Endometrial Cancer Risk Among Germline BRCA1/2 Pathogenic Variant Carriers: Review of Our Current Understanding and Next Steps.

PURPOSE: To review the literature exploring endometrial cancer (EC) risk among surgical candidates with germline BRCA1/2 pathogenic variants (PVs) to guide decisions around risk-reducing (rr) hysterectomy in this population. DESIGN: A comprehensive review was conducted of the current literature that influences clinical practice and informs expert consensus. We present our understanding of EC risk among BRCA1/2 PV carriers, the risk-modifying factors specific to this patient population, and the available research technology that may guide clinical practice in the future. Limitations of the existing literature are outlined. RESULTS: Patients with BRCA1/2 PVs, those with a personal history of tamoxifen use, those who desire long-term hormone replacement therapy, and/or have an elevated BMI are at higher risk of EC, primarily endometrioid EC and/or uterine papillary serous carcinoma, and may benefit from rr-hysterectomy. Although prescriptive clinical guidelines specific to BRCA1/2 PV carriers could inform decisions around rr-hysterectomy, limitations of the current literature prevent more definitive guidance at this time. A large population-based study of a contemporary cohort of BRCA1/2 PV carriers with lifetime follow-up compared with cancer-gene negative controls would advance this topic and facilitate care decisions. CONCLUSION: This review validates a potential role for rr-hysterectomy to address EC risk among surgical candidates with BRCA1/2 PVs. Evidence-based clinical guidelines for rr-hysterectomy in BRCA1/2 PV carriers are essential to ensure equitable access to this preventive measure, supporting insurance coverage for patients with either BRCA1 or BRCA2 PVs to pursue rr-hysterectomy. Overall, this review highlights the complexity of EC risk in BRCA1/2 PV carriers and offers a comprehensive framework to shared decision making to inform rr-hysterectomy for BRCA1/2 PV carriers.

Risk of venous thromboembolism for ovarian cancer patients during first-line therapy after implementation of an Enhanced Recovery After Surgery (ERAS) protocol.

OBJECTIVE: To determine incidence and risk factors for VTE for patients with advanced epithelial ovarian cancer undergoing first-line therapy, including cytoreductive surgery, on an Enhanced Recovery After Surgery (ERAS) protocol. METHODS: Medical records were reviewed for patients with FIGO stage IIIA-IVB epithelial ovarian, fallopian tube, or primary peritoneal cancer undergoing primary or interval cytoreductive surgery from March 2017 through September 2019. All patients were enrolled on an ERAS protocol, including 28-day postoperative VTE prophylaxis. Demographic information, medical history, perioperative characteristics, and ERAS compliance were evaluated using univariate and multivariate models. RESULTS: Of 230 patients undergoing cytoreductive surgery via laparotomy, 155 received neoadjuvant chemotherapy and 75 received primary cytoreduction. 38 patients had a VTE during the study period. 13 events (5.7%) were identified at time of diagnosis, 6 (3.9%) during neoadjuvant chemotherapy, 5 (2.2%) within 30 days after surgery, 5 (2.2%) between 30 days and 6 months after surgery, and 9 (3.9%) after the 6-month window. The cumulative incidence of VTE was 6.1% (95% CI, 4.3-8.8%) within 6 months after diagnosis and 8.5% (6.2-11.4%) within 1 year after diagnosis. Estimated blood loss (adjusted HR 1.22 [95% CI, 1.09-1.36], p = 0.001) and history of VTE (7.06 [2.34-21.29], p = 0.001) were independently associated with VTE. CONCLUSION: With implementation of an ERAS protocol, only 1 in 46 patients experienced a VTE within 30 days after surgery. However, overall VTE occurred in 1 in 16 patients during first-line therapy. Strategies to further reduce VTE risk, especially during neoadjuvant chemotherapy and surveillance, should be investigated.

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.

Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.

