The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

Utilization of sentinel lymph node biopsy in the early ovarian cancer surgery.

OBJECTIVE: Sentinel lymph node (SLN) biopsy has been incorporated into surgical care for many malignancies; however, the utility has not been examined in ovarian cancer. This study examined population-level trends, characteristics, and outcomes related to SLN biopsy in early stage ovarian cancer. METHODS: This is a retrospective cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Result Program from 2003-2018. The study population consisted of 11,512 women with stage I ovarian cancer who had adnexectomy-based surgical staging including lymph node evaluation. Exposure allocation was based on SLN biopsy use. Main outcomes measured were (i) trends and characteristics associated with SLN biopsy use, assessed by multivariable logistic regression model, and (ii) overall survival assessed with inverse provability of treatment weighting propensity score. RESULTS: SLN biopsy was performed in less than 1% of study population. In a multivariable analysis, recent surgery (2011-2018 versus 2003-2010, odds ratio [OR] 1.64, 95% confidence interval [CI] 1.03-2.59), smaller tumor size (< 10 versus ≥ 10 cm, OR 3.07, 95% CI 1.20-7.84), and East registry area (OR 2.74, 95% CI 1.73-4.36) remained independent characteristics for SLN biopsy use. In a propensity score weighted model, 5-year overall survival rate was 90.5% for the SLN biopsy-incorporated group and 88.6% for the lymphadenectomy group (hazard ratio 0.96, 95% CI 0.53-1.73). CONCLUSION: SLN biopsy was rarely performed for early ovarian cancer surgery during the study period with insufficient evidence to interpret the survival effect. SLN biopsy in early ovarian cancer appears to be in early development phase, warranting further study and careful evaluation to assess feasibility and oncologic outcome.

Uptake in sentinel lymph node biopsy for endometrial cancer with T3 classification.

OBJECTIVE: The current clinical practice guidelines for endometrial cancer specify sentinel lymph node (SLN) biopsy to be performed in apparent uterine-confined disease. However, a recent population-based analysis found that the utilization of SLN biopsy is increasing in extra-uterine disease such as T2 classification. The objective of this study was to examine trends and outcomes related to SLN biopsy for endometrial cancer with T3 classification, another extra-uterine disease. METHODS: A population-based retrospective cohort study was conducted to examine 7004 women with T3 endometrial cancer who underwent primary surgery between 2010 and 2018, identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Trends and characteristics related to SLN biopsy were assessed by multinomial regression analysis, and inverse probability of treatment weighting propensity score was used to assess overall survival related to SLN biopsy. RESULTS: Nodal evaluation type included lymphadenectomy (n = 5276, 75.3%), SLN biopsy (n = 287, 4.1%), and none (n = 1441, 20.6%). The utilization of SLN biopsy increased from 0.4% to 12.9% between 2010 and 2018 (P < 0.001) that this association remained independent in multivariable analysis (adjusted-odds ratio compared to 2010-2012, 2.63 [95% confidence interval 1.57-4.42] for 2013-2015 and 10.1 [95% confidence interval 6.30-16.2] for 2016-2018). When compared to the lymphadenectomy group, the SLN biopsy group was less likely to have T3b disease (adjusted-odds ratio 0.69, 95% confidence interval 0.51-0.94) but had similar postoperative chemotherapy and radiotherapy (both, P > 0.05). In a weighted model, the 3-year overall survival rate was 66.3% for the SLN biopsy group and 64.7% for the lymphadenectomy group (hazard ratio 0.85, 95% confidence interval 0.69-1.05). Similar association was observed in subcohorts for young, old, endometrioid, non-endometrioid, T3a, T3b, and N0 cases. CONCLUSION: Utilization of SLN biopsy in T3 endometrial cancer is increasing in the United States.

Sentinel lymph node biopsy for stage II endometrial cancer: Recent utilization and outcome in the United States.

