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.

Durable remission in a patient with ERBB2-amplified recurrent mucinous ovarian carcinoma treated with Trastuzumab-Carboplatin-Paclitaxel.

Patients with advanced stage or recurrent mucinous ovarian carcinoma exhibit poor response to standard platinum- and taxane-based chemotherapy and poor prognosis. We report a 29-year-old patient with recurrent ERBB2-amplified mucinous ovarian carcinoma (with expansile growth pattern at initial diagnosis and previously treated with adjuvant capecitabine/oxaliplatin) who underwent optimal secondary cytoreduction followed by 6 cycles of carboplatin/paclitaxel/trastuzumab and 1-year maintenance trastuzumab. This patient remains without radiologic or biochemical evidence of disease for more than 3 years after secondary cytoreduction. This case supports routine assessment of HER2 status in patients with advanced or recurrent mucinous ovarian carcinoma and highlights the potential of HER2-targeted therapy with trastuzumab in combination with standard carboplatin and paclitaxel in this disease. This case also raises the possibility that expansile mucinous ovarian carcinomas with ERBB2 amplification and p53 mutant immunohistochemical staining pattern (as this patient had) may be associated with a more aggressive behavior and higher risk of relapse.

Predictive validity of American College of Surgeons: National Surgical Quality Improvement Project risk calculator in patients with ovarian cancer undergoing interval debulking surgery.

INTRODUCTION: In gynecologic patients, few studies describe the accuracy of the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) pre-operative risk calculator for women undergoing surgery for ovarian cancer. OBJECTIVE: To determine whether the ACS-NSQIP risk calculator accurately predicts post-operative complications and length of stay in patients undergoing interval debulking surgery for advanced stage epithelial ovarian cancer. METHODS: For this multi-institutional retrospective cohort study, pre-operative risk factors, post-operative complication rates, and Current Procedural Terminology codes were abstracted from records of patients with ovarian cancer managed with open interval debulking surgery from January 2010 to July 2015. A power calculation was done to estimate the minimum number of complications needed to evaluate the accuracy of the ACS-NSQIP risk calculator. Predicted risk compared with observed risk was calculated using logistic regression. The predictive accuracy of the ACS-NSQIP risk calculator in estimating post-operative complications or length of stay was assessed using c-statistics and Briar scores. Complications with a c-statistic of >0.70 and Brier score of <0.01 were considered to have high discriminative ability. RESULTS: A total of 261 patients underwent interval debulking surgery, encompassing 21 unique Current Procedural Terminology codes. Readmission (n=25), surgical site infection (n=35), urinary tract infection (n=12), and serious post-operative complications (n=57) met the minimum event threshold (n>10). All predicted complication rates fell within the IQR of the observed incidence rates. However, the ACS-NSQIP calculator demonstrated neither discriminative ability nor accuracy for any post-operative complications based on c-statistics and Brier scores. The calculator accurately predicted length of stay within 1 day for only 32% of patients and could not accurately predict which patients were likely to have a prolonged length of stay (c-statistic=0.65). CONCLUSION: Among patients undergoing interval debulking surgery, the ACS-NSQIP did not accurately discriminate which patients were at increased risk of complications or extended length of stay. The risk calculator should be considered to have limited utility in informing pre-operative counseling or surgical planning.

Next-Generation Sequencing in the Diagnosis of Metastatic Lesions: Reclassification of a Glioblastoma as an Endometrial Cancer Metastasis to the Brain.

Endometrial cancer is the most common gynecologic cancer in the U.S., but metastasis to the brain is rare, and diagnosis can be challenging. Traditional tools for determining if a tumor is a primary or metastatic lesion include pan-imaging, histopathologic studies, and immunohistochemistry. Molecular testing with next-generation sequencing has been increasingly used to augment these tests. We present a case of a patient who initially presented with a brain lesion diagnosed as glioblastoma on histology and immunohistochemistry, but whose diagnosis was later changed to metastasis from an endometrial primary based on molecular findings. The two tumors shared a common microsatellite instability signature and 51 DNA variants, including oncogenic driver mutations KRAS p.G13D, PIK3CA p.E545A, and PTEN p.I135V and p.K267Rfs*9. This highlights the power of molecular analysis in making the diagnosis in cases of rare metastases. KEY POINTS: Brain metastasis from endometrial primary is rare, and histopathological features may be augmented with molecular analysis to aid in diagnosis. Comparison of the molecular makeup of the primary endometrial lesion with the metastatic lesion may reveal high-risk molecular features that may be indicative of metastatic potential.

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.

Differentiating leiomyosarcoma from leiomyoma: in support of an MR imaging predictive scoring system.

