate. Current guidelines for management of a twin pregnancy with coexistent mole recommend close clinical monitoring if the mother and fetus are stable and urgent delivery in the setting of complications. During the postpartum period, careful follow up with clinical evaluation and serial serum ß-HCG is important for the diagnosis and treatment of persistent trophoblastic disease.

Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel.

In vitro work suggests that cytokines may be important modulators of the cytotoxic effects of paclitaxel and subsequent drug resistance. This has been investigated in vivo in patients with ovarian cancer by ELISA. There was consistently elevated expression of IL-6 and IL-8 but not MCP-1, IL-1beta, IL-2, GM-CSF or TNFalpha. Peritoneal fluid concentrations of IL-6, IL-8 and MCP-1 were two to three logs greater than serum concentrations. Elevated concentrations of IL-6 correlated with a poor final outcome (P = 0.039), and increased IL-6 and IL-8 correlated with a poor initial response to chemotherapy (P = 0.041 and P = 0.041, respectively). There was a relatively clear pattern of change in all three cytokines. In serum, IL-6, IL-8 and MCP-1 decreased with the administration of steroids prior to paclitaxel, and increased in the 24 h after paclitaxel. Postoperative drainage fluid was relatively acellular, preventing flow-cytometric analysis of epithelial cells for apoptosis, but suggested activation of T cells by paclitaxel. IL-6 and IL-8 appear to be of prognostic importance in epithelial ovarian cancer. Treatment with paclitaxel is associated with an increase in expression of a limited number of cytokines in patients with ovarian cancer, notably IL-6, IL-8 and MCP-1.

Potential exposure levels and health effects of neighborhood exposure to a municipal incinerator bottom ash landfill.

An investigation was conducted to assess the potential exposure levels and pursuant public health implications of neighborhood exposure to a municipal incinerator bottom ash landfill. This site received ash from a single incinerator without pollution control devices from 1954-1973. Soil was sampled for 10 heavy metals, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, 2,3,7,8-tetrachlorodioxin and furan congeners, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. Soil concentrations for these substances were converted to estimates of exposure, health effects, and/or cancer risk by the application of a general exposure model and exposure/effect and exposure/risk models for specific substances. The results of soil analysis and modeling indicate that the level of lead detected on the site was considerably above the recommended levels of the Centers for Disease Control (CDC) and may lead to an elevated blood lead level in exposed children above that currently defining a case of lead poisoning. The potential for health effects resulting from exposure to other substances measured in the soil on this site is considered to be small, and no significant increased cancer risk is expected. Comparison of levels of various substances obtained at this site with levels obtained in fresh bottom ash in other studies suggests that these results may be applicable to exposures from other municipal incinerator bottom ash landfills.

Preventing lead poisoning in New York City: priorities for lead abatement in housing.

The major challenge for lead poisoning prevention programs is to increase the availability of lead-safe housing as quickly as possible. The approach proposed by the City of New York maximizes the impact of the limited resources available to address this problem. The approach, however, is based on an assumption that in the short-term, modest lead hazard reduction measures such as restoring surfaces to an intact condition is adequate for most units and that more extensive abatement should be reserved for the relatively fewer units in which there is a high risk of exposure of lead-poisoned children reside. Ideally, this plan would be implemented with voluntary efforts to abate lead hazards when other renovation or remodeling occurs or when dwellings are vacant and more extensive abatement work can be performed at lower cost and without the attendant difficulty of abating occupied units. Approaches ranking hazards and implementing varying levels of hazard reduction must be fully evaluated and modified as new information becomes available. The specific criteria used to rank hazards should be evaluated to determine what measures best differentiate risk. Given the magnitude of the problem and the numerous obstacle--lack of funding, limited trained workers, and limited technical knowledge--it will probably take years, if not decades, to abate lead hazards in all the dwellings in which they exist. We must not be deterred, however, from beginning this effort in the communities and dwellings that need intervention the most: deteriorated, older housing units in which young children reside. In major urban centers such as New York City the greatest lead hazards will generally be found in areas where poverty is greatest. Thus, every effort must be made to ensure that adequate resources are available to improve housing in the communities in greatest need.

Rubella in the workplace: the need for employee immunization.

From 1983 to 1985, the New York City Department of Health investigated five workplace outbreaks of rubella. Approximately 40 per cent of the 265 cases were detected among women of child-bearing age (15-44 years). Data are reviewed from the 1983 Financial District outbreak to illustrate the continued susceptibility of young adults, the missed opportunities for rubella immunization, and the danger of congenital infection. A comprehensive rubella immunization program is required to protect pregnant women and eliminate congenital rubella. As one important component of this effort, employee health physicians are urged to assess the immune status of women of child-bearing age and to vaccinate all susceptibles who are not pregnant.

Vaginal small cell carcinoma mimicking a Bartholin's gland abscess: a case report.

We report a case of a 32-year-old woman with a lesion in the vagina which clinically mimicked a Bartholin's gland abscess, but was demonstrated to be a small cell carcinoma by light microscopy. This tumor is very rare and to our knowledge there are 13 reported cases of primary vaginal small cell carcinoma in the English literature. The mean age of presentation of this neoplasm in the 13 reported cases is 61 with a median survival of 12 months. This case stresses the importance of considering this unusual diagnosis when confronted with a large or recurrent "Bartholin's gland lesion," and underlines the need for careful pathological examination of such specimens.