Triaging abnormal cervical cancer screening tests using p16INK4a detection by ELISA on fresh cervical samples.

PROBLEM: Cervical cancer screening strategies in the United States include cotesting (human papillomavirus (HPV) with cytology), primary HPV with genotyping and reflex cytology, and cytology alone. An ongoing challenge is the appropriate triage of patients to colposcopy to those at highest risk. We investigated whether incorporation of p16INK4a immunodetection by enzyme-linked immunosorbent assay (ELISA) on fresh cervical samples obtained at the time of screening could improve appropriate referral to colposcopy. METHOD OF STUDY: A derivation group comprised of cervical swabs collected from subjects with high-grade dysplasia or cancer (positive control) and from subjects with negative screening history (negative control). Samples collected from colposcopy were used to evaluate the existing screening strategies individually and with incorporation of p16INK4a ELISA. Histology was used as the gold standard. RESULTS: Among 163 subjects recruited, 138 were included. In the derivation group, mean p16INK4a level was 2.86 ng/mL (n = 31) and 0.58 ng/mL (n = 20) among positive and negative controls respectively (p = 0.002) with an area under the receiver operator characteristic curve of 0.79 (p < 0.001). Among colposcopy subjects, sensitivity/specificity for cotesting, primary HPV, and cytology were 94%/42%, 88%/45%, and 88%/49%, respectively. Incorporation of p16INK4a resulted in similar sensitivity and improved specificity (cotesting+p16 88%/58%, primary HPV+p16 88%/57%, cytology+p16 81%/62%; p = 0.23/p = 0.008) with decrease in colposcopy referrals by 15% to 22% (p = 0.01). CONCLUSIONS: These results demonstrate the feasibility of quantifying p16INK4a by ELISA in fresh cervical samples, and its potential as an adjunct to existing screening strategies in the identification of high grade-dysplasia while reducing the number of colposcopic referrals.

Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.

Prognostic Value of Preoperative Imaging: Comparing 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography to Computed Tomography Alone for Preoperative Planning in High-risk Histology Endometrial Carcinoma.

OBJECTIVE: 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) increases the sensitivity for preoperative detection of lymph nodes and distant metastases in endometrial cancer. The objective of this investigation was to determine the prognostic value of preoperative PET-CT compared with computed tomography (CT) alone for high-risk endometrial carcinoma. MATERIALS AND METHODS: We performed a retrospective review of high-risk histology endometrial cancer from 2008 to 2015. Clinical variables including surgical procedure, preoperative imaging modality, and outcome were collected. Survival analysis was performed utilizing the Kaplan-Meier and Cox proportional hazards methodologies. RESULTS: Of the 555 women treated for high-risk histology endometrial cancer, 88 (16%) had preoperative PET-CT, and 97 (17%) CT without PET available. PET-CT demonstrated positive findings in 37 women (42%) compared with 33 (30%) with preoperative CT alone. PET-CT had a positive predictive value of 96% for nodal metastasis compared with 60% for CT alone. The median follow-up time for the entire cohort was 59 months (range, 12 to 96 mo). Patients with a negative preoperative PET-CT (n=54) had a median progression-free survival (PFS) that was not reached, whereas the median PFS in the PET-CT positive group was 13 months (n=34). Women with a negative PET-CT had a longer median overall survival (OS) not yet reached compared with 34 months in the PET-CT positive cohort (hazard ratio, 2.4; P<0.001). CT findings did not associate with PFS or OS. CONCLUSIONS: PET-CT demonstrated superior sensitivity for lymph node metastasis and detecting distant disease compared with CT. Preoperative PET-CT, whether positive or negative, offered OS and PFS prognostic value not observed with CT alone.

Perioperative glycemic measures among non-fasting gynecologic oncology patients receiving carbohydrate loading in an enhanced recovery after surgery (ERAS) protocol.

