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Objective: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC)., Methods: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment., Results: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%)., Conclusions: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Background: Cancer-related sleep disturbance is common and can adversely affect physical and mental health. Bright light (BL) therapy is a novel intervention that targets sleep by promoting circadian regulation. Emerging evidence suggests BL can improve sleep disturbance, symptom burden, and health-related quality of life in cancer and other populations; however, this research is limited. The present two-phase pilot study assessed the feasibility and preliminary intended effects of BL therapy on sleep in ovarian and endometrial cancer survivors, and explored biologic and chronobiologic factors that may underlie intervention effects., Methods: In phase I, focus groups were conducted with 12 survivors and 9 gynecologic oncology clinicians to evaluate and gather feedback about the proposed study. In phase II, a pilot randomized controlled trial was conducted with 18 ovarian or endometrial cancer survivors who were randomized 1:1 to receive 45 min of BL or dim light (DL) for 4 weeks. Participants wore wrist actigraphs; completed sleep diaries and self-report questionnaires; and provided blood, saliva, and urine samples at baseline (T1), post-intervention (T2), and 3-month follow-up (T3)., Results: Study procedures were modified according to focus group results. Enrollment, retention, and adherence were all ≥ 80%. Mixed-model ANOVAs demonstrated that the number of nighttime awakenings per actigraphy, and sleep quality and depression per self-report, trended toward improvements in the BL condition compared to the DL condition. These variables improved from T1 to T2 before returning to baseline at T3. Effect sizes were generally medium to large., Conclusions: Study findings suggest that BL therapy is feasible among ovarian and endometrial cancer survivors. It may be an effective, non-pharmacological approach to reduce sleep disturbance and symptom burden in this population.

Objective: The aim of this study was to determine if cervical dysplasia during pregnancy is associated with pregnancy complications, including preterm delivery and pre-eclampsia., Study Design: A retrospective cohort analyses was performed with propensity-score matching to compare complication rates between pregnant women without history of abnormal cervical cancer screening and pregnant women referred for cervical dysplasia assessment to colposcopy clinic. A composite outcome of pregnancy complications included intra-amniotic infection, preterm premature rupture of membranes, pre-eclampsia, preterm delivery, low birth weight, oligohydramnios, and intrauterine fetal demise. Complication rates were compared between women with and without cervical dysplasia using logistic regression models., Results: Overall cohort included 2,814 women, 279 of whom attended colposcopy clinic for cervical dysplasia assessment. Propensity score-matched cohort included 1,459 women, 274 of whom attended colposcopy clinic. Composite complications of pregnancy rates were not significantly different between control and colposcopy groups in both cohorts (25.3% and 29.0%, P = 0.20; 26.5% and 29.3%, P = 0.45). Dysplasia was not associated with composite pregnancy complications in overall and matched cohorts (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 0.77-1.56) and (OR = 1.03, 95% CI: 0.72-1.49). When cervical dysplasia was determined on biopsy or colposcopy, dysplasia was not associated with complications in the overall and matched cohorts., Conclusion: Biopsy and/or colposcopy determined cervical dysplasia during pregnancy was not associated with pregnancy complications., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The purpose of this review is to explain how diffusion-weighted imaging (DWI) is used during magnetic resonance imaging (MRI) exams in pregnant patients for specific maternal indications, including evaluation of acute pelvic pain, adnexal masses, cancer diagnosis and staging, and morbidly adherent placenta. While ultrasound is often the appropriate initial imaging for evaluating a pregnant patient, MRI can be helpful when a pelvic ultrasound is indeterminate. MRI has advantages in that it does not use ionizing radiation and has shown no known deleterious effects to the fetus. The use of gadolinium-based contrast is controversial during pregnancy. DWI is a functional sequence performed during an MRI exam, which is valuable in the absence of gadolinium contrast, and can increase the visibility of inflammation, abscesses, and tumors. Case examples will be presented to demonstrate the utility and added value of DWI over conventional anatomic T1- and T2-weighted imaging in diagnosis of maternal disease in the pregnant patient's pelvis., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: This study evaluated pre-defined aspects of content validity of the 18-item NCCN FACT-Ovarian Symptom Index (NFOSI-18) and its Disease-Related Symptoms-Physical (DRS-P) subscale, as clinical trial outcome tools for patients with advanced ovarian cancer., Methods: Twenty-one women (mean age 59.5 years) diagnosed with advanced ovarian cancer completed the NFOSI-18 and participated in a cognitive interview to explore: (1) whether 'pain' and 'cramps' are considered redundant; (2) whether 'fatigue' and 'lack of energy' are overlapping concepts; (3) whether patients consider severity when responding to the item "I am bothered by constipation;" and (4) factors considered when responding to the item "I am sleeping well." Interviews were audio-recorded, transcribed, and analyzed qualitatively., Results: Pain was associated with discomfort, hurt, and life interference; 'cramps' was associated with pain, muscle tightening, and menstrual or digestive issues. Most (81%) considered the items "I have pain" and "I have cramps in my stomach area" to be more different than similar. Participants associated 'fatigue' with intense tiredness and 'lack of energy' with motivation and capability to complete daily activities. Item comparisons revealed a majority (65%) considered the items to be more different than similar. When responding to "I am bothered by constipation," patients indicated constipation severity was related to bother. Finally, patients considered disease, treatment, and other factors when responding to "I am sleeping well.", Conclusions: Findings support content validity of the NFOSI-18 and its DRS-P as originally constructed. We propose an alternative scoring option that excludes the item "I am sleeping well" from the DRS-P when used as a symptom-focused index for clinical research in a regulatory context.

Objective: The optimal adjuvant management of women with FIGO Stage III-IVA endometrial cancer (EC) is unclear. While recent prospective data suggest that treatment with pelvic radiotherapy (RT) prior to chemotherapy (CT) is not associated with a survival benefit compared to CT alone, no prospective randomized trial has included a treatment arm in which CT is given before RT., Methods: An observational cohort study was performed on women with FIGO Stage III-IVA Type 1 (grade 1-2, endometrioid) EC who underwent hysterectomy and received multi-agent CT and/or RT from 2004 to 2014 at Commission on Cancer-accredited hospitals. Multivariable parametric accelerated failure time models were performed to estimate the association of sequence of adjuvant CT and RT with overall survival (OS) using propensity score-adjusted matched cohorts., Results: Of 5795 women identified, 1260 (21.7%) received RT only, 2465 (42.5%) received CT only, 593 (9.7%) received RT before CT, and 1506 (26.0%) received RT after CT. Women who received RT after CT experienced significantly longer 5-year OS than women who received RT before CT (5-year OS: 80.1% vs 73.3%; time-ratio (TR) = 1.37, 95% CI = 1.18-1.58, P < 0.001), CT only (68.9%; TR = 1.33, 95% CI = 1.19-1.48, P < 0.001), or RT only (64.5%, TR = 1.50, 95% CI = 1.32-1.70, P < 0.001)., Conclusions: For women with advanced EC, treatment with multi-agent CT followed by RT is associated with longer OS compared with treatment with RT followed by CT or either treatment alone. These hypothesis-generating data support inclusion in future prospective trials of regimens in which multi-agent CT starts prior to RT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Molecular cancer subtyping is an important tool in predicting prognosis and developing novel precision medicine approaches. We developed a novel platform-independent gene expression-based classification system for molecular subtyping of patients with high-grade serous ovarian carcinoma (HGSOC)., Methods: Unprocessed exon array (569 tumor and nine normal) and RNA sequencing (RNA-seq; 376 tumor) HGSOC data sets, with clinical annotations, were downloaded from the Genomic Data Commons portal. Sample clustering was performed by non-negative matrix factorization by using isoform-level expression estimates. The association between the subtypes and overall survival was evaluated by Cox proportional hazards regression model after adjusting for the covariates. A novel classification system was developed for HGSOC molecular subtyping. Robustness and generalizability of the gene signatures were validated using independent microarray and RNA-seq data sets., Results: Sample clustering recaptured the four known The Cancer Genome Atlas molecular subtypes but switched the subtype for 22% of the cases, which resulted in significant ( P = .006) survival differences among the refined subgroups. After adjusting for covariate effects, the mesenchymal subgroup was found to be at an increased hazard for death compared with the immunoreactive subgroup. Both gene- and isoform-level signatures achieved more than 92% prediction accuracy when tested on independent samples profiled on the exon array platform. When the classifier was applied to RNA-seq data, the subtyping calls agreed with the predictions made from exon array data for 95% of the 279 samples profiled by both platforms., Conclusion: Isoform-level expression analysis successfully stratifies patients with HGSOC into groups with differing prognosis and has led to the development of robust, platform-independent gene signatures for HGSOC molecular subtyping. The association of the refined The Cancer Genome Atlas HGSOC subtypes with overall survival, independent of covariates, enhances the clinical annotation of the HGSOC cohort.