OBJECTIVE: To examine trends and outcomes related to sentinel lymph node (SLN) biopsy for stage II endometrial cancer. METHODS: This is a retrospective observational cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 6,314 women with T2 endometrial cancer who underwent hysterectomy from 2010-2018. Exposure allocation was based on nodal evaluation type: lymphadenectomy (LND; n=4,915, 77.8%), SLN biopsy (n=340, 5.4%), or no surgical nodal evaluation (n=1,059, 16.8%). The main outcomes were (i) trends and characteristics related to nodal evaluation assessed by multinomial regression, and (ii) overall survival (OS) assessed by an inverse probability of treatment weighting propensity score analysis. A sensitivity analysis was performed to examine concurrent LND in women who underwent SLN biopsy. RESULTS: The utilization of SLN biopsy increased from 1.6% to 16.1%, while the number of LND decreased from 81.5% to 65.7% between 2010-2018 (P<0.05). In multivariable analysis, the utilization of SLN biopsy increased 45% annually (adjusted-odds ratio 1.45, 95% confidence interval [CI] 1.37-1.54, P<0.001). The frequency of SLN biopsy alone exceeded the frequency of SLN biopsy with concurrent LND in 2017 (6.8% versus 3.4%), followed by continued increase in SLN biopsy alone (11.2% versus 4.9%) in 2018. In the weighted model, the 3-year OS rate was 79.9% for the SLN biopsy group and 78.6% for the LND group (hazard ratio 0.98, 95%Cl 0.80-1.20, P=0.831). Similarly, the SLN biopsy alone without concurrent LND had comparable OS compared to the LND group (hazard ratio 0.90, 95%CI 0.59-1.36, P=0.615). CONCLUSION: Utilization of SLN biopsy in stage II endometrial cancer increased significantly over time, and SLN biopsy-incorporated nodal assessment was not associated with worsened short-term survival outcome.

Population-level trends and outcomes of sentinel lymph node biopsy in vulvar cancer surgery in the United States.

OBJECTIVE: To examine population-level trends, characteristics, and outcomes related to nodal assessment for vulvar cancer surgery in the United States. METHODS: This is a retrospective cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 5604 women with T1b or T2-smaller(≤4 cm) squamous cell carcinoma of the vulva who underwent primary vulvectomy from 2003 to 2018. The exposure allocation was based on nodal evaluation type: lymphadenectomy (LND; n = 3319, 59.2%), sentinel lymph node (SLN) biopsy (n = 751, 13.4%), or no surgical nodal evaluation (n = 1534, 27.4%). The main outcomes were (i) trends and characteristics related to SLN biopsy assessed by multinomial regression model, and (ii) vulvar cancer-specific survival assessed by competing risk analysis and inverse probability of treatment weighting propensity score. Sensitivity analysis included evaluation of external cohort with T1a disease (n = 1291). RESULTS: The utilization of SLN biopsy increased from 5.7% to 23.3% in 2006-2018, while the proportion of LND decreased from 64.1% to 48.8% in 2010-2018, and these associations remained independent in multivariable analysis (adjusted-P < 0.05). In the propensity score weighted model, 5-year cumulative rate for vulvar cancer-specific mortality was 15.2% (interquartile range 12.1-18.9) for the SLN biopsy group and 16.9% (interquartile range 15.6-18.3) for the LND group (subdistribution-hazard ratio 0.90, 95% confidence interval 0.76-1.06, P = 0.217). The increasing SLN biopsy use was also observed in T1a disease from 1.3% to 7.3% during the study period (P < 0.001). CONCLUSION: The landscape of surgical nodal evaluation is shifting from lymphadenectomy to SLN biopsy in vulvar cancer surgery in the United States. SLN biopsy-incorporated treatment approach was not associated with worse survival compared to LND.

Population incidence and characteristics of secondary breast cancer after uterine cancer: a competing risk analysis.

PURPOSE: To examine incidence and characteristics of women who developed secondary breast cancer after uterine cancer. METHODS: This is a population-based retrospective cohort study utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Result Program from 1973 to 2013. Women with uterine cancer who did not have synchronous or a history of breast cancer were followed after their uterine cancer diagnosis (N = 236,561). A time-dependent competing risk analysis was performed to examine cumulative incidences and clinico-pathological characteristics of those who subsequently developed breast cancer. RESULTS: There were 7110 (3.0%) women who developed secondary breast cancers after uterine cancer with 5-, 10-, and 20-year cumulative incidence rates of 1.5, 2.8, and 4.7%, respectively. The increase in the rate of secondary breast cancer was particularly high in the first 3 years after a uterine cancer diagnosis (annual percent change [APC] 4.9), followed by 3-7 years (APC 1.6) after diagnosis (P < 0.001). The median time to develop secondary breast cancer was 6.4 years. Older women had significantly shorter time intervals between uterine and breast cancer diagnoses (3.7 years for aged > 71, 5.9 for aged 64-71, 7.6 for aged 56-63, and 9.4 for aged < 56, P < 0.001). In a multivariable analysis, older age, White race, married status, endometrioid, serous, and mixed histology types, and early-stage tumors remained as independent factors of developing secondary breast cancer (all, P < 0.05). CONCLUSION: Tumor factors with endometrioid and serous histology types and early-stage disease were the factors associated with secondary breast cancer after uterine cancer diagnosis. Older women had shorter time to develop secondary breast cancer.

