Mitigating disparity?: Treatment patterns, survival, and recurrence rates by race, ethnicity, and hospital site across a large urban health system.

Objective: National data have shown worse endometrial cancer (EC) outcomes among racial and ethnic minorities. We aimed to analyze EC patient outcomes within a large urban academic health system, with a focus on patterns of care and recurrence rates. Methods: This was a retrospective chart review of EC patients at three system hospitals from 1/1/07-12/31/17. Demographic and clinical factors, including time from EMB to surgery, rate of chemotherapy completion, persistent or recurrent disease, and palliative care referrals were extracted. Descriptive statistics and survival curves were generated. Analysis was done using SAS version 9.4. Results: Black patients had lower overall survival compared to all others on univariate analysis only (p < 0.0001). Hospital site was associated with OS, with the academic anchor and satellite 1 having higher rates of all-cause mortality compared to satellite 2 (HR 4.68 academic anchor, 95 % CI 1.72-12.76, HR 5.36 satellite 1, 95 % CI 1.85-15.52). Time from EMB to surgery and rates of persistent disease following primary treatment were higher in Black patients. After adjusting for stage and grade, chemotherapy completion rate was significantly associated with race. Palliative care was utilized more for Black than White patients after adjusting for stage and grade (p = 0.005). Conclusions: Racial disparities in EC are caused by a complex web of interconnected factors that ultimately lead to worse outcomes in Black women. While precision medicine has helped to close the gap, social determinants of health should be addressed, and models focusing on the complex interactions between biologic, genetic, and social factors should be utilized.

The robotic future of minimally invasive cytoreduction and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been increasingly utilized for peritoneal surface malignancies. This has been commonly utilized for a variety of neoplasms, but, especially mucinous neoplasms of the appendix, ovarian cancer, gastric cancer, colorectal cancer and mesothelioma. Traditionally, CRS/HIPEC has been performed as an open, extensive operation associated with prolonged hospitalization. However, when the peritoneal carcinomatosis index (PCI) is small (<10), minimally invasive approaches can be considered. Such less invasive approaches may be associated with improved postoperative recovery, less complications while preserving oncologic outcomes. The robotic platform offers distinct advantages over laparoscopy with superior visualization and ergonomics which account for its increased utilization in oncologic surgery. Herein, we review available data on minimally invasive approaches to CRS/HIPEC procedures, focusing on patient selection and comparative studies to open CRS/HIPEC. We summarize the existing initial studies on robotically assisted CRS/HIPEC and provide technical insights about our approach to robotically assisted CRS/HIPEC. Current data suggests that treatment of peritoneal surface malignancies with minimally invasive CRS/HIPEC is feasible in selected cases and is associated with improved postoperative recovery. The robotically assisted platform for CRS/HIPEC deserves further investigation and may improve outcomes after this procedure in the future for carefully selected patients with low PCI.

Differences between proximal and distal endometrial monolayer thickness in women aged over 50 years undergoing saline infusion sonohysterography.

BACKGROUND: Saline infusion sonohysterography (SIS) is a procedure performed to evaluate the endometrium in women with postmenopausal bleeding. PURPOSE: To investigate differences in endometrial monolayer measurements in women aged >50 years undergoing SIS. MATERIAL AND METHODS: Retrospective study of women aged >50 undergoing SIS. Endometrial echo (EE) was measured according to the International Endometrial Tumor Analysis (IETA) guidelines. Monolayer thickness was compared between anterior and posterior uterine walls and between the monolayer that was proximal or distal to the ultrasound probe. Presence and location of focal thickening and polyps on each of the monolayers were assessed. RESULTS: SIS was performed in 608 patients. Of them, 485 (79.8%) had anteverted, 85 (14%) retroverted, and 38 (6.2%) a midposition uterus. The mean posterior monolayer was thicker than the anterior monolayer (2.14 mm vs. 1.88 mm; P = 0.002). The distal monolayer was thicker than the proximal layer in both anteverted and retroverted uteri (2.18 mm vs. 1.84 mm; P < 0.0001). In 16% of women, the difference between distal and proximal monolayers was ≥1 mm. Focal thickening was seen 3.3 times more frequently in the distal endometrium. Among women with a double layer EE >4 mm, 18.8% had a proximal layer of <2 mm while only 4.6% had a distal EE <2 mm. CONCLUSION: Distal endometrium measures thicker than the proximal endometrium in most SIS cases and in one out of six women, the difference is >1 mm. The distal layer is three times more likely to contain focal thickening. Sonologists should be conscious of possible enhancement artifact when measuring the EE during SIS.

Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment.

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.

Thirty-day Postoperative Adverse Events in Minimally Invasive versus Open Abdominal Radical Hysterectomy for Early-stage Cervical Cancer.