PURPOSE: The purpose of this study was to determine the Magnetic Resonance (MR) imaging features that best differentiate leiomyosarcoma (LMS) from leiomyoma, and to explore a scoring system to preoperatively identify those at highest risk of having LMS. METHODS: Our Institutional Review Board approved this retrospective HIPAA-compliant study with a waiver for written informed consent. Institutional Research Patient Data Registry identified patients with histopathologically-proven LMS (n = 19) or leiomyoma (n = 25) and a pelvic MRI within six months prior to surgery. Qualitative differentiating MRI features were selected based on prior publications and clinical experience. Patient and MRI characteristics for leiomyomas versus LMS were compared using Wilcoxon rank-sum tests or Fisher's exact tests and using a basic classification tree. Hypothesis testing was two-tailed, with a p value < 0.001 used to determine inclusion of variables into an MR imaging predictive (MRP) score. Diagnostic performance [sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)] of the MRP in diagnosis of LMS used all possible scores as cutoffs. RESULTS: Seven out of 15 MRI features were found to have an association with LMS. The final MRP scores ranged from 0 to 7: a score of 0-3 was associated with 100% NPV for LMS, and a MRP score of 6-7 with 100% PPV for LMS. CONCLUSION: Seven qualitative MR imaging features, extracted from a standard MR imaging protocol, allow differentiation of LMS from leiomyoma. An exploratory risk stratification MRP score can be used to determine the likelihood of LMS being present.

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.

Neoadjuvant chemotherapy does not disproportionately influence post-operative complication rates or time to chemotherapy in obese patients with advanced-stage ovarian cancer.

OBJECTIVES: To determine whether neoadjuvant chemotherapy (NACT) disproportionately benefits obese patients. METHODS: Data were collected from stage IIIC-IV ovarian cancer patients treated between 01/2010-07/2015. We performed univariate/multivariate logistic regression analyses with post-operative infection, readmission, any postoperative complication, and time to chemotherapy as outcomes. An interaction term was included in models, to determine if the effect of NACT on post-operative complications was influenced by obesity status. RESULTS: Of 507 patients, 115 (22.6%) were obese and 392 (77.3%) were non-obese (obese defined as BMI ≥30). Among obese patients undergoing primary debulking surgery (PDS) vs. NACT, rates of postoperative infection were 42.9% vs. 30.8% (p = 0.12), 30-day readmission 30.2% vs. 11.5% (p < 0.02), and any post-operative complication were 44.4% vs 30.8% (p = 0.133). Among non-obese patients undergoing PDS vs. NACT, rates of post-operative infection were 20.0% vs. 12.9% (p = 0.057), 30-day readmission 16.9% vs. 9.2% (p = 0.02), and any post-operative complication were 19.4% vs 28% (p = 0.044). Obesity was associated with post-operative infection (OR 2.3; 95%CI 1.22-4.33), 30-day readmission/reoperation (OR 2.27; 95%CI 1.08-3.21) and the development of any post-operative complication (OR 2.1; CI 1.13-3.74). However, there was not a significant interaction between obesity and NACT in any of the models predicting post-operative complications. CONCLUSIONS: The decision to use NACT should not be predicated on obesity alone, as the reduction in post-operative complications in obese patients is similar to non-obese patients.

Female adnexal tumor of probable Wolffian Origin - A report of two cases at one institution.

•FATWOs are rare gynecologic neoplasms of low malignant potential derived from mesonephric (Wolffian) duct remnants.•FATWOs have diverse presentations from vague abdominal symptoms to incidental diagnosis.•In general, FATWOs require no additional management beyond initial surgical intervention.

A novel classification of residual disease after interval debulking surgery for advanced-stage ovarian cancer to better distinguish oncologic outcome.

BACKGROUND: Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease. OBJECTIVE: To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes. STUDY DESIGN: Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated. RESULTS: Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001). CONCLUSION: Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients.

Infection, thrombosis, and oncologic outcome after interval debulking surgery: Does perioperative blood transfusion matter?