Background: Minimally invasive surgery was adopted as an alternative to laparotomy (open surgery) for radical hysterectomy in patients with early-stage cervical cancer before high-quality evidence regarding its effect on survival was available. We sought to determine the effect of minimally invasive surgery on all-cause mortality among women undergoing radical hysterectomy for cervical cancer., Methods: We performed a cohort study involving women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer during the 2010-2013 period at Commission on Cancer-accredited hospitals in the United States. The study used inverse probability of treatment propensity-score weighting. We also conducted an interrupted time-series analysis involving women who underwent radical hysterectomy for cervical cancer during the 2000-2010 period, using the Surveillance, Epidemiology, and End Results program database., Results: In the primary analysis, 1225 of 2461 women (49.8%) underwent minimally invasive surgery. Women treated with minimally invasive surgery were more often white, privately insured, and from ZIP Codes with higher socioeconomic status, had smaller, lower-grade tumors, and were more likely to have received a diagnosis later in the study period than women who underwent open surgery. Over a median follow-up of 45 months, the 4-year mortality was 9.1% among women who underwent minimally invasive surgery and 5.3% among those who underwent open surgery (hazard ratio, 1.65; 95% confidence interval [CI], 1.22 to 2.22; P=0.002 by the log-rank test). Before the adoption of minimally invasive radical hysterectomy (i.e., in the 2000-2006 period), the 4-year relative survival rate among women who underwent radical hysterectomy for cervical cancer remained stable (annual percentage change, 0.3%; 95% CI, -0.1 to 0.6). The adoption of minimally invasive surgery coincided with a decline in the 4-year relative survival rate of 0.8% (95% CI, 0.3 to 1.4) per year after 2006 (P=0.01 for change of trend)., Conclusions: In an epidemiologic study, minimally invasive radical hysterectomy was associated with shorter overall survival than open surgery among women with stage IA2 or IB1 cervical carcinoma. (Funded by the National Cancer Institute and others.).

Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene recurrence score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT. Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the surveillance, epidemiology, and end results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts. Results: In both the NCDB ( N = 7,332) and SEER ( N = 3,087) cohorts, there was a significant interaction of RS and PMRT with OS ( P = 0.009 and P = 0.03, respectively). PMRT was associated with longer OS in women with a low RS [NCDB: time ratio (TR) = 1.70; 95% CI (confidence interval), 1.30-2.22; P < 0.001; SEER: TR = 1.85; 95% CI, 1.33-2.57; P < 0.001], but not in women with an intermediate RS (NCDB: TR = 0.89; 95% CI, 0.69-1.14; P = 0.35; SEER: TR = 0.84; 95% CI, 0.62-1.14; P = 0.26), or a high RS (NCDB: TR = 1.10; 95% CI, 0.91-1.34; P = 0.33; SEER: TR = 0.79; 95% CI, 0.50-1.23; P = 0.28). Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at the lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS. Clin Cancer Res; 24(16); 3878-87. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Importance: Circulating tumor cells (CTCs) represent the liquid component of solid tumors and are a surrogate marker for residual cancer burden. Although CTC status is prognostic of recurrence and death in breast cancer, its role in guiding clinical management remains unknown., Objective: To determine whether CTC status is predictive of radiotherapeutic benefit in early-stage breast cancer., Design, Setting, and Participants: The cohort studies in the present analysis included patients with stages pT1 to pT2 and pN0 to pN1 breast cancer and known CTC status from the National Cancer Database (NCDB) and the multicenter phase 3 SUCCESS clinical trial. Multivariable parametric accelerated failure time models were used to evaluate the association of CTC status and radiotherapy (RT) with survival outcomes. Data were collected from January 1, 2004, through December 31, 2014, from the NCDB cohort. The SUCCESS trial collected data from September 1, 2005, through September 30, 2013. The analyses were completed from November 1, 2016, through December 17, 2017., Exposure: Adjuvant RT., Main Outcomes and Measures: Overall survival (OS), local recurrence-free survival (LRFS), and disease-free survival (DFS)., Results: A total of 1697 patients from the NCDB (16 men [0.9%] and 1681 women [99.1%]; median age, 63 years; interquartile range, 53-71 years) and 1516 patients from the SUCCESS clinical trial (median age, 52 years; interquartile range, 45-60 years) were identified. Circulating tumor cells were detected in 399 patients (23.5%) in the NCDB cohort and 294 (19.4%) in the SUCCESS cohort. The association of RT with survival was dependent on CTC status within the NCDB cohort (4-year OS, 94.9% for CTC-positive RT vs 88.0% for CTC-positive non-RT vs 93.9% for CTC-negative RT vs 93.4% for CTC-negative non-RT groups; P < .001) and 5-year DFS within the SUCCESS cohort (88.0% for CTC-positive RT vs 75.2% for CTC-positive non-RT vs 92.3% for CTC-negative RT vs 88.3% for CTC-negative non-RT; P = .04). In the NCDB cohort, RT was associated with longer OS in patients with CTCs (time ratio [TR], 2.04; 95% CI, 1.55-2.67; P < .001), but not in patients without CTCs (TR, 0.80; 95% CI, 0.52-1.25; P = .33). In the SUCCESS cohort, CTC-positive patients treated with RT exhibited longer LRFS (TR, 2.73; 95% CI, 1.62-4.80; P < .001), DFS (TR, 3.03; 95% CI, 2.22-4.13; P < .001), and OS (TR, 1.83; 95% CI, 1.23-2.72; P = .003). Among patients from both cohorts who underwent breast-conserving surgery, RT was associated with longer OS in patients with CTCs (TR, 4.37; 95% CI, 2.71-7.05; P < .001) but not in patients without CTCs (TR, 0.87; 95% CI, 0.47-1.62; P = .77). Radiotherapy was not associated with OS after mastectomy in CTC-positive or CTC-negative patients., Conclusions and Relevance: Treatment with RT was associated with longer LRFS, DFS, and OS in patients with early-stage breast cancer and detectable CTCs. These results are hypothesis generating; a prospective trial evaluating CTC-based management for RT after breast-conserving surgery in women with early-stage breast cancer is warranted.