Significance of Malignant Peritoneal Cytology on Survival of Women with Uterine Sarcoma.

PURPOSE: This study was designed to examine the association between malignant peritoneal cytology and survival of women with uterine sarcoma. METHODS: This retrospective, observational study queried the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. Uterine sarcoma cases diagnosed from 2010 to 2016 with known peritoneal cytology results were examined. Propensity score inverse probability of treatment weighting was fitted to balance the measured covariates. Overall survival (OS) was compared between malignant and negative cytology cases. RESULTS: A total of 1481 uterine sarcomas were examined. Malignant peritoneal cytology was seen in 146 (9.9%) cases. Women who had T3 disease and distant metastases had the highest incidence of malignant peritoneal cytology (43.1%). In multivariable analysis, higher T stage, nodal involvement, distant metastasis, poorer tumor differentiation, and rhabdomyosarcoma/endometrial stromal sarcoma were significantly associated with an increased risk of malignant peritoneal cytology (all, P < 0.05). In the weighted model, malignant peritoneal cytology was associated with a nearly twofold increased risk of all-cause mortality compared with negative peritoneal cytology (3-year OS rate 34.7% versus 60.2%; hazard ratio 2.26; 95% confidence interval 1.88-2.71; P < 0.001). The absolute difference in the 3-year survival rate was particularly large in leiomyosarcoma (3-year OS rate 2.8% versus 51.9%; hazard ratio 2.64; 95% confidence interval 1.94-3.59; P < 0.001). Malignant peritoneal cytology was also associated with an increased all-cause mortality risk in early and advanced stages (both, P < 0.05). CONCLUSIONS: Our study suggests that malignant peritoneal cytology may be a prognostic factor for increased mortality in uterine sarcoma, particularly in uterine leiomyosarcoma.

Association Between Adjuvant Therapy and Survival in Stage II-III Endometrial Cancer: Influence of Malignant Peritoneal Cytology.

OBJECTIVE: The aim of this study was to examine the survival effect of adjuvant therapy in stage II-III endometrial cancer based on peritoneal cytology results. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results Program was retrospectively queried to examine 7467 women with stage II-III endometrial cancer who underwent hysterectomy, and with available peritoneal cytology results, from 2010 to 2016. A Cox proportional hazard regression model was fitted to assess the association between adjuvant therapy and all-cause mortality stratified by peritoneal cytology results. RESULTS: Malignant peritoneal cytology was reported in 1662 (22.3%) women and was associated with non-endometrioid histology, higher tumor stage, and nodal metastasis (p < 0.05). In a propensity score-weighted model, malignant peritoneal cytology was associated with increased all-cause mortality compared with negative peritoneal cytology (hazard ratio 1.35, 95% confidence interval 1.23-1.48). Adjuvant therapy types varied based on histology and peritoneal cytology results. In non-endometrioid histology, the combination of chemotherapy and whole pelvic radiotherapy (WPRT) was associated with improved overall survival compared with chemotherapy or WPRT alone irrespective of the peritoneal cytology results (p < 0.05). The combination of chemotherapy and WPRT was also associated with improved overall survival in women with endometrioid histology and malignant peritoneal cytology (p = 0.026). Women with endometrioid histology and negative peritoneal cytology represented the most common subpopulation (46.5%), and overall survival was similar regardless of which of the three adjuvant therapy modalities was used (p = 0.319). CONCLUSIONS: Malignant peritoneal cytology is prevalent and prognostic in stage II-III endometrial cancer. This study found that the surgeon's choice and benefit of adjuvant therapy for women with stage II-III endometrial cancer differed depending on the status of peritoneal cytology.

Possible candidate population for neoadjuvant chemotherapy in women with advanced ovarian cancer.