INTRODUCTION: Preoperative carbohydrate loading is an effective method to control postoperative insulin resistance. However, data are limited concerning the effects of carbohydrate loading on preoperative hyperglycemia and possible impacts on complication rates. METHODS: A prospective cohort study was performed of patients enrolled in an enhanced recovery after surgery pathway at a single institution. All patients underwent laparotomy for known or suspected gynecologic malignancies. Patients who had been diagnosed with diabetes preoperatively and those prescribed total parenteral nutrition by their providers were excluded. Data regarding preoperative carbohydrate loading with a commercial maltodextrin beverage, preoperative glucose testing, postoperative day 1 glucose, insulin administration, and complications (all complications, infectious complications, and hyperglycemia-related complications) were collected. The primary endpoint of the study was the incidence of postoperative infectious complications, defined as superficial or deep wound infection, organ/space infection, urinary tract infection, pneumonia, sepsis, or septic shock. RESULTS: Of 415 patients, 76.9% had a preoperative glucose recorded. The mean age was 60.5±12.4 years (range 18-93). Of those with recorded glucose values, 30 patients (9.4%) had glucose ≥180 mg/dL, none of whom were actually given insulin preoperatively. Median preoperative glucose value was significantly increased after carbohydrate loading (122.0 mg/dL with carbohydrate loading vs 101.0 mg/dL without, U=3143, p=0.001); however, there was no relationship between carbohydrate loading and complications. There was a significantly increased risk of hyperglycemia-related complications with postoperative day 1 morning glucose values ≥140 mg/dL (OR 1.85, 95% CI 1.07 to 3.23; p=0.03). Otherwise, preoperative and postoperative hyperglycemia with glucose thresholds of ≥140 mg/dL or ≥180 mg/dL were not associated with increased risk of other types of complications. DISCUSSION: Carbohydrate loading is associated with increased preoperative glucose values; however, this is not likely to be clinically significant as it does not have an impact on complication rates. Preoperative hyperglycemia is not a risk factor for postoperative complications in a carbohydrate-loaded population when known diabetic patients are excluded. PRECIS: While glucose increased with carbohydrate loading in non-diabetic patients, this was not associated with complications.

Retrospective detection of isolated tumor cells by immunohistochemistry in sentinel lymph node biopsy performed for endometrial carcinoma: is there clinical significance?

INTRODUCTION: Several studies have reported optimizing ultrastaging protocols using immunohistochemistry for sentinel lymph node (SLN) biopsy in endometrial carcinoma; however, the clinical significance of isolated tumor cells (ITCs) detected by ultrastaging is unknown. This study aimed to: (1) determine the frequency of retrospective ITC detection in patients with endometrial carcinoma and reported negative SLNs determined by hematoxylin and eosin (H&E) examination only; and (2) determine the clinicopathological features and outcomes of patients with endometrial carcinoma and previously undetected ITCs. METHODS: 474 SLNs from 155 patients with endometrial carcinoma and reported negative SLNs were subjected to an immunohistochemistry protocol which included staining slides with cytokeratin at 1, 10, 20, and 50 µm levels, to examine for ITCs. Clinicopathological data of patients with ITCs detected by this method were analyzed to determine patient outcomes. RESULTS: Using immunohistochemistry, ITCs were detected in 5.7% (27/474) of SLNs and 13.5% (21/155) of patients with previously reported negative SLNs. In this patient cohort, 95.2% (20/21) had endometrioid histology, with the remaining case being carcinosarcoma. 38.1% (8/21) received adjuvant therapy (either brachytherapy alone (4/8) or chemotherapy and radiation (4/8)) based on other parameters, while 61.9% (13/21) had no adjuvant therapy. Of the patients who did not receive adjuvant therapy, all had endometrioid histology and 84.6% (11/13) were International Federation of Gynecology and Obstetrics (FIGO) stage IA. No patients (0/13) recurred after a median follow-up of 31.5 (range 2-84.4) months. DISCUSSION: In this study, 38.1% of patients with previously undetected ITCs had adjuvant treatment based on other high risk factors; as such, reporting ITCs would not have altered patient management for those who received adjuvant chemotherapy. To date, no patients with previously undetected ITCs without adjuvant treatment had a recurrence, suggesting that ITC detection may not be clinically relevant.

Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids.

Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404-21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.

Human papillomavirus and nonhuman papillomavirus pathways to vulvar squamous cell carcinoma: A review.

Vulvar squamous cell carcinoma (VSCC) is a rare tumor of the female genital tract. While previously considered a disease of older women, the epidemiologic landscape is changing with more young women diagnosed with VSCC and its precursor lesions. This may be secondary to the global increase in human papillomavirus (HPV) infection of the lower genital tract. While VSCC precursor lesions have been described for many years, the terminology, and thus the understanding and reproducibility of these lesions have been debated. In the most recent publication from the International Society of the Study of Vulvovaginal Disease (ISSVD), there is a distinction between high-risk vulvar lesions associated with HPV infection (vulvar HSIL) and high-risk vulvar lesions that are not thought to be associated with HPV infection (differentiated VIN or dVIN). These precursors have different risk factors and thus affect different populations, leading to two separate pathways for developing VSCC. The HPV-related VSCC is likely to have a better prognosis than the non-HPV-related VSCC, as seen in other disease sites. Early-stage VSCC may be surgically treated with margin and node status affecting whether adjuvant radiation is recommended. Advanced stage VSCC may be unresectable, requiring neoadjuvant chemoradiation. Although VSCC is a rare disease, ongoing studies investigating the different pathways leading to carcinogenesis may increase the understanding of VSCC and improve therapeutic options for patients.

Evidence for lineage continuity between early serous proliferations (ESPs) in the Fallopian tube and disseminated high-grade serous carcinomas.

The distal Fallopian tube is a site of origin for many 'ovarian' high-grade serous carcinomas (HGSCs) with intraepithelial carcinomas (STICs) that share identical TP53 mutations with metastatic tumors. TP53 mutation-positive early serous proliferations (ESPs) comprise a spectrum including p53 signatures and serous tubal intraepithelial lesions (STILs) and are not considered malignant; however, ESPs are often the only abnormality found in Fallopian tubes of women with metastatic HGSC. The purpose of this study was to determine if a relationship exists between isolated ESPs and concurrent metastatic HGSCs in the absence of STIC. Fallopian tubes from 32 HGSCs without a co-existing STIC/HGSC in the endosalpinx were exhaustively sectioned. The presence of either STIC/HGSC or ESP in the endosalpinx was documented and DNA from tissues containing ESPs, concurrent HGSC, and control epithelia were interrogated for TP53 mutations by targeted amplicon-based sequencing with average coverage reads >4000 across DNA replicate samples. Serial sectioning revealed a previously unrecognized STIC/HGSC in 3 of 32 (9.3%) and ESPs in 13 (40.6%). Twelve contained TP53 mutations. Nine (75%) shared identical TP53 mutations with concurrent HGSCs, four at high (≥ 5%) and five at low (< 5%) allele frequency. All control epithelia were TP53 mutation-negative. This study, for the first time, indicates lineage identity between ESPs in the distal tube and some metastatic HGSCs via a shared site-specific TP53 mutation. It supports a novel serous carcinogenic sequence in which an ESP could eventually culminate in a metastatic serous cancer via 'precursor escape' and would explain the apparent sudden onset of cancers without co-existing STICs. This paradigm for serous cancer development underscores the likelihood that multiple precursor types in the Fallopian tube contribute to serous cancer development with implications for the evolution, pathologic classification, and prevention of this lethal malignancy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Extramammary Paget Disease of the Vulva: A Case Series Examining Treatment, Recurrence, and Malignant Transformation.