For recurrent ovarian cancer (ROC), secondary cytoreductive surgery (SCS) is recommended as one optional treatment. However, little is known about the expression and clinical significance of biomarkers during SCS. Human epididymis protein 4 (HE4) is a clinical biomarker for ovarian cancer. Eukaryotic translation initiation factor 3a (eIF3a) is investigated extensively as a potential biomarker for malignancy. The purpose of this study was to investigate the expressions of HE4 and eIF3a at SCS, as well as their associations with surgical outcome and survival in ROC patients. Immunohistochemistry was performed to determine the expressions of HE4 and eIF3a in ovarian tumors taken from both initial and secondary cytoreductive surgery of 35 ROC patients. eIF3a levels were significantly increased at SCS, compared to those at initial cytoreductive surgery (ICS), while HE4 levels were similar. Both HE4 and eIF3a expressions were associated with surgical outcome, in terms of residual tumor. For ICS, patients with high HE4 expression achieved a higher incidence of optimal cytoreduction than those with low HE4 expression (81.0% vs. 33.3%, P = 0.015). A similar result happened in SCS, indicated by higher incidence of no residual tumor in patients with high HE4 expression (76.4% vs. 44.4%, P = 0.046). And high HE4 expression at SCS was more likely to enhance surgical outcome of SCS (77.8% vs. 29.4%, P = 0.038). Therefore, high HE4 expression at either surgery is a predictor of better overall survival (OS) (P = 0.011 and 0.002). Furthermore, patients with an elevated total score (TS) of HE4 between the two surgeries tended to have prolonged OS, compared to those with a non-elevated TS of HE4 (P = 0.076). For eIF3a, initial eIF3a expression was associated with secondary residual tumor (P = 0.035), and the difference in eIF3a expression between the two surgeries correlated with OS (P = 0.052). The expressions of HE4 and eIF3a in tumor specimens correlated with surgical outcome and predicted OS in ROC patients with SCS, thus meriting further investigation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Uterine smooth muscle tumors (USMTs) consist of a group of histologically heterogeneous and clinically diverse diseases ranging from malignant leiomyosarcoma (LMS) to benign leiomyoma (ULM). The genetic alterations in LMS are complex, with some genetic alterations present in both LMS and other atypical histologic variants of USMT. In this study, we reviewed 119 USMTs with a diagnosis of LMS, smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, and cellular leiomyoma, as well as 46 ULMs and 60 myometrial controls. We selected 17 biomarkers highly relevant to LMS in 4 tumorigenic pathways including steroid hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]), cell cycle/tumor suppressor genes, AKT pathway markers, and associated oncogenes. ER and PR expression was significantly lower in LMS than smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, cellular leiomyoma, and ULM (P < .01). Sixty-five percent of LMSs showed complete loss of ER, and 75% of LMSs showed complete loss of PR. All cell cycle genes were differentially expressed in different types of tumor, but significant overlap was noted. More than 75% of LMSs had Ki-67 index greater than 33%, and only 5% in all other types of USMT. Expression of the selected oncogenes varied widely among different types of USMT. PR positivity and p53 had a borderline association with progression-free survival (P = .055 for PR and P = .0847 for p53). Furthermore, high PR expression was significantly associated with a longer overall survival (P = .0163, hazard ratio 0.198). Cell proliferative indices (Ki-67) and sex steroid hormone receptors were the most valuable markers in differentiating LMS from other USMT variants., (Copyright © 2017. Published by Elsevier Inc.)

Objective: Tumor expression of Anterior Gradient 2 ( AGR2 ), an endoplasmic reticulum protein disulfide isomerase, was associated with decreased breast cancer survival. We aimed to validate the association of tumor AGR2 mRNA expression with disease-specific survival (DSS) and identify differentially expressed signaling pathways between high and low AGR2 expression tumor groups., Methods: Primary tumor mRNA expression data from the METABRIC study was used to evaluate AGR2 expression as a prognostic factor for DSS while adjusting for survival-determining confounders using Cox proportional-hazards regression. Differentially expressed genes and signaling pathway differences between high and low AGR2 groups were determined by modular enrichment analyses using DAVID and Ingenuity Pathway Analysis., Results: Increased tumor AGR2 mRNA expression was associated with decreased DSS among 1,341 women (per each standard deviation increase of AGR2 expression: HR 1.14, 95% CI: 1.01-1.29, P = 0.03). Pathway analyses supported prior experimental studies showing that estrogen receptor 1 ( ESR1 ) regulated AGR2 expression. Canonical signaling pathways significantly differentially represented between high and low AGR2 groups included those involved in inflammation and immunity., Conclusion: Increased primary tumor AGR2 expression was associated with decreased DSS. Pathway analyses suggested that increased AGR2 was associated with endoplasmic reticular homeostasis, possibly allowing tumor cells to overcome hypoxic stress and meet the increased protein demand of tumorigenesis, thereby preventing unfolded protein response-mediated apoptosis., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Background: While positive peritoneal cytology is no longer included among the endometrial cancer staging criteria, Federation International de Gynecologie et Obstetrique recommends continued collection of pelvic washings for cytology to produce additional data that may be used to determine the significance of positive cytology for prognosis and treatment of endometrial cancer., Objectives: The objectives of the study was to validate that positive cytology is a predictor of decreased survival in early endometrial cancer and to test whether adjuvant chemotherapy for positive cytology is associated with increased survival., Study Design: We performed an observational retrospective cohort analysis of the 2010-2013 National Cancer Database including women with cytology status and Federation International de Gynecologie et Obstetrique stage IA-II endometrial cancer. Overall cohort and matched cohort survival analyses were performed with and without imputation of missing data. We also performed survival analyses of women with positive cytology grouped by chemotherapy exposure. Multivariable Cox proportional-hazards regressions were performed to adjust for possible confounders. A variety of sensitivity analyses, including robustness of results to possible unmeasured confounding, were reported., Results: A total of 16,851 women including 953 with positive cytology were included. Four-year overall survival was 79.5% (range, 76.2-83.0%) for women with stage I/II with positive cytology vs 92.2% (range, 91.5-92.9%), 83.3% (range, 81.6-84.9%), and 86.8% (range, 85.1-88.5%) for stage IA, IB, and II with negative cytology, respectively (P ≤ .001). Positive cytology was associated with decreased survival (hazard ratio [95% confidence interval], 1.85 [range, 1.54-2.21], P < .001). For women with Federation International de Gynecologie et Obstetrique grade 1/2 endometrioid adenocarcinoma, the hazard of death associated with positive cytology was similar (hazard ratio [95% confidence interval], 1.85 [1.28-2.67], P < .001). Use of adjuvant chemotherapy by women with positive cytology was associated with increased survival (hazard ratio [95% confidence interval], 0.62 [0.40-0.95], P = .03)., Conclusion: Positive peritoneal cytology was associated with decreased overall survival of women with Federation International de Gynecologie et Obstetrique stage I/II endometrial cancer, including low-grade endometrioid endometrial cancer. Treatment of women with stage I/II endometrial cancer and positive cytology with adjuvant chemotherapy was associated with increased survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

There is no reliable way to distinguish symptomatic uterine fibroids from sarcoma without a surgical specimen. Many women with a uterine sarcoma are initially managed without hysterectomy under a presumed fibroid diagnosis, without understanding sarcoma risks. Currently many alternatives to hysterectomy, including medical and procedural interventions, for treatment of fibroids are promoted. The sarcoma incidence among women with presumed fibroids is 0.29% (1/340) to 0.05% (1/2000). Nonmetastatic leiomyosarcoma has a 63% 5-year survival rate whereas metastatic leiomyosarcoma has a 14% 5-year survival rate. In uterine sarcoma, we often cannot identify who has sarcoma before making a potentially cure-denying decision by delaying surgery. Therefore, women electing an alternative to hysterectomy for fibroids should undergo an informed consent process that specifically includes discussion of uterine sarcoma incidence and mortality. Alternatives to hysterectomy for presumed fibroids remain preferable treatment options for many women with symptomatic fibroids, so long as underlying sarcoma risks are adequately discussed. The challenge for obstetrician- gynecologists then is how to provide better informed consent and maintain the primacy of patient autonomy over our concern to "First, do no harm." Major threats to patient's autonomy are faced in the sarcoma risk discussion. How we should present sarcoma risk information to avoid being dismissive of sarcoma or frightening women toward hysterectomy is unstudied. Research is needed to determine how to provide sarcoma risk information with less bias during informed consent., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: We describe survival disparities among women with uterine, ovarian, or cervical cancer by cancer-specific mean annual hospital volume., Methods: National Cancer Database 1998-2011 uterine (n = 441,863), ovarian (n = 223,017), and cervical (n = 146,698) cancer data sets were used. Cancer-specific mean annual hospital volumes were calculated. Overall survival (OS) was plotted by hospital volume using restricted mean OS times from Cox regression., Results: Uterine, ovarian, and cervical cancers were reported from 1,651, 1,633, and 1,600 hospitals, respectively. Median values of mean annual hospital volumes among hospitals were 8.6 (interquartile range [IQR], 2.6 to 20.8), 4.4 (IQR, 1.4 to 10.3), and 2.4 (IQR, 0.6 to 6.6) for uterine, ovarian, and cervical cancers, respectively. Increased hospital volume was associated with increased OS among women with stage III to IV high-grade serous ovarian cancer, stage II to IV squamous or adenocarcinoma cervical cancer, and stage I to IV endometrioid, clear cell, serous, or carcinosarcoma uterine cancers (all P < .03). Differential OS between women treated at higher- versus lower-volume cancer centers exceeded 5, 5, and 13 months among women with advanced endometrial, ovarian, or cervical cancer, respectively (all P < .001). Hospital volume was not associated with OS among patients with stage II to IV cervical cancer treated with brachytherapy ( P = .17). Use of adjuvant therapies decreased OS disparities by hospital volume among women with advanced ovarian or endometrial cancer., Conclusion: Increased delivery of brachytherapy for treatment of cervical cancer may decrease survival disparities by hospital volume. Standardization of adjuvant therapies may diminish survival disparities by hospital volume among women with advanced ovarian or endometrial cancer. In addition, survival of American women with gynecologic cancer may be increased by centralization of care.

