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Background: First-line treatment of epithelial ovarian cancer (EOC) consists of a combination of cytoreductive surgery and platinum-based chemotherapy. Recently, targeted therapies such as bevacizumab have been shown to improve oncologic outcomes in a subset of a high-risk population. The objective of this study is to evaluate the patterns of practice and outcomes of first-line systemic treatment of advanced EOC, focusing on the adoption of bevacizumab., Methods: A population cohort study was conducted using administrative data in Ontario, Canada. Patients diagnosed with advanced stage non-mucinous EOC between 2014 and 2018 were identified. Datasets were linked to obtaining information on first-line treatment including surgery, systemic therapy, providers of care, systemic therapy facilities, and acute care utilization (emergency department (ED) visits and hospitalizations) during systemic treatment. Multivariate logistic regression was used to determine factors associated with systemic therapy utilization., Results: Among 3726 patients with advanced EOC, 2838 (76%) received chemotherapy: 1316 (47%) received neoadjuvant chemotherapy, 1060 (37%) underwent primary cytoreductive surgery followed by chemotherapy, and 462 (16%) received chemotherapy only. The median age was 67 (range: 20-100). Most chemotherapies were prescribed by gynecologic oncologists (60%) and in level 1 academic cancer centres (58%). Only 54 patients (3.1%) received bevacizumab in the first-line setting after its approval in Ontario in 2016. Bevacizumab was more likely to be administered by medical oncologists compared to gynecologic oncologists (OR 3.95, 95% CI 2.11-7.14). In total, 1561 (55%) and 1594 (56%) patients had at least one ED visit and/or hospitalization during systemic treatment, respectively. The most common reasons for ED visits were fever and bowel obstruction., Conclusion: Patterns of care for EOC in Ontario differed between care providers. The uptake of bevacizumab for first-line treatment of EOC was low. Acute care utilization related to EOC was high.

Opinion Statement: Most individuals with gestational trophoblastic neoplasia (GTN) are cured with chemotherapy; however, about 5% of them will develop chemotherapy-resistant disease and will die of disease progression. Most GTN tissues express programmed death ligand-1 (PDL-1), making immune checkpoint inhibitors (ICIs) targeting this pathway an attractive treatment option for individuals with GTN. There is increasing evidence to support the use of ICIs for individuals with recurrent or resistant GTN, but available data are derived from case reports and small single arm trials. As promising as it seems, not all individuals with GTN respond to ICIs, and there is lack of evidence toward which factors mediate the effect of ICIs on GTN. In addition, treatment-related adverse events and impact on future fertility are not negligible and should be considered before initiating this treatment. Therefore, additional research is needed to evaluate treatment outcome of ICIs in GTN compared to standard treatment, and to identify molecular and clinical predictors for treatment response, before this treatment is incorporated into the standard of care., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background The Ovarian-Adnexal Reporting and Data System (O-RADS) US risk stratification and management system (O-RADS US) was designed to improve risk assessment and management of ovarian and adnexal lesions. Validation studies including both surgical and nonsurgical treatment as the reference standard remain lacking. Purpose To externally validate O-RADS US in women who underwent either surgical or nonsurgical treatment and to determine if incorporating acoustic shadowing as a benign finding improves diagnostic performance. Materials and Methods This retrospective study included consecutive women who underwent pelvic US between August 2015 and April 2017 at a tertiary referral oncology center. Two independent readers blinded to clinical and histologic outcome assigned an O-RADS risk category and an International Ovarian Tumor Analysis (IOTA) Assessment of Different NEoplasias in the adneXa (ADNEX) model risk of malignancy score to assessable lesions. Reference standards were surgical histopathology or 2-year imaging follow-up. Receiver operating characteristic (ROC) curve analysis was used to evaluate performance of the O-RADS US, ADNEX, and modified O-RADS models incorporating acoustic shadowing. Results In total, 227 women (mean age, 52 years ± 16 [SD]) with 262 ovarian or adnexal lesions were evaluated. Of these lesions, 187 (71%) were benign and 75 (29%) were malignant. The proportion of malignancy was 0% (0 of 100) for O-RADS 2, 3% (one of 32) for O-RADS 3, 35% (22 of 63) for O-RADS 4, and 78% (52 of 67) for O-RADS 5. The area under the ROC curve (AUC) for O-RADS and ADNEX was 0.91 (95% CI: 0.88, 0.94) and 0.95 (95% CI: 0.92, 0.97; P = .01), respectively. The addition of acoustic shadowing as a benign finding improved O-RADS AUC to 0.94 (95% CI: 0.91, 0.96; P = .01). Use of O-RADS 4 as a threshold yielded a sensitivity of 99% (74 of 75; 95% CI: 96, 100) and a specificity of 70% (131 of 187; 95% CI: 64, 77). Conclusion In a tertiary referral oncology center, the Ovarian-Adnexal Reporting and Data System US risk stratification and management system enabled accurate distinction of benign from malignant ovarian and adnexal lesions. Adding acoustic shadowing as a benign finding improved its diagnostic performance. © RSNA, 2022 See also the editorial by Levine in this issue.