OBJECTIVES: Extramammary Paget disease (EMPD) of the vulva is a rare lesion with a high recurrence rate ranging from 12% to 61%. The rate of underlying adenocarcinoma varies, but in the largest series was reported at 4%. Given the rarity of the disease there is a paucity of data to optimize treatment. This study aims to describe the management and recurrence patterns in a tertiary care setting and to offer suggestions for management in a modern-day setting. METHODS: Patients with pathologically confirmed EMPD treated from 2000 to 2015 were retrospectively identified using an IRB approved database. Clinical data were abstracted from the electronic medical record. Pathology underwent central review. RESULTS: Forty-four patients met criteria and underwent central pathology review. Forty-two patients were treated with surgical excision. Alternative treatment modalities included Mohs surgery in 3 patients and medical therapy in 20 patients. The median number of surgical procedures was 1 and the number of procedures ranged from 1 to 16. Twenty-five patients (56.8%) had recurrent disease with a median of 2 (1-6) recurrences per patient. The median disease-free interval was 28.7 months with a median follow up of 45.8 months (1.2-178.9 months). Three patients (7%) had invasive cancer and 7 patients (16%) were diagnosed with a separate malignancy at or following diagnosis of EMPD. Despite radical resection, the majority of patients had positive margins and there was no significant difference in disease recurrence between simple and radical resection (P = 0.69). CONCLUSIONS: Patients with EMPD in this series have a high rate of recurrence. Many undergo multi-modal therapy often with multiple providers. However, patients experience relatively long disease-free intervals with a low rate of associated malignancy. We propose an algorithm for management that focuses on symptom control and minimizing morbidity of treatment intervention once invasive disease has been excluded.

Evaluation of AJCC and an Alternative Tumor Classification System for Primary Vulvar Squamous Cell Carcinoma.

Background: Currently, no studies have attempted to validate the AJCC tumor (T) class for vulvar cancer or examine its performance via clinical data. The goal of this study was to identify risk factors associated with poor outcomes in vulvar squamous cell carcinoma (vSCC) and compare prognostic discrimination of these outcomes between the AJCC T-classification system and the newly developed Brigham and Women's Vulvar Tumor Classification system (BWVTC). Methods: A 15-year, 2-center retrospective cohort study of primary vSCCs (N=226) was undertaken. Risk factors for poor outcomes, including local recurrence (LR), nodal and distant metastasis (NM and DM, respectively), disease-specific death (DSD), and overall death (OD) were determined using competing risks models. Poor outcomes were analyzed by T stage with regard to each classification system's distinctiveness, homogeneity, and monotonicity. Results: AJCC T stages were indistinct, with overlapping 95% confidence intervals for 10-year cumulative incidences of poor outcomes. Most poor outcomes occurred in low AJCC T stages: T1a/T1b contained 77% of LR, 79% of NM, 66% of DM/DSD, and 78% of OD, indicating poor homogeneity and monotonicity. Five risk factors were independent predictors of poor outcomes: history of lichen sclerosus, tumor diameter ≥2.0 cm, tumor depth ≥3.0 mm, poor differentiation, and mucosal involvement, and these were used to develop the BWVTC (BWVTC BWT1 = 0 risk factors; BWT2 = 1 risk factor; BWT3 = 2 risk factors; and BWT4 = ≥3 risk factors). The BWVTC displayed superior homogeneity and monotonicity, with most poor outcomes occurring in high T stages: T3/T4 contained 87% of LR, 92% of NM, 91% of DM/DSD, and 78% of OD (P<.001), although not all T stages were statistically distinct in this small cohort. Conclusions: The BWVTC offers improved prognostic discrimination over the AJCC T-classification system. Validation in population-based cohorts and in vulvar cancers other than SCC is needed.

Sentinel lymph node mapping reduces practice pattern variations in surgical staging for endometrial adenocarcinoma: A before and after study.