Many human diseases result from the dysregulation of the complex interactions between tens to thousands of genes. However, approaches for the transcriptional modulation of many genes simultaneously in a predictive manner are lacking. Here, through the combination of simulations, systems modelling and in vitro experiments, we provide a physical regulatory framework based on chromatin packing-density heterogeneity for modulating the genomic information space. Because transcriptional interactions are essentially chemical reactions, they depend largely on the local physical nanoenvironment. We show that the regulation of the chromatin nanoenvironment allows for the predictable modulation of global patterns in gene expression. In particular, we show that the rational modulation of chromatin density fluctuations can lead to a decrease in global transcriptional activity and intercellular transcriptional heterogeneity in cancer cells during chemotherapeutic responses to achieve near-complete cancer cell killing in vitro. Our findings represent a 'macrogenomic engineering' approach to modulating the physical structure of chromatin for whole-scale transcriptional modulation., Competing Interests: Competing interests The authors declare no competing financial interests.

Purpose: To estimate whether pelvic and para-aortic lymphadenectomy was associated with increased survival in stage I endometrioid endometrial cancer., Methods: We performed matched cohort analyses of women with stage I endometrioid endometrial cancer who underwent hysterectomy with no lymphadenectomy, pelvic lymphadenectomy, or combined pelvic and para-aortic lymphadenectomy. Cox proportional hazards survival analyses were performed with inverse probability weights. Hazard ratios (HRs) were covariate and propensity score adjusted. Covariates included cancer center type, age, race, Hispanic ethnicity, insurance type, community median income quartile, comorbidity score, history of prior cancer, depth of myometrial invasion, tumor grade, tumor size, lymphovascular space invasion, cytology status, surgical margin status, hospital volume, and use of adjuvant radiotherapy or chemotherapy. Additional analyses included subset analyses by grade, sensitivity analyses with imputation of missing data, and testing for sensitivity to possible unmeasured confounding., Results: Median (interquartile range [IQR]) lymph node counts were 0, 10 (5-15), and 20 (15-27) nodes in the no lymphadenectomy, pelvic, and combined pelvic and para-aortic lymphadenectomy-matched cohorts, respectively. Matched cohorts were well balanced. Two analyses were performed: no lymphadenectomy (n = 7,487) versus pelvic lymphadenectomy (n = 7,487), and pelvic lymphadenectomy (n = 7,060) versus combined pelvic and para-aortic lymphadenectomy (n = 7,060). Performance of pelvic lymphadenectomy was associated with increased survival compared with no lymphadenectomy (5-year survival [95% CI], 91.4% [90.2% to 92.6%] v 87.3% [85.9% to 88.8%]; HR, 0.71 [95% CI, 0.64 to 0.78]; P < .001). Addition of para-aortic lymphadenectomy was associated with increased survival compared with pelvic lymphadenectomy alone (5-year survival [95% CI], 91.0% [89.8% to 92.2%] v 89.8% [88.4% to 91.1%]; HR, 0.85 [95% CI, 0.77 to 0.95]; P = .003). Associations were robust to sensitivity analyses., Conclusion: Lymphadenectomy was associated with increased survival in stage I endometrioid endometrial cancer. An adequately powered randomized trial is needed.

Objective: The aim of this study was to compare overall survival (OS) of women with advanced ovarian cancer treated with primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) using a large national cohort., Methods: The 1998-2011 National Cancer Database was queried to identify women with stage III or IV ovarian cancer treated with multiagent chemotherapy and stage-appropriate surgery. Overall survival was estimated and compared using Kaplan-Meier analysis between women who received PDS followed by multiagent chemotherapy or NAC followed by interval surgery. Multivariable Cox proportional hazards regression model tested for associations of potential explanatory variables with OS. Analyzed confounders included age, composite comorbidity scores, stage, grade, histology, insurance status, income quartile, and race., Results: Overall, 44,907 women (85.9%) underwent PDS, and 7348 women (14.1%) received NAC. Women who received NAC were older (64 vs 61 years, P < 0.001), had higher comorbidity scores (P < 0.001), and more often had stage IV disease (44.1% vs 26.1%, P < 0.001). Median OS was 41.1 (40.5-41.7) months among women who underwent PDS compared with 30.3 (29.3-31.1) months among women who received NAC (log-rank, P < 0.001). Among women with stage III disease, PDS was associated with increased OS compared with NAC (median OS, 44.9 [44.2-45.7] vs 31.4 [30.2-33.0] months; hazard ratio [95% confidence interval], 0.70 [0.66-0.76]; P < 0.001). Among women with stage IV disease, there was no OS difference between PDS and NAC cohorts (median OS, 31.2 [30.4-32.3] vs 28.4 [27.2-30.2] months; hazard ratio [95% confidence interval], 0.93 [0.85-1.02]; P = 0.12)., Conclusions: Primary debulking surgery was associated with increased OS among women with stage III but not stage IV ovarian cancer in a nationally representative cohort with low NAC use. If this finding reflects treatment assignment bias, it suggests that providers often well select candidates for PDS rather than NAC, although median OS times remain low.

Background: To determine the cost-effectiveness of transversus abdominis plane block with liposomal bupivacaine (TAP) compared to oral opioids alone for acute postoperative pain after laparoscopic hysterectomy for early endometrial cancer., Methods: A cost-effectiveness analysis using a decision tree structure with a 30.5 day time-horizon was used to calculate incremental cost-effectiveness ratio (ICER) values per quality-adjusted life-year (QALY). Base-case costs, probabilities, and QALY values were identified from recently published all-payer national database studies, 2017 Medicare fee-schedules, randomized trials, institutional case series, or assumed, when published values were not available. One-way, two-way and multiple probabilistic sensitivity analyses were performed., Results: The TAP strategy dominated the oral opioid-only strategy, with decreased costs and increased effectiveness. Specifically, the TAP strategy saved $235.90 under the base-case assumptions. Threshold analyses demonstrated that if the relative same-day discharge probability was ≥ 12% higher in the TAP group, then TAP was cost-saving over oral opioids-alone. Similarly, TAP was cost-saving whenever the costs saved by same-day discharge compared to admission were ≥ $1115.22. Cost-effectiveness of the TAP strategy was highly robust of a variety of sensitivity analyses., Conclusions: TAP with liposomal bupivacaine was robustly cost-effective at conventional willingness-to-pay thresholds. Further, TAP was cost-saving compared to opioids-only when the same-day discharge rate among TAP users was greater than among opioid-only users.