Objectives: Same day discharge after minimally invasive hysterectomy has been shown to be safe and feasible. We designed and implemented a quality improvement perioperative program based on early recovery after surgery principles to improve the rate of same day discharge from 30% to 75% after minimally invasive gynecologic oncology surgery over a 12 month period., Methods: We enrolled 102 consecutive patients undergoing minimally invasive hysterectomy at a single cancer center during a 12 month period. A pre-intervention cohort of 100 consecutive patients was identified for comparison of clinicodemographic variables and perioperative outcomes. A multidisciplinary team developed a comprehensive perioperative care program and followed quality improvement methodology. Patients were followed up for 30 days after discharge. A statistical process chart was used to monitor the effects of our interventions, and a multivariate analysis was conducted to determine factors associated with same day discharge., Results: Same day discharge rate increased from 29% to 75% after implementation (p<0.001). The post-intervention cohort was significantly younger (59 vs 62 years; p=0.038) and had shorter operative times (180 vs 211 min; p<0.001) but the two groups were similar in body mass index, comorbidity, stage, and intraoperative complications. There was no difference in 30 day perioperative complications, readmissions, reoperations, emergency department visits, or mortality. Overnight admissions were secondary to nausea and vomiting (16%), complications of pre-existing comorbidities (12%), and urinary retention (8%). On multivariate analysis, longer surgery, timing of surgery, and narcotic use on the ward were significantly associated with overnight admission. Overall, 89% of patients rated their experience as 'very good' or 'excellent', and 87% felt that their length of stay was adequate., Conclusions: Following implementation of a perioperative quality improvement program targeted towards minimally invasive gynecologic oncology surgery, our intervention significantly improved same day discharge rates while maintaining a low 30 day perioperative complication rate and excellent patient experience., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Parastomal hernia (PSH) is the most common complication of stoma formation. The safety and efficiency of prophylactically placing mesh to prevent PSH remain controversial. To address this question, we examined the incidence of clinical and radiological PSH when using parastomal prophylactic mesh (PPM)., Methods: We performed a retrospective, single-center, cohort study that included all patients with permanent stoma creation between 2015 and 2018. Patients were divided into two groups according to the utilization of PPM or not., Results: During the study period, 185 patients had a permanent stoma created, 144 with colostomy and 41 with ileostomy. PPM was placed in 79 patients. There was no difference in the need for early surgical reintervention (p = 0.652) or rehospitalization (p = 0.314) for stoma-related complications in patients with mesh as compared with patients without. Similarly, there was no difference in operative time (p = 0.782) or in length of hospital stay (p = 0.806). No patients experienced infection of the mesh or required prosthesis removal. There was a lower incidence rate of PSH with PPM placement in patients with permanent colostomy [adjusted hazard ratio (HR) 0.50 (95% confidence interval 0.28-0.89); p = 0.018]. In contrast, a higher incidence rate of PSH was observed in patients with ileostomy and PPM [adjusted HR 5.92 (95% confidence interval 1.07-32.65); p = 0.041]., Conclusion: Parastomal prophylactic mesh placement to prevent PSH is a safe and efficient approach to reduce the incidence of PSH in patients requiring a permanent colostomy. However, mesh may increase the rate of PSH after permanent ileostomy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Objectives: Timely treatment of epithelial ovarian cancer (EOC) by gynecologic oncologists (GOs) with a combination of surgery and/or chemotherapy has been advocated. Nonetheless, some patients are not assessed by GOs prior to starting their treatment or have surgery by non-GOs. This study aims to determine trends over time in non-mucinous EOC care and to evaluate the impact of care on survival., Methods: Using province-wide administrative data, patients diagnosed with non-mucinous EOC between 2007 and 2018 were identified. Multivariate Cox proportional hazards regression models were used to evaluate the impact of GO assessment prior to initiating treatment or having surgery done by a non-GO on mortality., Results: A total of 10,086 EOC patients were included between 2007 and 2018. During the study period, there was an 8% increase in GO assessment (79% in 2007 to 87% in 2018-19, p ≤  0.001) and a 19% increase in surgeries performed by GOs (69% in 2007 to 88% in 2018-19, p ≤ 0.001). On multivariate analysis, there was an increased hazard of all-cause mortality for patients not assessed by GOs before first treatment (Hazard ratio (HR): 1.61; 95% CI 1.46-1.79). There was an increased hazard of all-cause mortality if ovarian cancer surgery was performed by non-GOs (HR 2.03; 95% CI 1.80-2.30)., Conclusion: Assessment by GO before starting initial treatment is