OBJECTIVES: To determine whether perioperative red blood cell transfusion (PRBCT) affects infection, thrombosis, or survival rates in epithelial ovarian cancer (EOC) patients undergoing neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS). METHODS: Demographics, operative characteristics, and outcome data were abstracted from records of stage IIIC-IV EOC patients managed with NACT-IDS from 01/2010-07/2015. Associations of PRBCT with morbidity and oncologic outcomes were evaluated. RESULTS: Of 270 patients, 136 (50.4%) received PRBCT. Patients with preoperative anemia and higher estimated blood loss (EBL) were more likely to undergo PRBCT (OR,95%CI 1.80, 1.02-3.17) and (OR,95%CI 1.00, 1.002-1.004), respectively. There were no significant differences in PRBCT based on patient age, Charlson Comorbidity Index, or stage. When compared to low complexity operations, patients with moderate and high complexity surgeries were more likely to receive PRBCT (OR,95%CI 1.81, 1.05-3.09) and (OR,95%CI 2.25, 1.13-4.50), respectively. On univariate analysis, PRBCT was associated with intraabdominal infection (OR,95%CI 8.31, 1.03-67.41), but not wound complications (OR,95%CI 1.57, 0.76-3.23) or venous thromboembolism/pulmonary embolism (VTE/PE) (OR,95%CI 2.02, 0.49-8.23). After adjusting for surgical complexity and preoperative anemia, PRBCT was not independently associated with intraabdominal infection (OR,95%CI 7.66, 0.92-63.66), wound complications (OR,95%CI 1.70, 0.80-3.64), or VTE/PE (OR,95%CI 2.15, 0.51-9.09). When comparing patients undergoing PRBCT versus those who did not, there were no significant differences in median progression-free survival (PFS) or median overall survival (OS) on univariate analysis after adjusting for age, stage and residual disease. CONCLUSIONS: Among patients undergoing NACT-IDS, intraabdominal infection, wound complication and VTE/PE rates are similar, regardless of PRBCT. PRBCT does not impact PFS or OS.

Assessment of a Chemotherapy Response Score (CRS) System for Tubo-Ovarian High-Grade Serous Carcinoma (HGSC).

A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS system. We retrospectively identified advanced stage HGSC patients who received neoadjuvant chemotherapy and underwent interval debulking. If available, a hemotoxylin and eosin slide from the omentum and the adnexa was selected for the study. Slides were independently scored by 13 pathologists using the 3-tiered CRS system. Reviewers then received web-based training and rescored the slides. Overall survival and progression-free survival were estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 68 patients with omental (n=65) and/or adnexal (n=59) slides were included in the study. Interobserver reproducibility was moderate for omentum (κ, 0.48) and poor for adnexa (κ, 0.40), which improved for omentum (κ, 0.62) but not for adnexa (κ, 0.38) after online training. For omental slides, a consensus CRS of 1/2 was associated with a shorter median progression-free survival (10.9 mo; 95% confidence interval, 9-14) than a CRS of 3 (18.9 mo; 95% CI, 18-24; P=0.020). In summary, a 3-tiered CRS system of hemotoxylin and eosin-stained omental deposits can yield prognostic information for HGSC patients receiving neoadjuvant chemotherapy, and web-based training improved reproducibility but did not alter determination of clinical outcomes. The CRS system may allow oncologists to identify potential nonresponders and triage HGSC patients for heightened observation and/or clinical trials.

Diagnosis and management of a heterotopic pregnancy and ruptured rudimentary uterine horn.

BACKGROUND: Heterotopic pregnancies implanted in a rudimentary uterine horn account for 1 in 2-3 million gestations, and confer significant risk of morbidity due to uterine rupture and hemorrhage. CASE PRESENTATION: A 34-year-old nullipara presented with acute pelvic pain at 17 weeks of gestation with dichorionic-diamniotic twins, one in each horn of an anomalous uterus first diagnosed in pregnancy as bicornuate. Three-dimensional ultrasound and MRI revealed myometrial disruption in the left rudimentary uterine horn, and the patient underwent an uncomplicated abdominal hemi-hysterectomy. Fourteen days later, an uncomplicated dilation and curettage was performed for a fetal anomaly in the remaining twin in the right unicornuate uterus. CONCLUSION: This case demonstrates the utility of magnetic resonance imaging and three-dimensional ultrasound in the assessment of myometrial integrity in a gravid patient with a heterotopic pregnancy and ruptured rudimentary uterine horn. This case demonstrates the importance of pre-pregnancy diagnosis and management of mullerian anomalies.

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.

Endometrial cancer with an EML4-ALK rearrangement.

An 85-yr-old woman was diagnosed with endometrial adenocarcinoma, endometrioid type. Imaging studies showed a large tumor distending the endometrial canal without evidence of local invasion or extrauterine disease. A hysterectomy was performed, followed by microscopic examination of longitudinal tissue sections. Histopathological review showed only focal myometrial invasion, equivocal lymphovascular invasion, and negative bilateral sentinel lymph nodes (FIGO stage IA). A sample of the tumor was submitted for molecular testing (massively parallel sequencing on OncoPanel) and was found to harbor an inversion on Chromosome 2 resulting in an EML4-ALK gene fusion. Confirmatory immunohistochemistry showed ALK overexpression in just a portion of the tumor. Additional genomic characterization on a region of the tumor lacking ALK overexpression by immunohistochemistry was highly congruous with the genomic profile of the ALK-positive portion, showing similar patterns of copy-number variation and mutations in TP53 and KDM5C, with no evidence for an EML4-ALK gene fusion, confirming that EML4-ALK rearrangement had occurred as a subclonal process. EML4-ALK fusions are driver events in 2%-5% of non-small-cell lung cancers; crizotinib is an approved targeted therapy for these patients. EML4-ALK rearrangements have not previously been reported in endometrial cancer.