Objective: To compare the overall survival of non-Hispanic white and Hispanic women with endometrial cancer., Methods: We performed an observational retrospective cohort study of Hispanic and non-Hispanic women with endometrial cancer from the 2004-2014 National Cancer Database. Baseline characteristics were compared with the Chi-squared test for categorical variables or the Mann-Whitney U test for ordinal or continuous variables. The Kaplan-Meier method was used to estimate unadjusted survival times, which were compared with the log-rank test. Missing data was imputed using multiple imputation with chained equations. A multivariable parametric accelerated failure time model for survival was used. Sensitivity analyses were performed using matched cohort analyses of the overall cohort, and of subgroups based on stage or type., Results: 112,574 non-Hispanic and 6313 Hispanic women met inclusion criteria. Five-year survival was slightly higher for Hispanic women (83.1% (82.1-84.3%) versus 81.4% (81.2-81.7%), P=0.002). Hispanic women were younger, treated at lower volume hospitals, and more often diagnosed with a type II histology and stage II-IV disease compared to non-Hispanic women (all P<0.001). With multivariable adjustment for measured confounders, Hispanic women lived 8% longer than non-Hispanic women (time-ratio (95% CI) 1.08 (1.02-1.14), P=0.01). When bias-reducing matched cohort analyses were used for sensitivity analyses, Hispanic women did not have significantly different survival than non-Hispanic women., Conclusion: Hispanic ethnicity was not associated with a clinically meaningful difference in survival among women with endometrial cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To provide refined prognostic information from large cohorts of women with low-grade or high-grade endometrial stromal sarcoma (ESS)., Methods: We performed an observational retrospective cohort analysis of women diagnosed with low-grade or high-grade ESS from the 1998-2013 National Cancer Database. Kaplan-Meier and multivariable accelerated failure time survival analyses were performed to identify prognostic factors after multiple imputation of missing data. Recursive partitioning methods were used to rank prognostic factors in high-grade ESS. Matched cohort analyses were performed to hypothesis-test effects of adjuvant treatments., Results: We identified 2414 and 1383 women with low-grade or high-grade ESS, respectively. Women with high-grade ESS had markedly decreased survival compared to women with low-grade ESS (five-year survival (95% CI): 32.6 (30.1-35.3%) versus 90.5% (89.3-91.8%), P<0.001). Among women with high-grade ESS, median survival (95% CI) was only 19.9 (17.1-22.1) months. Increased age and tumor size were associated with decreased survival in low-grade ESS. In high-grade ESS, additional negative prognostic factors were distant or nodal metastasis, omission of lymphadenectomy, and pathologically-positive surgical margins (all P<0.001). Use of adjuvant chemotherapy (time ratio (TR) (95% CI): 1.36 (1.17-1.58), P<0.001) and radiotherapy (TR (95% CI): 1.57 (1.32-1.87), P<0.001) were associated with increased survival for high-grade ESS., Conclusion: The contrasting excellent versus poor prognosis of low-grade versus high-grade ESS, respectively, was confirmed. The best treatment of high-grade ESS is early and complete surgical resection including lymphadenectomy. Adjuvant chemotherapy and radiotherapy may increase survival of women with high-grade ESS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To provide prognostic information from a large cohort of women with granulosa cell tumor we analyzed the National Cancer Database., Methods: We performed an observational retrospective cohort analysis of 2680 women with ovarian granulosa cell tumor from the 1998-2013 National Cancer Database. Kaplan-Meier and multivariable Cox proportional-hazards survival analyses were performed for the overall cohort and propensity score matched cohorts to examine the association of surgical staging and adjuvant chemotherapy with survival. A random forest was used to determine important prognostic factors in stages II-IV granulosa cell tumor., Results: Adjuvant chemotherapy, hormonal therapy, and radiotherapy were not associated with survival. Older age, more comorbidities, prior malignancy, higher stage, poor differentiation, larger tumor size, incomplete surgical staging, and residual disease at a surgical margin were independently associated with increased hazard of death. Among women with stage I disease, each one centimeter increase in tumor size was associated with 4% (2-6%) increased hazard of death (P<0.001). By matched cohort analyses, the hazard ratio (HR) (95% CI) for death associated with incomplete surgical staging was 1.77 (1.30-2.41), P<0.001 among women with stage I disease. Receiving adjuvant chemotherapy was not associated with increased survival among women with stages II-IV disease compared to no adjuvant treatment., Conclusion: Incomplete surgical staging was associated with increased hazard of death. There was no evidence of increased survival with use of adjuvant chemotherapy. Early and complete surgical resection remains the best evidenced treatment for ovarian granulosa cell tumor., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine overall survival and factors associated with survival of women with uterine leiomyosarcoma., Methods: We performed an observational cohort study of women with uterine leiomyosarcoma (n=7455) from the 1998-2013 National Cancer Database. Kaplan-Meier and multivariable accelerated failure time survival analyses were performed to investigate predictors of survival. Sensitivity and matched cohort analyses were performed to evaluate the roles of oophorectomy, lymphadenectomy, and chemotherapy in early leiomyosarcoma and chemotherapy in metastatic leiomyosarcoma., Results: Median (interquartile range) age at diagnosis was 54 (48-63) years. Older age, higher comorbidity, black race, higher stage or grade, larger tumor size, lymph node involvement, metastasis at diagnosis, positive surgical margin, adjuvant chemotherapy, and brachytherapy were independently associated with decreased survival by unmatched cohort analyses. Private insurance was associated with increased survival. By matched cohort analyses, omitting oophorectomy was not associated with survival among women≤51years old at diagnosis (event time ratio (ETR) (95% CI) 1.06 (0.90-1.25), P=0.48). Omitting lymphadenectomy was not associated with survival (ETR (95% CI) 1.02 (0.94-1.10), P=0.60). Among women with stage I leiomyosarcoma, adjuvant chemotherapy was not associated with increased survival (ETR (95% CI) 0.91 (0.78-1.05), P=0.18). Chemotherapy was associated with increased survival of women with metastatic leiomyosarcoma (median survival (95% CI) 19.4 (16.4-23.0) versus 10.9 (7.7-14.3) months, ETR (95% CI) 1.66 (1.46-1.90), P<0.001)., Conclusion: Early and complete resection is the best-evidenced treatment for uterine leiomyosarcoma. Oophorectomy and lymphadenectomy may be safely omitted for clinically uterus-confined leiomyosarcoma. Chemotherapy increases survival of women with metastatic leiomyosarcoma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine if lymphadenectomy, chemotherapy and radiotherapy are associated with survival benefit among women with stage I uterine carcinosarcoma., Methods: Women with stage I uterine carcinosarcoma (n=5614) were identified from the 1998-2013 National Cancer Data Base. Kaplan-Meier survival estimates and Cox proportional-hazards regression models were used to evaluate predictors of overall survival. Effects of these predictors were also estimated using propensity score matched analyses for lymphadenectomy, adjuvant chemotherapy, and radiotherapy., Results: 42.0% (2360/5614) of women in the cohort received no adjuvant radiation or chemotherapy. Black race and positive surgical margin status were associated with decreased survival by multivariable Cox regression. Among women with pathologically node-negative disease, the hazard of death increased 5% (4-7%) per each one centimeter increase in tumor size (P=1.9×10 -10 ). From matched cohort analyses, omitting lymphadenectomy was associated with decreased median (interquartile range) survival: 45.2 (36.4-57.6) versus 73.9 (63.8-91.6) months, hazard ratio (HR) (95% CI) 1.38 (1.20-1.59), P=9.4×10 -6 . Hazard of death decreased by 3% (1-5%) for each five lymph nodes removed (P=0.01). Multiagent chemotherapy and vaginal brachytherapy were associated with decreased hazard of death (HR (95% CI) 0.62 (0.54-0.73), P=1.1×10 -9 and HR (95% CI) 0.83 (0.70-0.97), P=0.02, respectively). Highest five-year survival was observed after brachytherapy and multiagent chemotherapy (74.1% (68.3-80.3%), P<2.0×10 -16 )., Conclusion: Lymphadenectomy to at least 15-20 removed nodes is associated with increased survival of women with node-negative uterine carcinosarcoma. Adjuvant "cuff and chemo" with vaginal brachytherapy and multiagent chemotherapy is associated with increased survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To determine the cost-effectiveness of dose-dense versus standard intravenous adjuvant chemotherapy for ovarian cancer using results from the no-bevacizumab cohort of the Gynecologic Oncology Group protocol 262 (GOG-262) randomized controlled trial, which reported a smaller absolute progression-free survival (PFS) benefit than the prior Japanese trial., Methods: A three-state Markov decision model from a healthcare system perspective with a 21day cycle length and 28month time-horizon was used to calculate incremental cost-effectiveness ratio (ICER) values per progression-free life-year saved (PFLYS) using results from GOG-262. Costs of chemotherapy, complications, and surveillance were from Medicare or institutional data. PFS, discontinuation, and complication rates were from GOG-262. Time-dependent transition probabilities and within-cycle corrections were used. One-way and probabilistic sensitivity analyses were performed., Results: The model produces standard and dose-dense cohorts with 84.3% and 68.3% progression event proportions at 28months, matching GOG-262 rates at the trial's median follow-up. With a median PFS of 10.3months after standard chemotherapy and a hazard ratio for progression of 0.62 after dose-dense therapy, the ICER for dose-dense chemotherapy is $8074.25 (95% confidence interval: $7615.97-$10,207.16) per PFLYS. ICER estimates are sensitive only to the hazard ratio estimate but do not exceed $100,000 per PFLYS. 99.8% of ICER estimates met a more stringent willingness-to-pay of $50,000 per PFLYS. The willingness-to-pay value at which there is a 90% probability of dose-dense treatment being cost-effective is $12,000 per PFLYS., Conclusions: Dose-dense adjuvant chemotherapy is robustly cost-effective for advanced ovarian cancer from a healthcare system perspective based on results from GOG-262., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for cervical cancer., Methods: Women with cervical cancer who underwent exenteration (n = 517) were identified from the 1998 to 2011 National Cancer Database. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, insurance status, income, distance from home to treatment center, stage, exenteration type, surgical margin status, and treatment with adjuvant radiation and/or chemotherapy., Results: Among the entire cohort with clinical follow-up (n = 313), median OS was 24 months. Stage (P = 2.5 × 10), lymph node status (P = 1.3 × 10), insurance status (P = 1.5 × 10), and histologic type (P = 0.04) were significantly associated with OS by the log-rank test. Unadjusted median OS was 24.2 and 61.8 months for women with squamous and adenocarcinoma histologies, respectively. By multivariate Cox regression, age, insurance status, stage, margin status, and adjuvant radiation were associated with OS. Histology was not independently associated with OS on multivariate regression. Among women with node-negative disease, median OS was 73.2 months., Conclusions: Exenteration may be curative for more than half of women with node-negative cervical cancer. Stage, insurance status, lymph node status, and surgical margin are independently associated with differential OS after exenteration.