associated with improved survival in women with non-mucinous EOC as the type of surgeon performing primary ovarian cancer surgery. Assessment by GO for all patients with new or suspected ovarian cancer diagnosis before initiation of primary treatment should be advocated., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate treatment outcomes, survival, and predictive factors in patients ≥70 with advanced epithelial ovarian cancer (AEOC)., Methods: A retrospective single institution cohort study of women ≥70 with Stage III-IV AEOC between 2010 and 2018. Patients had either primary cytoreductive surgery (PCS), neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery (ICS), chemotherapy alone, or no treatment. Demographics, surgical outcome, complications, and survival outcome were compared between groups., Results: Among 248 patients, 69 (27.7%) underwent PCS, 99 (39.9%) had ICS, 56 (22.5%) had chemotherapy alone. Twenty-four (9.6%) remained untreated. Optimal cytoreduction (≤1 cm) was achieved in 72.4% of PCS and 77.8% of NACT/ICS (p = 0.34), without difference in grade ≥3 postoperative complications (15.9% vs. 9.1%, p = 0.37). Progression-free survival (PFS) was 23.5 months in PCS and 15.0 months in ICS patients (hazard ratio [HR]: 1.4, p = 0.041). Patients in the surgical arms, PCS or ICS, had better 2-year overall survival (OS) compared to chemotherapy alone (79%, 68%, 41%, respectively, HR: 3.58, p < 0.001). In a subgroup analysis, patients ≥80 had improved 2-year OS when treated with NACT compared to PCS (82% vs. 57%) and a trend toward improved PFS. Age, stage, and CA-125 were determinants of undergoing PCS., Conclusion: In patients ≥70 with AEOC, surgery should not be deferred based on age alone. Fit, well selected patients ≥70 can benefit from PCS, while patients ≥80 might benefit from NACT over PCS., (© 2021 Wiley Periodicals LLC.)

The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that cross-talk between tumor and stromal cells within the tumor microenvironment results in activation of key biological pathways depending on their position in the tumor (edge vs. core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts from the tumor core, established from human lung adenocarcinomas. A multiomics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize cross-talk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential posttranslational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 (CDK4) and phosphorylated retinoblastoma protein axis in the stroma and indirectly modulates proinvasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma cross-talk and a potential avenue to improve the anticancer efficacy of CDK4 inhibitors., Significance: A multiomics analysis of spatially distinct fibroblasts establishes the importance of the stromal O-glycoproteome in tumor-stroma interactions at the leading edge and provides potential strategies to improve cancer treatment. See related commentary by De Wever, p. 537., (©2021 American Association for Cancer Research.)

Objective: To determine the 30-day incidence of venous thromboembolism (VTE) after gynecologic oncologic surgery and identify perioperative factors associated with postoperative VTE., Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify all gynecologic oncology cases from 2013 to 2019. Clinical and surgical characteristics, VTE events and 30-day postoperative complications were retrieved. Chi-square analysis and logistic regression models were performed to compare characteristics and postoperative outcomes of patients with and without VTE., Results: A total of 63,198 gynecologic oncology patients were included. The incidence of 30-day postoperative VTE was 1.2% (n = 781). On multivariable analysis, postoperative VTE was significantly associated with ascites (odds ratio (OR) 1.8), disseminated cancer (OR 1.7), pre-operative albumin <30 g/L (OR 1.9), laparotomy (OR 2.8), operative time > 180 min (OR 2.0), and increased surgical complexity (OR 2.2) (all p < 0.001). The incidence of VTE was higher after laparotomy compared to minimally invasive surgery (MIS) (2.3% v. 0.6%, p < 0.001). When stratified by type of gynecologic malignancy undergoing laparotomy, incidence of VTE was higher in patients with ovarian (2.4%) and uterine (2.4%) malignancies, compared to cervical cancer (1.1%) (p < 0.001). The 30-day incidence of VTE was 1.7% in 2013 compared to 0.9% in 2019 (laparotomy: 2.6% in 2013 to 1.6% in 2019 and MIS: 0.8% in 2013 to 0.4% in 2019)., Conclusion: Postoperative VTE is a potentially preventable complication of gynecologic oncology surgery. Our findings indicate that laparotomy, ascites, disseminated cancer, longer operative time, and low pre-operative albumin are risk factors for VTE., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8 + T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses., Competing Interests: Declaration of interests Z.B.: research funding from Bristol-Myers Squibb & Genentech/imCORE; honoraria from UpToDate. X.G.: advisory board for Exelixis, Bayer and Guardant Health. D.A.B.: non-financial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and Aveo, and consulting/personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy outside of the submitted work. N.I.V.: advisory board to Sanofi/Genzyme, Oncocyte, and Lilly. M.S.H.: consultant, Janssen