OBJECTIVE: To examine trends and outcomes related to neoadjuvant chemotherapy (NACT) use for advanced ovarian cancer based on patient and tumor factors. METHODS: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program to examine women with stage III-IV high-grade serous ovarian carcinoma from 2010 to 2016. Propensity score inverse probability of treatment weighting was used to assess the age-, cancer stage-, and tumor extent-specific survival estimates related to NACT use. RESULTS: Utilization of NACT has significantly increased in older women (≥65 years; 48.4% relative increase), followed by stage IV disease (35.2% relative increase), and stage III disease (25.0% relative increase) (all, P-trend < 0.05). Women who received NACT had overall survival (OS) similar to those who had primary cytoreductive surgery (PCS) in older women (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.95-1.20, P = 0.284), stage IV disease (HR 0.96, 95%CI 0.84-1.10, P = 0.564), and more disease extent cases (T3/N1/M1, HR 1.06, 95%CI 0.84-1.32, P = 0.640). Moreover, NACT use was associated with decreased other cause mortality risk compared to PCS in the older women (sub-distribution HR 0.61, 95%CI 0.40-0.94, P = 0.025) and stage IV disease (sub-distribution HR 0.49, 95%CI 0.27-0.90, P = 0.021). In contrast, women who received NACT had decreased OS compared to those who had PCS in the younger group (HR 1.22, 95%CI 1.07-1.38, P = 0.004), stage III disease (HR 1.26, 95%CI 1.13-1.41, P < 0.001), and lesser disease extent cases (T3/N0/M0, HR 1.38, 95%CI 1.20-1.58, P < 0.001). CONCLUSION: Our study suggests that survival effect of NACT for advanced ovarian cancer may differ based on patient and tumor factors. In older women, stage IV disease, and greater disease extent, NACT was associated with similar OS compared to PCS.

Trends in peritoneal cytology evaluation at hysterectomy for endometrial cancer in the United States.

OBJECTIVE: The collection of a peritoneal cytologic sample at the time of surgery for endometrial cancer has traditionally been an important part of surgical staging. In 2009, the International Federation of Gynecology and Obstetrics revised the cancer staging schema for endometrial cancer and removed peritoneal cytology from the staging criteria. The current National Comprehensive Cancer Network guidelines and the International Federation of Gynecology and Obstetrics organization, however, recommend evaluation of peritoneal cytology at the time of hysterectomy. This study examined population-based trends, characteristics, and outcomes of peritoneal cytologic sampling for endometrial cancer surgery following the 2009 staging revision in the United States. METHODS: This is a retrospective observational study querying the Surveillance, Epidemiology, and End Results Program to examine women with stage I-III endometrial cancer who underwent hysterectomy from 2010 to 2017. Trends, characteristics, and survival associated with peritoneal cytologic evaluation at the time of hysterectomy were assessed in multivariable analysis and with propensity score weighting. RESULTS: Among 62,809 women who underwent hysterectomy, 43,873 (69.9%) had peritoneal cytologic evaluation at surgery and 18,936 (30.1%) did not. Utilization of peritoneal cytologic evaluation decreased from 75.5% to 64.9% during the study period (P < 0.001). In multivariable analysis, more recent year of surgery was independently associated with a decreased likelihood of performance of peritoneal cytology (adjusted-odds ratio of peritoneal cytology evaluation in 2017 versus 2010 0.56, 95% confidence interval [CI] 0.52-0.60). Peritoneal cytologic evaluation at the time of hysterectomy was associated with improved all-cause mortality (hazard ratio in the whole cohort 0.94, 95%CI 0.89-0.99; and hazard ratio in endometrioid histology 0.90, 95%CI 0.84-0.97). CONCLUSION: Performance of peritoneal cytologic sampling has gradually decreased following the 2009 staging revision in the United States. Our study suggests that peritoneal cytology evaluation at hysterectomy may be associated with improved survival in certain tumor groups.

Clinico-pathological significance of suspicious peritoneal cytology in endometrial cancer.

BACKGROUND AND OBJECTIVES: Suspicious peritoneal cytology refers to the result of peritoneal cytology testing that is insufficient in either quality or quantity for a definitive diagnosis of malignancy. This study examined characteristics and survival outcomes related to suspicious peritoneal cytology in endometrial cancer. METHODS: A population-based retrospective study by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program was conducted. A total of 41,229 women with Stage I-III endometrial cancer who had peritoneal cytologic sampling at hysterectomy from 2010 to 2016 were examined. A Cox proportional hazard regression model and a competing risk analysis with Fine-Gray model were fitted to assess survival outcome related to suspicious peritoneal cytology. RESULTS: Suspicious peritoneal cytology was seen in 702 (1.7%) cases. In multivariable models, suspicious peritoneal cytology was associated with increased risk of endometrial cancer mortality (subdistribution-hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.29-2.20, p < 0.001) and all-cause mortality (adjusted-HR: 1.55, 95% CI: 1.27-1.90, p < 0.001) compared with negative peritoneal cytology. Sensitivity analysis demonstrated that suspicious peritoneal cytology had discrete overall survival improvement compared with malignant peritoneal cytology in a propensity score weighting model (HR: 0.85, 95% CI: 0.72-0.99, p = 0.049). CONCLUSION: Our study suggests that suspicious peritoneal cytology may be a prognostic factor for decreased survival in endometrial cancer.