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.

Moving beyond "complete surgical resection" and "optimal": Is low-volume residual disease another option for primary debulking surgery?

OBJECTIVES: To examine the relationship between volume of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing primary debulking surgery (PDS). For patients that did not undergo a complete surgical resection (CSR), a surrogate for volume of residual disease was used to assess oncologic outcomes. METHODS: Medical records of patients with FIGO stage IIIC and IV epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing PDS between January 2010 and November 2014 were reviewed. Patient demographics, operative characteristics, residual disease, anatomic site of residual disease and outcome data were collected. Among patients who did not undergo CSR, but had ≤1 cm of residual disease, the number of anatomic sites (single location vs. multiple locations) with residual disease was utilized as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival (PFS) and overall survival (OS) was evaluated. RESULTS: Of 240 patients undergoing PDS, 94 (39.2%) had CSR, 41 (17.1%) had ≤1 cm of residual disease confined to a single anatomic location (≤1 cm-SL), 67 (27.9%) had ≤1 cm of residual disease in multiple anatomic locations (≤1 cm-ML) and 38 (15.8%) were sub-optimally (SO) debulked. Median PFS for CSR, ≤1 cm-SL, ≤1 cm-ML and SO-debulked were: 23, 19, 13 and 10 months, respectively (p < 0.001). Median OS for CSR, ≤1 cm-SL, ≤1 cm-ML and SO-debulked were: Not yet reached, 64, 50 and 49 months, respectively (p = 0.001). CONCLUSIONS: Following PDS, CSR and ≤ 1 cm-SL patients have the best prognosis. In contrast, despite being considered "optimally debulked", ≤1 cm-ML patients have survival similar to those SO-debulked.

Combined Oocyte Retrieval and Robot-assisted Hysterectomy in a Super Morbidly Obese Patient with Endometrial Carcinoma.

AIM: To report on the unique, innovative management of a super morbidly obese patient presenting for fertility preservation in the setting of Grade 2 endometrioid endometrial adenocarcinoma. CASE REPORT: A back-to-back oocyte retrieval and robot-assisted total laparoscopic hysterectomy (RA-TLH) with bilateral salpingo-oophorectomy (BSO) was performed in a 37-year-old nulligravid woman with super morbid obesity (BMI 63 kg/m2) with endometrial cancer. MAIN OUTCOME MEASURE: the successful retrieval of oocytes for fertility preservation and oncologic intervention via RA-TLH with BSO in the same operative and anesthetic episode. RESULTS: This combined procedure strategy was successful in our case and is a feasible option for similar high-risk patients in the future. CONCLUSION: Identifying safe and effective approaches for oocyte retrieval in morbidly obese patients represents a pressing need as obesity rates rise among reproductive-aged women. Back-to-back oocyte retrieval and RA-TLH with BSO are not only feasible, but could also decrease significant anesthetic risks for morbidly obese patients.

Comparison of benign peritoneal fluid- and ovarian cancer ascites-derived extracellular vesicle RNA biomarkers.

BACKGROUND: Extracellular vesicles (EVs) are considered as a new class of resources for potential biomarkers. We analyzed expression of specific mRNA and miRNA in EVs derived from ovarian cancer ascites and the ideal controls, peritoneal fluids from benign patients for potential early detection and prognostic biomarkers. METHODS: Fluids were collected from subjects with benign cysts or endometrioma (n = 10), or low/high grade serous ovarian carcinoma (n = 8). EV particles were captured using primarily ExoComplete filterplate or ultracentrifugation and analyzed by nanoparticle tracking analysis, ELISA, and scanning electron microscopy. EV RNAs extracted from two ascites and three peritoneal fluids were submitted for next-generation sequencing. The expression of 34 mRNA and 18 miRNAs in the EVs isolated from patient fluids and cell line media was determined using qPCR. RESULTS: EVs isolated from patient samples had concentrations greater than 1010 EV particles/mL and 30% were EpCAM-positive based on ELISA. EV particle sizes averaged 113 ± 11.5 nm. The qPCR studies identified five mRNA (CA11, MEDAG, LAMA4, SPINT2, NANOG) and six miRNA (let-7b, miR23b, miR29a, miR30d, miR205, miR720) that were significantly differentially expressed between cancer ascites and peritoneal fluids. In addition, CA11 mRNA was decreased to 0.5-fold and SPINT2 and NANOG mRNA were significantly increased up to 100-fold in conditioned media of cancer cells compared to immortalized ovarian surface and fallopian tube epithelial cell lines, the hypothesized cells of origin for ovarian cancer development. CONCLUSIONS: This study indicates that EV mRNA profiles can reflect the disease stage and may provide a potentially novel source for discovery of biomarkers in ovarian cancer.