STUDY OBJECTIVE: To identify the incidence, type, and grade of postoperative adverse events in minimally invasive radical hysterectomy vs abdominal radical hysterectomy (ARH) for patients with early-stage cervical cancer and determine risk factors associated with these adverse events. DESIGN: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was queried to identify patients with early-stage cervical cancer undergoing radical hysterectomy. Multivariable logistic regression was used to assess risk factors associated with adverse postoperative outcomes among patients undergoing radical hysterectomy. SETTING: ACS NSQIP participating institutions within the United States. PATIENTS: Patients were collected from the ACS NSQIP databases (2014-2017) undergoing radical hysterectomy for early-stage cervical cancer. INTERVENTIONS: N/A MEASUREMENTS AND MAIN RESULTS: ARH had a significantly increased incidence of any 30-day postoperative adverse event compared with minimally invasive radical hysterectomy (31.2% vs 19.9%, p <.001). There was a higher incidence of surgical site infection, both deep and superficial, and blood transfusions in ARH. On multivariable logistic regression, the abdominal surgical approach was the only risk factor significantly associated with any postoperative adverse event (odds ratio, 1.4; confidence interval, 1.1-1.9; p = .018; 95% CIs). CONCLUSIONS: In this study, the abdominal surgical approach for radical hysterectomy in early-stage cervical cancer was associated with a higher incidence of postoperative adverse events than the minimally invasive approach.

Alterations of the 70 kDa heat shock protein (HSP70) and sequestosome-1 (p62) in women with breast cancer.

Peripheral blood mononuclear cells (PBMCs) respond to altered physiological conditions to alleviate the threat. Production of the 70 kDa heat shock protein (HSP70) is up-regulated to protect proteins from degradation. Sequestosome-1 (p62) binds to altered proteins and the p62-protein complex is degraded by autophagy. P62 is also a regulator of intracellular kinase activity and cell differentiation. We hypothesized that the PBMC response to a malignant breast mass involves elevated production of HSP70 and a decrease in intracellular p62. In this study 46 women had their breast mass excised. PBMCs were isolated and intracellular levels of HSP70 and p62 were quantitated by ELISA. Differences between women with a benign or malignant breast mass were determined. A breast malignancy was diagnosed in 38 women (82.6%) while 8 had a benign lesion. Mean intracellular HSP70 levels were 79.3 ng/ml in PBMCs from women with a malignant lesion as opposed to 44.2 ng/ml in controls (p = 0.04). The mean PBMC p62 level was 2.3 ng/ml in women with a benign breast lesion as opposed to 0.6 ng/ml in those with breast cancer (p < 0.001). Mean p62 levels were lowest in women with invasive carcinoma and a positive lymph node biopsy when compared to those with in-situ carcinoma or absence of lymphadenopathy, respectively. Intracellular HSP70 and p62 levels in PBMCs differ between women with a malignant or benign breast lesion. These measurements may be of value in the preoperative triage of women with a breast mass.

Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors.

Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed the immunogenicity of frameshift peptides in T cell stimulation experiments using blood mononuclear cells isolated from both healthy donors and MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common "off-the-shelf" cancer vaccines.

Histology-specific FGFR2 alterations and FGFR2-TACC2 fusion in mixed adenoid cystic and neuroendocrine small cell carcinoma of the uterine cervix.

Neuroendocrine small cell carcinoma of the uterine cervix portends a dismal prognosis with limited treatment options. Rarely, tumors of mixed-lineage appear in gynecologic malignancies. Here, we report a 77-year-old woman who presented with complete uterine prolapse and 4-month history of vaginal bleeding. Histopathologic evaluation revealed a mixed adenoid cystic carcinoma and neuroendocrine small cell carcinoma of the uterine cervix. The tumor was PD-L1 and HPV 35 positive. The patient was treated with up-front surgery and adjuvant radiation. Independent, histology-specific alterations in FGFR2 and a FGFR2-TACC2 fusion were identified. Progression of disease occurred within 6 months for which she received chemotherapy and immunotherapy. However, the patient expired within a year. We comprehensively review how screening for and targeting of FGFR alterations in recurrent and metastatic cervical cancer might serve as a touchstone for future treatment regimens.

Secondary surgical resection for patients with recurrent uterine leiomyosarcoma.