Proposing the 3-tier staging system for improving prognostication in Stage I uterine leiomyosarcoma.

BACKGROUND AND OBJECTIVES: To examine the utility of a 3-tier schema (≤5 cm, 5.1-10 cm, and > 10 cm) in determining characteristics and survival in Stage I uterine leiomyosarcoma. METHODS: This retrospective observational study queried the National Cancer Institute's Surveillance, Epidemiology, and End Result Program from 1988 to 2016. Surgically treated stage I uterine leiomyosarcomas with known tumor size were examined (N = 2217). Trends, characteristics, and survival were assessed based on tumor size. RESULTS: The most common tumor size was 5.1-10 cm (45.7%) followed by >10 cm (35.0%) and ≤5 cm (19.4%). Tumor size-shift occurred during the study period; the percentage of tumor size >10 cm increased from 12.9% to 44.5% and the groups with smaller tumor sizes decreased (p < .001). In weighted models, 5-year overall survival rates ranged from 49.9% to 71.6% in the 3-tier system and 55.2%-70.6% in the 2-tier system: the absolute difference was larger in the 3-tier system (21.7% vs. 15.4%). In the 3-tier system, all-cause mortality risk of tumor size >10 cm versus ≤5 cm nearly doubled (hazard ratio 1.96, 95% confidence interval 1.78-2.16). CONCLUSION: In the past decades, tumors of stage I uterine leiomyosarcoma have become larger. Our study suggests that a tumor size-based 3-tier staging system may be useful to differentiate survival in stage I uterine leiomyosarcoma.

Utilization and outcomes of adjuvant systemic chemotherapy alone in high risk, early stage cervical cancer in the United States.

OBJECTIVE: To examine trends and outcomes related to adjuvant systemic chemotherapy alone for high risk, early stage cervical cancer. METHODS: This retrospective observational study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2000 to 2016. Surgically treated women with American Joint Commission on Cancer stages T1-2 cervical cancer who had high risk factors (nodal metastasis and/or parametrial invasion) and received additional therapy were examined. Propensity score inverse probability of treatment weighting was used to assess the survival estimates for systemic chemotherapy versus external beam radiotherapy with chemotherapy. RESULTS: Among 2462 patients with high risk factors, 185 (7.5%) received systemic chemotherapy without external beam radiotherapy, of which the utilization significantly increased over time in multivariable analysis (adjusted odds ratio per 1 year increment 1.06, 95% confidence interval (CI) 1.02 to 1.09). In weighted models, adjuvant chemotherapy and combination therapy (external beam radiotherapy and chemotherapy) had comparable overall survival among patients aged <40 years (hazard ratio (HR) 0.73, 95% CI 0.41 to 1.33), in adenocarcinoma or adenosquamous histologies (HR 0.90, 95% CI 0.62 to 1.32), and in those with nodal metastasis alone without parametrial tumor invasion (HR 1.17, 95% CI 0.84 to 1.62). In contrast, systemic chemotherapy alone was associated with increased all cause mortality compared with combination therapy in patients aged ≥40 years (HR 1.57, 95% CI 1.19 to 2.06), with squamous histology (HR 1.63, 95% CI 1.19 to 2.22), and with parametrial invasion alone (HR 1.87, 95% CI 1.09 to 3.20) or parametrial invasion with nodal metastasis (HR 1.64, 95% CI 1.06 to 2.52). CONCLUSION: Utilization of adjuvant systemic chemotherapy alone for high risk, early stage cervical cancer is increasing in the United States in the recent years. Our study suggests that survival effects of adjuvant systemic chemotherapy may vary based on patient and tumor factors. External beam radiotherapy with chemotherapy remains the standard for high risk, early stage cervical cancer, and use of adjuvant systemic chemotherapy without external beam radiotherapy should be considered with caution.

National trends and outcomes of morbidly obese women who underwent inpatient hysterectomy for benign gynecological disease in the USA.