Pharmaceuticals and UpToDate. R.H.: research funding from Novartis. B.A.M.: consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol Myers Squibb, Calithera, and EMD Serono; research funding to the institution from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. A.S.F.: consultant, Olympus America, Inc.; honoraria, Roche, Janssen; advisory board, Vessi Medical. C.J.W.: equity holder of BioNTech, Inc; research funding from Pharmacyclics. D.F.M.: honoraria from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai, Inc., Werewolf Therapeutics, and Calithera Biosciences; research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc. D.Y.C.H.: consultancies and research funding from Pfizer, Novartis, BMS, Merck, Eisai, Ipsen, and Exelixis. S.S.: grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR; a patent for Biogenex with royalties paid. E.M.V.A.: advisory/consulting, Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support, Novartis, BMS; equity, Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; patents, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation. T.K.C.: research (institutional and personal), Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, and Tracon; consulting/honoraria or advisory role, Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Nuscan, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, and Up-to-Date; CME-related events (e.g., OncLIve, PVI, MJH Life Sciences); NCI GU Steering Committee; stock ownership, Pionyr and Tempest; patents filed, royalties, or other intellectual properties, related to biomarkers of immune checkpoint blockers and ctDNA; travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; no speaker’s bureau. S.R.V.: consulting, MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors report no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Opioids are routinely prescribed after minimally invasive gynecologic oncology surgery, with minimal data to inform the ideal dose. The aim of this study was to evaluate the impact of a restrictive opioid prescription protocol on the median morphine milligram equivalents prescribed and pain control in patients undergoing minimally invasive surgery., Methods: A restrictive opioid prescription protocol was implemented from January through December 2020 at a single tertiary cancer center in Ontario, Canada. Consecutive patients undergoing minimally invasive hysterectomy for suspected malignancy were included. Simultaneously, we implemented use of multimodal analgesia, patient and provider education, pre-printed standardized prescriptions, and tracking of opioid prescriptions. Total median morphine milligram equivalents prescribed were compared between pre- and post-intervention cohorts. Patients were surveyed regarding opioid use and pain control at 30 days post-surgery., Results: A total of 101 women in the post-intervention cohort were compared with 92 consecutive pre-intervention controls. Following protocol implementation, median morphine milligram equivalents prescribed decreased from 50 (range 9-100) to 25 (range 8-75) (p<0.001). In the post-intervention cohort, 75% (76/101) used 10 median morphine milligram equivalents or less and 55 patients (54%) used 0 median morphine milligram equivalent. There was no additional increase in opioid refill requests after implementation of our strategy. Overall, patients reported a median pain score of 3/10 at 30 days post-surgery; the highest pain scores and most of the pain occurred in the first week after surgery., Conclusions: Implementation of a restrictive opioid prescription protocol led to a significant reduction in opioid use after minimally invasive gynecologic oncology surgery, with over 50% of patients requiring no opioids postoperatively., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Objective: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280)., Data Sources: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials., Study Eligibility Criteria: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data., Methods: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool., Results: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m 2 (range, 19.4-43.7 kg/m 2 ). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I 2 =59%) and 64% bilaterally (95% confidence interval, 53%-73%; I 2 =69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I 2 =44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I 2 =0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I 2 =0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I 2 =0%)., Conclusion: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Patients with lung cancer (LC) are susceptible to severe outcomes from COVID-19. This study evaluated disruption to care of patients with LC during the COVID-19 pandemic., Methods: The COVID-19 and Cancer Outcomes Study (CCOS) is a prospective cohort study comprised of patients with a current or past history of hematological or solid malignancies with outpatient visits between March 2 and March 6, 2020, at two academic cancer centers in the Northeastern United States (US). Data was collected for the three months prior to the index week (baseline period) and the following three months (pandemic period)., Results: 313 of 2365 patients had LC, 1578 had other solid tumors, and 474 had hematological malignancies. Patients