OBJECTIVES: To assess outcomes after secondary surgical resection in patients with recurrent uterine leiomyosarcoma (uLMS). METHODS: We retrospectively identified all patients who had no evidence of disease after initial surgery for uLMS, who underwent surgery for a first recurrence at our institution between 1/1991 and 10/2013. We excluded patients who received any therapy for recurrence prior to secondary resection, and patients who underwent surgery soon after morcellation [of presumed benign fibroids] showed widespread disease. Overall survival (OS) was determined from time of first recurrence to death or last follow-up. RESULTS: We identified 62 patients: 29 with abdominal/pelvic recurrence only, 30 with lung recurrence only, 3 with both. Median time to first recurrence was 18 months (95% CI: 13.3-23.3): 15.8 months (95% CI: 13.0-18.6) abdominal/pelvic recurrence; 24.1 months (95% CI: 14.5-33.7) lung-only recurrence (p = 0.03). Median OS was 37.7 months (95% CI: 25.9-49.6) abdominal/pelvic recurrence; 78.1 months (95% CI: 44.8-11.4) lung recurrence (p = 0.02). Complete gross resection (CGR) was achieved in 58 cases (93%), with gross residual ≤1 cm in 2 (3.5%) and >1 cm in 2 (3.5%). Median OS based on residual disease was 54.1 months (95% CI: 24.9-83.3), 38.7 months (95% CI: NE), 1.7 months (95% CI: NE), respectively (p < 0.001). In cases with CGR, neither adjuvant radiation (N = 9), chemotherapy (N = 8) nor hormonal therapy (N = 10) was associated with improved OS. CONCLUSIONS: Secondary surgical resection of recurrent uLMS is reasonable in patients with a high probability of achieving CGR. Lung-only recurrences were associated with more favorable outcome. Following CGR, additional therapy may not offer benefit.

Role of adjuvant chemotherapy in the management of non-granulosa cell ovarian sex cord-stromal tumors.

OBJECTIVE: To investigate the role of adjuvant chemotherapy (CT) in the management of ovarian non-granulosa cell (GC) sex cord-stromal tumors (SCSTs). METHODS: The National Cancer Database was accessed and patients diagnosed between 2004 and 2013 with a malignant non-GC SCST were selected. Overall survival (OS) was evaluated with Kaplan-Meier curves and compared with the log-rank test. Multivariate survival analysis was performed with Cox regression. Factors associated with the administration of CT were evaluated with the chi-square test and binary logistic regression. RESULTS: A total of 391 patients were identified. The majority had a Sertoli-Leydig cell tumor (SLCT) (73.2%) and early stage disease (84.8%). A total of 203 (51.9%) patients received CT. Advanced disease stage, younger age, high-grade histology, White race, large tumor size and SLCT histology were associated with administration of CT. For patients with early stage disease, there was no difference in OS between those who did (n=134) and did not receive CT (n=157), p=0.40; 5-year OS rates were 81.7% and 84.6%, respectively. No mortality benefit was observed (hazard ratio=0.73; 95% confidence interval=0.38-1.4) after controlling for tumor histology. Median OS of women with advanced stage disease who received CT (n=41) was 34.96 months compared to 15.51 months for those who did not (n=11), p=0.013. CONCLUSION: Adjuvant CT was associated with improved survival for patients with advanced stage non-GC SCSTs. No clear benefit was found for those with early stage disease.

Morbidity and Mortality Risk Assessment in Gynecologic Oncology Surgery Using the American College of Surgeons National Surgical Quality Improvement Program Database.

INTRODUCTION: Gynecologic oncology patients represent a distinct patient population with a variety of surgical risks. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database provides an opportunity to analyze large cohorts of patients over extended periods with high accuracy. Our goal was to develop a postoperative risk assessment calculator capable of providing a standardized, objective means of preoperatively identifying high-risk patients in the gynecologic oncology population. METHODS: We queried the ACS NSQIP database for gynecologic oncology patients from 2005 to 2013. Multivariate logistic regression was performed to generate predictive models specific for 30-day postoperative mortality and major morbidity. RESULTS: There were 12,831 patients with a primary gynecologic malignancy identified: 7847 uterine, 3366 adnexal, 1051 cervical, and 567 perineum cancers. In this cohort, 125 (0.97%) patients died, and 784 (6.11%) major morbidity events were recorded within 30 days of their surgery. For 30-day mortality, the mean calculated predictive probability was 0.128 (SD, 0.219) compared with 0.009 (SD, 0.027) in patients alive 30 days postoperatively (P < 0.0001). The mean predictive probability of major morbidity was 0.097 (SD, 0.095) compared with 0.059 (SD, 0.043) in patients who did not experience major morbidity 30 days postoperatively (P < 0.0001). CONCLUSIONS: Using NSQIP data, these predictive models will help to determine patients at risk for 30-day mortality and major morbidity. Further clinical validation of these models is required.

Ogilvie's Syndrome after Robotic-Assisted Radical Hysterectomy for Cervical Cancer.

Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie's syndrome, is defined by poor peristaltic activity of the colon that mimics mechanical obstruction in the absence of any mechanical occlusive gut lesion. This case report is the first to be published on ACPO occurring after robotic-assisted radical hysterectomy. Given that robotic-assisted laparoscopic surgery has become the next major stage of advancement for a range of operations, especially in gynecologic oncology surgery, this report emphasizes the importance of recognizing precipitating factors associated with this syndrome, including minimally invasive surgery.

A Case Report of Aggressive Angiomyxoma in Pregnancy: Do Hormones Play a Role?

Aggressive angiomyxoma is a rare, locally invasive tumor that generally affects the perineum and pelvis of reproductive age females. Aggressive angiomyxoma is often misdiagnosed, resulting in the delay of the treatment. Case reports show increased growth of the tumor during pregnancy, thus suggesting a hormonal dependency. We report this rare condition in a 29-year-old primigravid female with a growing mass on the right labium majus at 20 weeks' gestation. The patient also developed a smaller mass on the left labium majus at 37 weeks' gestation. The patient underwent a primary cesarean section with resection of the right labial mass, with a final diagnosis of aggressive angiomyxoma. The lesion on her left labium majus resolved spontaneously postpartum. This case report supports a hormonal involvement in this tumor.

Nonbacterial thrombotic endocarditis: A rare manifestation of gynecologic cancer.

•Nonbacterial thrombotic endocarditis (NBTE) is a rare complication of cancer.•NBTE may precede the diagnosis of an occult gynecologic malignancy.•Malignancy-induced NBTE must be considered in patients with unprovoked venous thromboembolism.•The most effective treatment is anticoagulation and treatment of the underlying cancer.

Inhibition of autophagy in peripheral blood mononuclear cells by vaginal fluid from women with a malignant adnexal mass.

Inhibition of autophagy is a characteristic of ovarian cancer. We determined whether inhibition of autophagy by vaginal fluid could provide a non-invasive test for cancer risk stratification in women presenting with an adnexal mass. Vaginal fluid supernatants from 90 women undergoing evaluation for a suspicious adnexal mass were incubated with peripheral blood mononuclear cells (PBMCs) obtained from healthy women under conditions that induce autophagy. Rapamycin, an autophagy inducer, was added to some cultures. After 48 hr the cells were collected, lysed and assayed by ELISA for intracellular p62 concentration. p62 is a cytoplasmic protein that is consumed during autophagy induction. Its concentration is inversely proportional to the extent of autophagy induction. Clinical information including pathological diagnoses was obtained after completion of laboratory studies. Mean p62 levels were 9.4 ng/ml in the 21 women with a subsequent malignant diagnosis, 4.5 ng/ml in the eight women with a borderline tumor diagnosis and 3.6 ng/ml in the 61 women with benign disease (p < 0.0001, malignant vs. others). When rapamycin was added to the vaginal fluid-PBMC co-incubation, p62 levels in samples from women with a malignant diagnosis decreased to 3.3 ng/ml, a level comparable to what was observed with the nonmalignant samples. Vaginal fluid inhibition of autophagy can differentiate between women with malignant and benign adnexal masses.

Human epididymis protein 4 and secretory leukocyte protease inhibitor in vaginal fluid: relation to vaginal components and bacterial composition.

Human epididymis protein 4 (HE4) is a protease inhibitor and a recently identified serum biomarker for ovarian cancer. Properties of HE4 in the genital tract of healthy women have not been evaluated. We evaluated associations between HE4 and a second vaginal protease inhibitor, secretory leukocyte protease inhibitor (SLPI), with vaginal concentrations of innate immune mediators or proteases and with the types of vaginal bacterial communities. Vaginal secretions were collected from 18 healthy reproductive age women and assayed by enzyme-linked immunosorbent assay for concentrations of HE4, SLPI, kallikrein 5, cathepsin B, interleukin 1ß (IL-1), IL-1 receptor antagonist (IL-1 ra), mannose-binding lectin (MBL), the inducible 70-kDa heat shock protein, and matrix metalloproteinase (MMP)-8. The species composition of vaginal bacterial communities in 16 women was characterized by sequencing amplicons derived from 16S bacterial ribosomal RNA genes. Correlations between any 2 assays were analyzed by the Spearman rank correlation tests. Differences in the concentrations of HE4 and SLPI, and between soluble components and vaginal community types, were analyzed by the Mann-Whitney U tests. Vaginal HE4 concentrations, but not SLPI levels, were positively correlated with levels of IL-1ß (P = .0152), IL-1ra (P = .0061), MBL (P = .0100), and MMP-8 (P = .0315). The median vaginal HE4 level, as well as concentrations of MBL, IL-1ß, IL-1ra, and MMP-8, was highest when Gardnerella vaginalis dominated a vaginal community. The association between HE4, elevated levels of proteases, immune mediators and high proportions of G vaginalis strongly suggests that HE4 is a component of the proinflammatory immune response in the female genital tract.