Association of chemotherapy and radiotherapy sequence with overall survival in locoregionally advanced endometrial cancer.

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.

Survival after Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer.

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.).

Association of Circulating Tumor Cell Status With Benefit of Radiotherapy and Survival in Early-Stage Breast Cancer.

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.

Association of increased primary breast tumor AGR2 with decreased disease-specific survival.

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.

21-Gene Recurrence Score Assay Predicts Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer.

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.

Discussing sarcoma risks during informed consent for nonhysterectomy management of fibroids: an unmet need.

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.

Prognosis and treatment of positive peritoneal cytology in early endometrial cancer: matched cohort analyses from the National Cancer Database.

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.

Survival After Primary Debulking Surgery Compared With Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: A National Cancer Database Study.

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.

Transversus abdominis plane block with liposomal bupivacaine compared to oral opioids alone for acute postoperative pain after laparoscopic hysterectomy for early endometrial cancer: a cost-effectiveness analysis.

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.

Low-grade and high-grade endometrial stromal sarcoma: A National Cancer Database study.

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.

Association of body mass index with ER, PR and 14-3-3σ expression in tumor and stroma of type I and type II endometrial carcinoma.

Obesity is a prominent risk factor for endometrial cancer (EC) and can impede on surgical and hormonal treatments. Markers of EC, estrogen receptor (ER), progesterone receptor (PR), phospho(Ser473)-AKT (pAKT) and 14-3-3 sigma (14-3-3σ) were measured in EC tissues in both the tumor and stroma and grouped by body mass index (BMI). Immunohistochemical scoring of 82 cases of Type 1 and Type II EC tissues revealed a significantly increased tumor expression of ER, PR and 14-3-3σ in women with Type I (BMI < 40) as compared to Type II (BMI < 30) EC. With higher BMI, only PR and 14-3-3σ in the tumor epithelium was significantly higher in Type I than Type II. In particular, Type I EC exhibited significantly increased levels of only PR from patients with BMI > 40 compared to BMI < 40. Type II EC showed increased expression of ER in the stroma only between high and low BMI. Analysis of the TCGA RNA-Seq mRNA expression of ER, PR, PIK3CA, PTEN and SFN (gene for 14-3-3σ) confirmed increased PR expression in EC of obese women. In conclusion, ER, PR and 14-3-3σ are differentially regulated in Type I compared to Type II EC while PR is dysregulated in obese women with Type I EC. These findings have potential implications for efficacy of progestin treatment in obese women.

Ovarian granulosa cell tumor: A National Cancer Database study.

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.

The Hispanic Paradox in endometrial cancer: A National Cancer Database study.

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.

Stage I uterine carcinosarcoma: Matched cohort analyses for lymphadenectomy, chemotherapy, and brachytherapy.

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.

Prognosis and treatment of uterine leiomyosarcoma: A National Cancer Database study.

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.

Cost-effectiveness analysis of dose-dense versus standard intravenous chemotherapy for ovarian cancer: An economic analysis of results from the Gynecologic Oncology Group protocol 262 randomized controlled trial.

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.

Macrogenomic engineering via modulation of the scaling of chromatin packing density.

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.

Association of Lymph Node Count and Overall Survival in Node-Negative Endometrial Cancers.

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.