Objective: To determine the association of chemotherapy delay with overall survival (OS) and investigate predictors of delay among a population-representative American ovarian cancer cohort., Methods: An observational retrospective cohort analysis of women with ovarian cancer who received National Comprehensive Cancer Network guideline-consistent care was performed with the 1998-2011 National Cancer Data Base. Chemotherapy delay was defined as initiation of multiagent chemotherapy >28days from primary debulking surgery. Associations of patient and disease characteristics with chemotherapy delay were tested with multivariate logistic regression. Survival analyses for women diagnosed from 2003 to 2006 approximated a 21-daycycle intravenous platinum-taxane chemotherapy cohort. Overall survival was estimated by Kaplan-Meier analyses and Cox proportional-hazards regressions, with sensitivity analyses using matched cohorts., Results: 58.1% (26,149/45,001) of women experienced chemotherapy delay. Race, insurance status, cancer center type, and community median income were significantly associated with chemotherapy delay (P<0.001). Odds for chemotherapy delay were higher for older or sicker women, women with endometrioid or mucinous histology, lower stage or grade disease, and uninsured or low-income women (P<0.05). Chemotherapy delay >35days from surgery was associated with a 7% (95% confidence interval, 2-13%) increased hazard of death (P=0.01). Relative hazard of death was lowest between 25 and 29days after surgery but was not significantly different within the longer two-week interval from 21 to 35days., Conclusion: A survival benefit may be achieved by consistently starting chemotherapy between 21 and 35days from primary debulking surgery. Women at higher risk for chemotherapy delay may be targeted for close follow-up., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To estimate whether the number of lymph nodes removed during surgery is associated with overall survival among women with endometrial cancer., Methods: We performed a retrospective cohort study of women with node-negative, stage I to IIIB endometrial cancer (n = 152,702) identified from the 1998-2011 National Cancer Database. Multivariable Cox proportional hazards regression tested for an association of lymph node count with survival. Restricted mean survival and relative hazard curves were plotted for survival as a function of number of removed lymph nodes., Results: Among women with node-negative endometrioid endometrial cancer, for each additional five lymph nodes removed, the hazard for death decreased: stage I, the hazard ratio (HR) was 0.95 (95% CI, 0.93 to 0.97; P < .001), stage II, HR was 0.90 (95% CI, 0.87 to 0.94; P < .001); and stage IIIA-B, HR was 0.92 (95% CI, 0.88 to 0.96; P < .001). When grouped by grade, each additional five lymph nodes removed was also associated with decreased hazard for death: grade 1, HR was 0.96 (95% CI, 0.93 to 0.99; P = .009); grade 2,HR was0.91 (95%CI, 0.89 to0.94; P <.001);and grade 3,HR was 0.95 (95%CI, 0.92 to 0.97; P <.001). Increased lymph node dissection was also associated with increased survival among women with node-negative stage II (HR, 0.92; 95% CI, 0.86 to 0.98; P = .01) or stage IIIA-B (HR, 0.94; 95% CI, 0.89 to 0.99; P = .025) uterine serous carcinoma, but not among women with carcinosarcoma or clear cell adeno-carcinoma. Five-year survival for women with one to four nodes removed and endometrioid or serous histology was 85% (95% CI, 84% to 85%) and 54% (95% CI, 50% to 59%), respectively. Five-year survival was significantly higher for women with ≥ 20 removed nodes and endometrioid (91%; 95% CI, 90% to 91%) or serous (72%; 95% CI, 68% to 76%) histology ( P < .001)., Conclusion: Increased lymph node count is associated with a 1% to 14% decreased hazard of death per each additional five lymph nodes removed and a 5% to 20% increased 5-year survival among women with pathologically node-negative endometrioid and serous endometrial cancers.

Objective: To determine overall survival (OS) and factors associated with OS of women with Mullerian adenosarcoma., Methods: Women with adenosarcoma of the uterus, cervix or ovary (n=2205) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. A subset analysis of women with uterine adenosarcoma was also performed. Analyzed confounders included age, insurance status, income, race, surgical margin status, nodal and distant metastasis, surgical procedure type, and treatment with radiation and/or chemotherapy., Results: Primary sites were uterus (n=1884), cervix (n=229) and ovary (n=92), representing 0.43% of uterine, 0.16% of cervical, and 0.04% of ovarian cancers in the NCDB. Only 36/1176 (3.1%) and 2.5% (33/1,342) had nodal and/or distant metastasis, respectively, at diagnosis. Distant metastasis, positive surgical margin, increased age, higher composite comorbidity score and adjuvant radiotherapy were independently associated with decreased OS. Primary site, lymph node status, surgical procedure, chemotherapy use, race, insurance status and income quartiles were not significantly associated with OS. Each 1cm increase in tumor size was associated with increased hazard for death (HR (95% CI) 1.06 (1.01-1.12), p=0.018) among women with uterine adenosarcoma., Conclusion: Complete surgical resection remains the only treatment with well-evidenced OS benefit among women with Mullerian adenosarcoma. Early surgical resection may increase survival of Mullerian adenosarcoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for uterine cancer., Methods: Women with uterine cancer who underwent exenteration (n=1160) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, comorbidity score, insurance status, income, distance from home to treatment center, stage, distant and nodal metastasis, tumor size, surgical margin status, exenteration type, and treatment with radiation and/or chemotherapy., Results: Among women with follow-up data (n=652), median (IQR) OS was 63.1 (42.2-107.2) and 17.6 (14.7-23.9) months for women with node-negative versus node-positive disease, respectively. Histology (p=1.5×10 -4 ), grade (p=7.9×10 -14 ), race (p=0.0002), lymph node status (p=1.0×10 -14 ), surgical node evaluation (p=2.8×10 -8 ), surgery for distant metastasis (p=0.004), distant metastasis at diagnosis (p=1.3×10 -10 ), positive surgical margins (p=1.6×10 -9 ), radiotherapy (p=0.004), and insurance status (p=6.5×10 -6 ) were significantly associated with differential, unadjusted Kaplan-Meier OS estimates. Exenteration type was not associated with OS (p=0.357). By multivariate regression, increased age, positive surgical margins, nodal metastasis or unknown nodal status, higher histologic grade, and black race were associated with increased hazards for death., Conclusion: Exenteration may be curative for well-selected women with uterine cancer, particularly among women with pathologically negative lymph nodes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the utility of urine protein/creatinine ratio (uPCR) measurements among healthy parturients at term we performed a prospective cohort study at a community teaching hospital., Methods: Serial urine samples were collected. Ninety-three women contributed 284 urine samples. uPCRs were determined. Multiple imputation and paired sampled analysis was performed when appropriate., Results: Two-thirds (63/93) of women had at least one measured uPCR ≥ 0.3. One-third (31/93) had a uPCR ≥ 0.3 at admission, including 39.1% (9/23) of women not in labor. Median (IQR) uPCRs increased during labor and after delivery: latent phase/no labor, 0.15 (0.06-0.32); active phase, 0.29 (0.10-0.58); early postpartum, 0.45 (0.18-1.36) (all p < 0.04). Median uPCRs were significantly < 0.3 in the latent phase and significantly > 0.3 in the immediate postpartum period (p < 0.01). Women who labored before cesarean delivery had the highest early postpartum uPCRs: median (IQR) 1.16 (0.39-1.80). A negative urine dipstick protein result did not exclude uPCR ≥ 0.3. uPCRs were similar when compared by method of urine collection., Conclusion: uPCR ≥ 0.3 is common among healthy women with uncomplicated pregnancies at term. uPCR increases during labor and is not a reliable measure of pathologic proteinuria at term or during the peripartum period.