INTRODUCTION: The US population has witnessed an epidemic expansion of obesity in the past several decades; nearly 50% of the population is projected to be obese by 2030 and 25% morbidly obese. This study examined trends, characteristics and outcomes of morbidly obese women who underwent benign hysterectomy. MATERIAL AND METHODS: This is a population-based retrospective observational study querying the National Inpatient Sample from January 2012 to September 2015. The study population included 509 395 women who underwent hysterectomy for benign gynecological disease: 430 865 (84.6%) non-obese women, 50 435 (9.9%) women with class I-II obesity and 28 095 (5.5%) women with class III obesity. Main outcome measures were (i) cohort-level trends of obesity and perioperative complications assessed by piecewise linear regression with log transformation and (ii) patient-level perioperative complication risk by body habitus assessed with a generalized estimating equation after using a multiple-group generalized boosted model. RESULTS: The rate of class III obesity increased by 40.4%, higher than the rate of class I-II obesity (22.2%) (both, P < .001). In parallel, cohort-level rates of perioperative complication and prolonged hospitalization for ≥7 days increased by 19.4% and 54%, respectively (P < .001). In a weighted model, class I-II obesity (16.4% vs 14.6%, odds ratio 1.15, 95% confidence interval 1.08-1.21) and class III obesity (19.2% vs 14.6%, odds ratio 1.39, 95% confidence interval 1.28-1.51) had a significantly increased risk of perioperative complications compared with non-obesity. Larger body habitus was associated with higher total charge (median, $35 180, $36 094 and $39 382; all values cited in US dollars) and prolonged admission rate for ≥7 days (2.9%, 3.1% and 3.9%) (both, P < .001). CONCLUSIONS: The rate of obesity, particularly morbid obesity, has significantly increased among women undergoing benign hysterectomy in the USA. Morbidly obese women had adverse perioperative outcomes, and the increasing number of morbidly obese women resulted in both an increased perioperative morbidity and total charges as a cohort. National and society-based approaches are necessary to reduce the obesity rate and hysterectomy morbidity.

Risk of Upper-body Adverse Events in Robot-assisted Total Laparoscopic Hysterectomy for Benign Gynecologic Disease.

STUDY OBJECTIVE: Recent studies suggest that prolonged Trendelenburg positioning during robot-assisted total laparoscopic hysterectomy (RA-TLH) may lead to fluid shifts and pulmonary, airway, head and neck, and cranial complications in the upper body. This study examined the upper-body complications during RA-TLH for benign gynecologic disease. DESIGN: Population-based retrospective study. SETTING: The National Inpatient Sample. PATIENTS: A total of 771 412 women who had total hysterectomy for benign gynecologic disease from October 2008 to September 2015, including 661 284 women who had total abdominal hysterectomy (TAH), 51 544 women who had traditional TLH, and 58 584 women who had RA-TLH. INTERVENTIONS: A multiple-group generalized boosted model to balance the measured baseline covariates across the 3 hysterectomy groups and a generalized estimating equation model to assess the effect size of complication risk (overall and upper-body complications). MEASUREMENTS AND MAIN RESULTS: Women in the RA-TLH group were more likely to be older, white, and have a higher comorbidity index (all, p <.001). The overall rate of upper-body complications was 4.6% across the 3 groups. RA-TLH was not associated with increased risk of upper-body complications compared with traditional TLH (odds ratio [OR] 1.06; 95% confidence interval [CI], 0.90-1.26) or TAH (OR 0.98; 95% CI, 0.87-1.11). In contrast, RA-TLH was associated with decreased risk of overall perioperative complications compared with TAH (12.0% vs 18.6%; OR 0.64; 95% CI, 0.59-0.70; p <.001). RA-TLH and traditional TLH had similar risk of overall perioperative complications (12.0% vs 13.1%; OR 0.91; 95% CI, 0.8-1.02; p = .099). Women who developed upper-body complications had a higher perioperative mortality rate (0.4% vs <0.01%; OR 79.1; 95% CI, 36.0-174). The highest rates of complications (62.5%) were observed in morbidly obese women aged 70-79 with a comorbidity index of ≥4. CONCLUSION: In hysterectomy for benign gynecologic disease, RA-TLH was not associated with an increased risk of upper-body complications compared with TAH or traditional TLH. However, older age and higher comorbidity are key risk factors that increase the risk of upper-body complications which carry a disproportionally high mortality rate.

Wait-time for hysterectomy and survival of women with early-stage cervical cancer: A clinical implication during the coronavirus pandemic.