OBJECTIVE: To examine the effects of universal sentinel lymph node mapping on the use of nodal staging in endometrial adenocarcinoma. METHODS: Two approaches to laparoscopic staging for endometrial adenocarcinoma were compared using a before and after study design. The before cohort underwent selective lymphadenectomy from January 1, 2014-October 1, 2015 while the after cohort underwent universal sentinel lymph node (SLN) mapping from October 2, 2015-September 29, 2016. RESULTS: The before cohort comprised 215 patients and the after cohort 166 patients. In women undergoing SLN mapping, a sentinel node was identified at least unilaterally in 146/153 cases (95.4%), and bilaterally in 114/153 (74.5%) of cases. Pelvic nodes were removed in 35.8% of the before cohort versus 92.2% of the after cohort (p<0.0001) with more nodal evaluation among both low risk (9.6% vs. 91%, p<0.0001) and high risk cases (66% vs. 94%, p<0.0001). While the proportion of low risk cases diagnosed with nodal involvement did not significantly change (0.9% to 3.1%, p=0.32), there was a trend toward more diagnoses of nodal involvement in high risk cases (5% to 13.2%, p=0.06). Mean number of pelvic lymph nodes removed (15 vs. 4, p<0.0001), mean operative time (181min vs. 137min, p<0.0001), estimated blood loss (80ml vs. 56ml, p=0.004), and rate of post-operative complications (13% vs. 5.2%, p=0.04) all decreased after the adoption of SLN dissection. CONCLUSIONS: Universal sentinel lymph node dissection for laparoscopic endometrial cancer staging reduces heterogeneity in surgeon staging practice, increases nodal detection, and lowers post-operative complications.

Universal Screening for Mismatch-Repair Deficiency in Endometrial Cancers to Identify Patients With Lynch Syndrome and Lynch-like Syndrome.

Although consensus has yet to be reached on universal mismatch-repair (MMR) protein immunohistochemical (IHC) screening for Lynch syndrome (LS) in endometrial cancer (EC), an increasing number of institutions have adopted universal screening protocols similar to those used for colorectal carcinoma. Here we describe our institution's experience with a prospective universal screening protocol in which all ECs resected over a period of 19 months (n=242) were screened for MLH1, PMS2, MSH2, and MSH6 deficiencies using IHC, followed by MLH1 promoter methylation testing when appropriate. When consent was obtained, tumor samples underwent next-generation sequencing. A total of 11 unmethylated MMR-deficient cases (4.5% of cohort) were identified through IHC screening. Germline testing was performed in 10 cases and confirmed LS in 4 patients (1.7% of cohort). Of our 4 confirmed LS cases, 1 did not meet traditional LS screening criteria (eg, age below 50 y, Revised Bethesda criteria). In addition, universal screening identified 6 germline-negative MMR-deficient nonmethylated cases, 4 of which occurred in women older than 50. Although our next-generation sequencing data suggest somatic mutations in 4 of these cases, it is possible that these cases may represent cases of "Lynch-like syndrome." We conclude that a subset of LS cases could be missed using traditional screening guidelines. The value of screening for Lynch-like syndrome has yet to be determined. Although the cost-effectiveness of universal screening in EC has yet to be elucidated, we conclude that universal IHC screening is currently a reasonable, and arguably superior, approach to screening for LS.

Same-Day Discharge After Laparoscopic Hysterectomy for Endometrial Cancer.