Objective: Ovarian cancer is the gynecologic malignancy with the highest case-fatality rate due to the development of chemotherapy resistance. Predictors of chemotherapy response are needed to guide chemotherapy selection and improve survival for patients with ovarian cancer. Wnt signaling may impact chemoresistance in ovarian cancer., Methods: We studied The Cancer Genome Atlas patients with ovarian cancer treated with intraperitoneal or intravenous-only adjuvant chemotherapy. Cox regression tested associations of expression of 26 Wnt pathway genes with progression-free survival and overall survival. Permutation tests compared survival between chemotherapy groups stratified by expression. P values are two-tailed., Results: Increased FZD3 was associated with increased survival (intraperitoneal group, overall survival: hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.72, P = 0.009; progression-free survival: HR, 0.58; 95% CI, 0.37-0.92, P = 0.020) (intravenous-only group, overall survival: HR, 0.85; 95% CI, 0.72-0.99, P = 0.039; progression-free survival: HR, 0.83; 95% CI, 0.73-0.95, P = 0.006). Low FZD3 predicted decreased overall survival after intraperitoneal versus intravenous-only chemotherapy (21.7 vs 33.3 months, P < 0.0001). Increased APC2 was associated with decreased overall survival (HR, 1.22; 95% CI, 1.05-1.42; P = 0.009) and progression-free survival (HR, 1.28; 95% CI, 1.12-1.45; P = 0.0002)., Conclusions: Up-regulated tumor Wnt signaling predicts increased ovarian cancer survival. FZD3 may predict benefit from intraperitoneal chemotherapy.

Objective: To evaluate factors associated with delayed surgical treatment among women with endometrial cancer., Methods: Using the National Cancer Database (NCDB), we analyzed time to first surgery for epithelial endometrial cancer patients who underwent surgical treatment from 2003 to 2011. Poisson regression was used to examine delays >6weeks between diagnosis and surgery, controlled for patients' sociodemographic and clinical characteristics. Survival for women diagnosed between 2003 and 2006 with timely versus delayed surgery was compared using Cox proportional hazards regression., Results: The study included 112,041 women diagnosed at 1108 continuously reporting NCDB hospitals. Survival through 2011 was available for 40,184 women. All patients underwent hysterectomy. Twenty-eight percent of patients underwent surgery >6weeks after diagnosis. Poisson regression estimates indicated that being younger than 40years old, being black or Hispanic, having Medicaid or being uninsured, or being from the lowest education quartile were associated with a significantly higher likelihood of surgical wait time>6weeks. Patients diagnosed in 2010-2011 were more likely (IRR 1.32, 95% CI 1.24-1.40) to undergo surgery >6weeks after diagnosis compared to patients treated in 2003. Survival for women with surgical wait times >6weeks was worse than those treated within 6weeks of diagnosis (HR 1.14, 95% CI 1.09-1.20)., Conclusions: Being a minority patient and having lower socioeconomic status or poor insurance coverage were associated with an increased likelihood of delayed surgical treatment. Wait times >6weeks from diagnosis of endometrial cancer to definitive surgery may have a negative impact on survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Tumor mRNA expression was used to discover genes associated with worse survival or no survival benefit after intraperitoneal (IP) chemotherapy. Data for high grade serous ovarian cancer patients treated with IP (n = 90) or IV-only (n =  398) chemotherapy was obtained from The Cancer Genome Atlas. Progression free survival (PFS) and overall survival (OS) were compared between IP and IV groups using Kaplan-Meier analysis and Cox regression. Validations were performed by analyses of microarray and RNA-Seq mRNA expression data. PFS and OS were compared between IP and IV groups by permutation testing stratified by gene expression. P-values are two-tailed. IP chemotherapy increased PFS (26.7 vs 16.0 months, HR 0.43 (0.28-0.66), p = 0.0001) and OS (49.6 vs 38.2 months, HR 0.46 (0.25-0.83), p = 0.01). Increased expression of NCAM2 and TSHR and decreased expression of GCNT1 was associated with decreased PFS and OS after IV chemotherapy (p < 0.05). High tumor expression of LMAN2, FZD4, FZD5, or STT3A was associated with no significant PFS increase after IP compared to IV chemotherapy. Low expression of APC2 and high expression of FUT9 was associated with 5.5 and 7.2 months, respectively, decreased OS after IP compared to IV chemotherapy (p ≤ 0.007).

Background: In 2012, Iranian's economy collapsed under strain from sanctions instituted to stop Iran from violating the International Nuclear Non-Proliferation Treaty. Sanctions have indirectly led to serious healthcare concerns, specifically cancer treatment. This is the first report to evaluate Iranian cancer healthcare while under international economic sanctions., Methods: Data and information were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms: "Iran", "health policy", "sanctions", "ethics", and "cancer". Articles published in the English language between 1966 and present were included, based on relevance to sanctions or the specific case of sanctions in Iran., Results: The Program of Action for Cancer Therapy evaluated Iran's National Cancer Control Program (NCCP), reporting it has substantial deficits, including prevention, diagnosis/treatment, palliative care, monitoring, and technology, with a serious drug shortage for cancer care. Sanctions have exemptions for medicines and food, but lead to disruption of health services through complications in transportation, transferring currencies or lack of money., Conclusion: There is increasing evidence that sanctions harm vulnerable populations, while blocking globalization and not creating political or social change quickly. Improvement of Iran's NCCP is not feasible, and the health of cancer patients will continue to decline while the sanctions are in effect. The solution is complex, but a modern and innovative approach to diplomacy, which includes human rights, is necessary., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The accurate preoperative evaluation of endometrial cancer is needed to inform disease staging, but the evaluation may be more prone to error if the physical signs of advanced stage disease are difficult to appreciate in morbidly obese patients., Case: A morbidly obese (BMI = 56.9 kg/m2) 67-year-old woman with postmenopausal uterine bleeding was diagnosed with low-grade stage IB endometrial endometrioid adenocarcinoma after surgical staging. She received adjuvant vaginal brachytherapy. Fourteen months after surgery she presented with an ulcerating left inguinal mass. Fine-needle biopsy demonstrated adenocarcinoma consistent with her primary endometrioid adenocarcinoma. At the time of initial diagnosis, a preoperative physical examination was negative for inguinal lymphadenopathy and a computed tomography(CT) demonstrated inguinal lymphadenopathy that was not appreciated., Conclusion: In morbidly obese patients, the sensitivity of a physical examination is limited by body habitus. Obese patients with limited physical examinations may benefit from imaging studies to aid early diagnosis of extraperitoneal disease.