OBJECTIVE: A global pandemic caused by a novel coronavirus (Covid-19) has created unique challenges to providing timely care for cancer patients. In early-stage cervical cancer, postponing hysterectomy for 6-8 weeks is suggested as a possible option in the Covid-19 burdened hospitals. Yet, literature examining the impact of surgery wait-time on survival in early-stage cervical cancer remains scarce. This study examined the association between surgery wait-time of 8 weeks and oncologic outcome in women with early-stage cervical cancer. METHODS: This is a single institution retrospective observational study at a tertiary referral medical center examining women who underwent primary hysterectomy or trachelectomy for clinical stage IA-IIA invasive cervical cancer between 2000 and 2017 (N = 217). Wait-time from the diagnosis of invasive cervical cancer via biopsy to definitive surgery was categorized as: short wait-time (<8 weeks; n = 110) versus long wait-time (≥8 weeks; n = 107). Propensity score inverse probability of treatment weighting was used to balance the measured demographics between the two groups, and disease-free survival (DFS) and overall survival (OS) were assessed. A systematic literature review with meta-analysis was additionally performed. RESULTS: In a weighted model (median follow-up, 4.6 years), women in the long wait-time group had DFS (4.5-year rates, 91.2% versus 90.7%, hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.47-2.59, P = 0.818) and OS (95.0% versus 97.4%, HR 1.47, 95%CI 0.50-4.31, P = 0.487) similar to those in the short wait-time group. Three studies were examined for meta-analysis, and a pooled HR for surgery wait-time of ≥8 weeks on DFS was 0.96 (95%CI 0.59-1.55). CONCLUSION: Our study suggests that wait-time of 8 weeks for hysterectomy may not be associated with short-term disease recurrence in women with early-stage cervical cancer.

Malignant peritoneal cytology and increased mortality risk in stage I non-endometrioid endometrial cancer.

OBJECTIVE: To examine the survival of women with stage I non-endometrioid endometrial cancer with malignant peritoneal cytology. METHODS: A retrospective observational cohort study was conducted to examine the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2016. Women with stage I serous, clear cell, carcinosarcoma, undifferentiated, and mixed endometrial cancer with known peritoneal cytology results at hysterectomy were examined (N = 4506). Propensity score inverse probability of treatment weighting was used to balance the measured covariates, and survival outcomes were assessed according to peritoneal cytology results. RESULTS: Malignant peritoneal cytology was reported in 401 (8.9%) women. In multivariable analysis, older age, serous histology, and large tumors were associated with an increased likelihood of malignant peritoneal cytology (all, P < 0.05). In a propensity score weighted model, malignant peritoneal cytology was associated with a nearly two-fold increase in all-cause mortality risk compared to negative peritoneal cytology (5-year rates, 63.4% versus 80.2%, hazard ratio 2.18, 95% confidence interval 1.78-2.66). In sensitivity analyses, malignant peritoneal cytology was associated with decreased overall survival in old and young age groups, serous, clear cell, carcinosarcoma, and mixed histology groups, stage T1a disease, and staged and unstaged cases, but not for stage T1b disease. Difference in 5-year overall survival rates between the malignant and negative peritoneal cytology groups was particularly large among those with clear cell histology (24.0%), stage T1a disease (19.4%), aged >78 years (18.2%), and serous tumors (17.6%). CONCLUSION: Malignant peritoneal cytology can be prevalent in stage I non-endometrioid endometrial cancer. Our study suggests that malignant peritoneal cytology is a prognostic factor for decreased survival in stage I non-endometrioid endometrial cancer.

The rapid adoption of opportunistic salpingectomy at the time of hysterectomy for benign gynecologic disease in the United States.