PURPOSE: The aim of this study was to investigate the relationship between same-day discharge (SDD) and postoperative complications within 30 days of laparoscopic hysterectomy for endometrial cancer and endometrial intraepithelial neoplasia (EIN). METHODS: This single-institution retrospective cohort included all patients who underwent conventional and robotic-assisted laparoscopic hysterectomy for endometrial cancer or EIN in a large teaching hospital between 2011 and 2013. Temporal trends in frequency of SDD and rates of postoperative complications were investigated to assess whether adoption of routine SDD was associated with increased postoperative complications. Associations between SDD and postoperative complications were also investigated in univariate and multivariate models. RESULTS: Overall, 696 patients underwent laparoscopic hysterectomy. Of these, 37.1 % had pelvic lymphadenectomy, 3.0 % had para-aortic lymphadenectomy, and 9.3 % underwent omentectomy. The rate of SDD increased from 3.9 to 69.6 % during the study period (p < 0.001), and the frequency of postoperative readmission, unscheduled surgery, infection, and composite complications within 30 days of hysterectomy did not differ during the study period. The composite complication rate did not differ significantly between patients who underwent surgery before and after the adoption of routine SDD (rate ratio 0.7, 95 % CI 0.4-1.2, p = 0.24). After controlling for demographic, intraoperative, and comorbid factors, patients who underwent SDD were not at increased risk for postoperative complications. CONCLUSIONS: Adoption of routine SDD after laparoscopic surgery for endometrial cancer and EIN did not result in increased complication rates within our institution. A larger prospective study is required to definitively establish the safety of this approach.

Concepts in creating an evidence-based anesthetic protocol for robot-assisted laparoscopic pelvic surgery.

BACKGROUND: Robotic-assisted surgery has increased in popularity in recent years. Benefits have been observed for both the patient and hospital system as the technology shifts surgery from the open to the laparoscopic arena. Some of the advantages of robotic-assisted surgery include increased patient satisfaction along with shorter hospital stays, decreased risk of infection, and improved postsurgical cosmetic outcomes. METHODS: We developed an evidence-based protocol for the anesthetic management of the preoperative, intraoperative, and postoperative phases of patient care based on the review of primary literature and consensus from surgeons and anesthesiologists at our institution. RESULTS: Robotic-assisted surgery creates a unique set of anesthetic considerations to ensure patient safety. Anesthetic considerations include the physiological changes associated with steep Trendelenburg patient positioning, pneumoperitoneum, fluid management, management of pressure points, and spatial restrictions imposed by the robot relative to the conventional anesthetic area. CONCLUSION: A perioperative protocol can help ensure optimal clinical care, patient safety, and better patient and provider satisfaction with the utilization of robotic surgery.

Does plastic surgical consultation improve the outcome of patients undergoing radical vulvectomy for squamous cell carcinoma of the vulva?

OBJECTIVES: To analyze margin status and prognostic factors for complications in patients undergoing vulvectomy for invasive squamous cell cancer (iSCC) with and without plastic-assisted closure. METHODS: Demographic and clinical data were collected on 94 patients with iSCC who underwent vulvectomy between 2004 and 2013. All pathology slides were re-reviewed by two gynecologic pathologists. Data were analyzed using XLSTAT-Pro v2014.2.02. RESULTS: Of 88 eligible patients, 15 (17%) had plastic-assisted vulvar closure and 73 (83%) did not. There were significantly more patients in the plastics group with recurrent disease (53% v 10%) and history radiation therapy prior to surgery (40% versus 5%). Plastic-assisted closure was associated with larger tumors (3.73 cm versus 2.03 cm, p<0.01) and a higher frequency of adequate margins (53% versus 29%, p=0.06). For tumors≥3.0 cm, plastic-assisted closure was significantly associated with adequate margins (44% versus 6%, p=0.03). Prior radiation use was associated with plastic-assisted closure, larger tumors, older age, and recurrent disease. Complications occurred in 36 patients (41%) and significantly more occurred in those with plastic-assisted closure (67% versus 36%, p=0.04). On multivariate analysis including age, tumor size, recurrent disease, plastic-assisted closure, and history of radiation, only history of radiation therapy was a significant predictor of complications (OR=17, 95%CI 2.05-141.35; p=0.01). CONCLUSIONS: Plastic-assisted vulvectomy closure was more often utilized in cases involving past radiation therapy and larger tumors. Plastic-assisted closure significantly increased the frequency of adequate margins in tumors≥3 cm and did not impact complications.