The objective of this study was to determine if ovarian cancer patients with a TP53 mutation grouped by location of the mutation within the p53 protein structure exhibit differential survival outcomes. Data from patients with high grade serous ovarian cancer (HGS OvCa) (N = 316) or breast cancer (BrCa) (N = 981) sequenced by The Cancer Genome Atlas (TCGA) was studied by Kaplan-Meier and Cox proportional hazards survival analysis. A TP53 DNA binding domain (BD) missense mutation (MM) occurred in 58.5% (185/316) of HGS OvCas and 16.8% (165/981) of BrCas. Patients with a TP53 DNA BD MM grouped by structural location had significantly different overall survival (OS) and progression free survival (PFS). Median OS (months) of HGS OvCa patients by structural group were: Sheet-loop-helix stabilizers, 31.1; DNA minor groove residue R248, 33.6; Wild-type, 34.2; all other MMs, 44.5; DNA major groove residues, 84.1, and zinc ion coordinating residues, 87.0 (log-rank p = 0.006). PFS of DNA major groove MM cases was longer than TP53 wild-type cases (19.1 versus 10.1 months, log-rank p = 0.038). HGS OvCa and BrCa patients with structurally-grouped TP53 DNA BD MMs have different survival outcomes.

The objective of this study was to determine the feasibility and diagnostic performance of cytopathologic evaluation of postprocedure washings collected after hysterectomy for gynecologic cancer. A total of 92 cases of hysterectomy for malignancy having cytology reports of both pre- and postprocedure washings were retrospectively identified. In all, 98.7% of preprocedure and 99.3% of postprocedure washings (P = 1.00) were satisfactory for cytopathology. Discordance regarding the observation of malignant cells between preprocedure and postprocedure washings was insignificant (P = .267). The sensitivity of postprocedure cytology for detecting malignant cells in cases of positive peritoneal histology was significantly lower than the sensitivity of preprocedure cytology (28.6% vs 57.1%, P = .041), with similar specificities (both 94%). Four patients with endometrial cancer having negative preprocedure peritoneal cytology were discovered to have positive postprocedure cytology. Postprocedure peritoneal cytology is feasible and may benefit patients with early-stage cancer by increasing the detection of microscopic peritoneal metastasis or cancer cell seeding during surgery., (© The Author(s) 2014.)

Objective: To test if TP53 hot spot mutations (HSMs) confer differential chemotherapy resistance or survival outcomes, the effects of microtubule stabilizers on human ovarian carcinoma cells (OCCs) expressing TP53 HSMs were studied in vitro. Survival outcomes of patients with high grade serous epithelial ovarian carcinoma (HGS EOC) expressing matched HSMs were compared using The Cancer Genome Atlas (TCGA) data., Methods: Growth inhibition of OCCs transfected with a HSM (m175, m248 or m273) was measured during treatment with paclitaxel, epothilone B (epoB), or ixabepilone. Effects of epoB on p53 expression, phosphorylation, and acetylation, as well as p53-regulated expression of p21 and mdm2 proteins, were determined by Western blot analysis. Expression of p53 target genes P21, GADD45, BAX, PIDD, NF-kB2, PAI-1, and MDR1 was measured by RT-PCR. cBioPortal.org identified patients with codon R175, R248 or R273 HSMs from TCGA data. Survival outcomes were characterized., Results: p53-m248 confers chemoresistance and is not acetylated during epoB treatment. m273 demonstrated high MDR1 expression and resistance to paclitaxel. P21, GADD45 and PAI-1 expression were down-regulated in mutant OCCs. Optimally cytoreduced patients with codon R273 (n=17), R248 (n=13), R175 (n=7) HSMs, or any other TP53 mutation demonstrated median 14.9, 17.6, 17.8 and 16.9months (p=0.806) progression free survival and 84.1, 33.6, 62.1 and 44.5months (p=0.040) overall survival, respectively., Conclusions: Human OCCs harboring different TP53 HSMs were selectively resistant to microtubule stabilizers. Patients with different HSMs had significantly different overall survival. Both in vitro data and clinical experience support further studying the outcomes of particular TP53 HSMs., Competing Interests: statement The study authors have no conflicts of interest to declare., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To increase opportunities for Obstetrics and Gynecology(Ob/Gyn) residents to present their research, an Annual State of Connecticut Ob/Gyn Resident Research Day (RRD) was created. At the first annual RRD, 33 residents, representing five of six Connecticut Ob/Gyn residency programs, presented 39 poster and eight oral presentations. RRD evaluators rated the overall symposium and the quality of resident oral and poster presentations as either "excellent" or "above average." Residency program directors reported that the symposium was "very helpful" for evidencing resident scholarship as required by the Accreditation Council for Graduate Medical Education (ACGME). Surveyed residents reported that the symposium promoted their research and was a valuable investment of their time. An annual specialty-specific, statewide RRD was created, experienced good participation, and was well evaluated. The annual, statewide Ob/Gyn RRD may serve as a model for development of other specialty-specific, statewide RRD events.

Aplastic anemia is characterized by bone marrow failure and pancytopenia. In women, this can lead to menorrhagia secondary to thrombocytopenia which may require treatment depending on its severity. We report a patient with aplastic anemia-associated menorrhagia requiring emergency inpatient endometrial ablation due to transfusion dependence. A 42-year-old G3P3003 female presented with severe anemia, thrombocytopenia, and metrorrhagia. Her subsequent bone marrow biopsy revealed aplastic anemia. Her menometrorrhagia progressively worsened and she remained transfusion dependent. In the hospital, the patient underwent an uneventful endometrial ablation to control her vaginal bleeding. Patient reports only minor spotting after the procedure. Endometrial ablation is a safe and effective technique of treating acute menorrhagia in patients with aplastic anemia. It can reduce vaginal bleeding and decrease transfusion dependence.

Uterine sarcomas spread via lymphatic and hematogenous dissemination, direct extension, or transtubal transport. Distant metastasis often involves the lungs. Ovarian metastasis is uncommon. Here we present an unusual case of a large, high-grade uLMS with metastatic disease internal to both ovaries without capsular involvement or other abdominal diseases, and discovered in a patient with distant metastases to the lungs, suggesting likely hematogenous dissemination of uLMS to the ovaries in this case. Knowledge of usual uLMS metastases may influence surgical management in select cases.

This paper will present a case of benign metastasizing leiomyoma, incidentally found during the preoperative evaluation for acute cholecystitis. The preoperative chest X-ray revealed diffuse bilateral lung nodules suspicious for hematogenous metastasis and the densities measured 1-1.5 cm. A pelvis computed tomography (CT) scan showed in-homogeneous uterine mass with unusual vascular supply raising concern for leiomyosarcoma. Open lung biopsy revealed benign-appearing smooth-muscle neoplasm suggestive of metastatic leiomyoma. The patient was then treated with total abdominal hysterectomy with bilateral salpingo-oopherectomy which had identical pathology to the lung. As there were innumerable pulmonary metastases where complete resection was impossible, surgical castration appeared to be effective in reducing tumor size. The patient was also started on an aromatase inhibitor that subsequently improved her clinical outcome. Management strategies, cytogenetics, and histological diagnosis are discussed.

We have refined the technique for isolating and propagating cultures of primary ovarian carcinosarcoma cells (OSCs) derived from ascites, which allowed the cells to obtain the biphasic features of carcinosarcoma in cell culture conditions (presence of both carcinoma and mesenchymal morphologic types). This protocol involves a simple yet rapid method for the growth and propagation of ascites OSC in a basal culture medium. Autologous ascitic fluid was used as source of growth factors, and minimal manipulation was involved to establish the culture. The methodology allowed for the direct application of multiple molecular, cellular, and functional analyses within a few weeks of initial cell isolation, with the further potential of retrospective analyses of archived cells and tissues.

Ovarian cancer remains the most common cause of gynecologic cancer-related death among women in developed countries. Nevertheless, subgroups of ovarian cancer patients experience relatively longer survival. Efforts to identify prognostic factors that characterize such patients are ongoing, with investigational areas including tumor characteristics, surgical management, inheritance patterns, immunologic factors, and genomic patterns. This review discusses various demographic, clinical, and molecular factors implicating longevity and ovarian cancer survival. Continued efforts at identifying these prognosticators may result in invaluable adjuncts to the treatment of ovarian cancer, with the ultimate goal of advancing patient care.