BACKGROUND: Mounting evidence for the role of distal fallopian tubes in the pathogenesis of epithelial ovarian cancer has led to opportunistic salpingectomy being increasingly performed at the time of benign gynecologic surgery. Opportunistic salpingectomy has now been recommended as best practice in the United States to reduce future risk of ovarian cancer even in low-risk women. Preliminary analyses have suggested that performance of opportunistic salpingectomy is increasing. OBJECTIVE: To examine trends in opportunistic salpingectomy in women undergoing benign hysterectomy and to determine how the publication of the tubal hypothesis in 2010 may have contributed to these trends. STUDY DESIGN: This is a population-based, retrospective, observational study examining the National Inpatient Sample between January 2001 and September 2015. Women younger than 50 years who underwent inpatient hysterectomy for benign gynecologic disease were grouped as hysterectomy alone vs hysterectomy with opportunistic salpingectomy. All women had ovarian conservation, and those with adnexal pathology were excluded. Linear segmented regression with log transformation was used to assess temporal trends. An interrupted time-series analysis was then used to assess the impact of the 2010 publication of the tubal hypothesis on opportunistic salpingectomy trends. A regression-tree model was constructed to examine patterns in the use of opportunistic salpingectomy. A binary logistic regression model was then fitted to identify independent characteristics associated with opportunistic salpingectomy. Sensitivity analysis was performed in women aged 50-65 years to further assess surgical trends in a wider age group. RESULTS: There were 98,061 (9.0%) women who underwent hysterectomy with opportunistic salpingectomy and 997,237 (91.0%) women who underwent hysterectomy alone without opportunistic salpingectomy. The rate at which opportunistic salpingectomy was being performed gradually increased from 2.4% to 5.7% between 2001 and 2010 (2.4-fold increase; P<.001), predicting a 7.0% rate of opportunistic salpingectomy in 2015. However, in 2010, the rate of opportunistic salpingectomy began to increase substantially and reached 58.4% by 2015 (10.2-fold increase; P<.001). In multivariable analysis, the largest change in the performance of opportunistic salpingectomy occurred after 2010 (adjusted odds ratio, 5.42; 95% confidence interval, 5.34-5.51; P<.001). In a regression-tree model, women who had a hysterectomy at urban teaching hospitals in the Midwest after 2013 had the highest chance of undergoing opportunistic salpingectomy during benign hysterectomy (76.4%). In the sensitivity analysis of women aged 50-65 years, a similar exponential increase in opportunistic salpingectomy was observed from 5.8% in 2010 to 55.8% in 2015 (9.8-fold increase; P<.001). CONCLUSION: Our study suggests that clinicians in the United States rapidly adopted opportunistic salpingectomy at the time of benign hysterectomy following the publication of data implicating the distal fallopian tubes in ovarian cancer pathogenesis in 2010. By 2015, nearly 60% of women had undergone opportunistic salpingectomy at benign hysterectomy.

Populational trends and outcomes of postoperative radiotherapy for high-risk early-stage cervical cancer with lymph node metastasis: concurrent chemo-radiotherapy versus radiotherapy alone.

BACKGROUND: Pelvic lymph node metastasis carries the highest impact on decreased survival among surgical-pathological risk factors for early-stage cervical cancer. Although concurrent administration of chemotherapy during postoperative radiotherapy is the current standard treatment for surgically treated high-risk early-stage cervical cancer, its effectiveness specific to node-positive disease has not been completely studied. OBJECTIVE: To examine the association between the use of concurrent chemotherapy and survival in women with early-stage cervical cancer and nodal metastasis receiving adjuvant radiotherapy. MATERIALS AND METHODS: This is a population-based cohort study using the Surveillance, Epidemiology, and End Results Program from 1988 to 2016. Women with stage T1-2 cervical cancer with pelvic lymph node metastasis who underwent hysterectomy and received postoperative radiotherapy were examined. Trends, characteristics, and overall survival were compared between women who received postoperative radiotherapy alone (n = 729) or in combination with concurrent chemo-radiotherapy (n = 1809). Propensity score-based inverse probability of treatment weighting was used to account for the effect of measured covariates on treatment selection. RESULTS: Among 2538 women, there was a marked increase in the use of concurrent chemotherapy from 1997 to 2000 (20.7% to 78.5%, P = .052), followed by a more gradual rise through 2016 (88.3%, P < .001). In a multivariable model, women with non-squamous cell carcinomas and those diagnosed more recently were more likely to receive concurrent chemo-radiotherapy, whereas older women were less likely to receive concurrent chemo-radiotherapy (all, P < .05). At the population level, the 5-year overall survival rates remained unchanged (annual percent change for 1997-2012: -0.1; 95% confidence interval, -1.2 to 1.0; P = .776). In a propensity score weighted cohort, women who received concurrent chemo-radiotherapy had a 5-year overall survival rate similar to women treated with radiotherapy alone (73.1% vs 73.6%; hazard ratio, 1.004; 95% confidence interval, 0.887-1.136; P = .955). Significant differences were also not seen in older women, nonsquamous types, stage T2 disease, and multiple node metastases (all, P > .05). CONCLUSION: Despite the marked increase in the use of concurrent chemo-radiotherapy for women with early-stage cervical cancer and nodal metastases, there was no association between use of concurrent chemotherapy during postoperative radiotherapy and improved survival.