with LC were not at increased risk of COVID-19 diagnosis compared to patients with other solid or hematological malignancies. When comparing data from the pandemic period to the baseline period, patients with LC were more likely to have a decrease in in-person visits compared to patients with other solid tumors (aOR 1.94; 95% CI, 1.46-2.58), but without an increase in telehealth visits (aOR 1.13; 95% CI 0.85-1.50). Patients with LC were more likely to experience pandemic-related treatment delays than patients with other solid tumors (aOR 1.80; 95% CI 1.13-2.80) and were more likely to experience imaging/diagnostic procedure delays than patients with other solid tumors (aOR 2.59; 95% CI, 1.46-4.47) and hematological malignancies (aOR 2.01; 95% CI, 1.02-3.93). Among patients on systemic therapy, patients with LC were also at increased risk for decreased in-person visits and increased treatment delays compared to those with other solid tumors., Discussion: Patients with LC experienced increased cancer care disruption compared to patients with other malignancies during the early phase of the COVID-19 pandemic. Focused efforts to ensure continuity of care for this patient population are warranted., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Parastomal hernia (PSH) is a frequent complication of stoma creation during colorectal surgery. Radiological classification systems have been proposed for PSH but are primarily used for research. Our objective was to determine if PSH radiological classification at diagnosis could predict the need for surgical repair during follow-up., Methods: In this retrospective cohort study, we reviewed 705 postoperative CT scans from 154 patients with permanent stoma creation from 2015 to 2018. Patients were included for analysis if a primary PSH was diagnosed on any exam. PSH were classified according to the European Hernia Society (EHS) and Moreno-Matias (MM) classification systems., Results: The incidence of radiological PSH was 41% (63/154) after a median radiological follow-up of 19.2 months (interquartile range, 10.9-32.9). Surgical repair was required in 17 of 62 patients with a primary PSH. There was no significant correlation between PSH classification and surgical hernia repair for either the EHS (p = 0.56) or MM classification systems (p = 0.35) in a univariate analysis. However, in a multivariate analysis, the type of PSH according to the EHS classification was significantly correlated with PSH repair during follow-up (p = 0.02). Type III PSH were associated with a lower incidence of surgical hernia repair as compared with type I, with a hazard ratio (HR) of 0.01 (95% CI, <0.00-0.20). A similar correlation was not seen using the MM classification (p = 0.10)., Conclusion: EHS classification of PSH was significant correlated with the need for surgical repair during short-term follow-up. Prospective studies are required to establish a potential role in patient care., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare gynecologic oncology surgical treatment modifications and delays during the first wave of the COVID-19 pandemic between a publicly funded Canadian versus a privately funded American cancer center., Methods: This is a retrospective cohort study of all planned gynecologic oncology surgeries at University Health Network (UHN) in Toronto, Canada and Brigham and Women's Hospital (BWH) in Boston, USA, between March 22,020 and July 302,020. Surgical treatment delays and modifications at both centers were compared to standard recommendations. Multivariable logistic regression was performed to adjust for confounders., Results: A total of 450 surgical gynecologic oncology patients were included; 215 at UHN and 235 at BWH. There was a significant difference in median time from decision-to-treat to treatment (23 vs 15 days, p < 0.01) between UHN and BWH and a significant difference in treatment delays (32.56% vs 18.29%; p < 0.01) and modifications (8.37% vs 0.85%; p < 0.01), respectively. On multivariable analysis adjusting for age, race, treatment site and surgical priority status, treatment at UHN was an independent predictor of treatment modification (OR = 9.43,95% CI 1.81-49.05, p < 0.01). Treatment delays were higher at UHN (OR = 1.96,95% CI 1.14-3.36 p = 0.03) and for uterine disease (OR = 2.43, 95% CI 1.11-5.33, p = 0.03)., Conclusion: During the first wave of COVID-19 pandemic, gynecologic oncology patients treated at a publicly funded Canadian center were 9.43 times more likely to have a surgical treatment modification and 1.96 times more likely to have a surgical delay compared to an equal volume privately funded center in the United States., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8 + T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8 + T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC., Competing Interests: Declaration of interests D.A.B. reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. S.H.G. has patents licensed to Novalgen Inc, outside of the submitted work. Z.B. reports nonfinancial support from Bristol Myers Squibb and Genentech/imCore. D.B.K. has acted as an advisor to and has received consulting fees from Neon Therapeutics and owns equity in Agenus, Armata pharmaceuticals, Breakbio, Biomarin Pharmaceutical, Bristol Myers Squibb, Celldex Therapeutics, Chinook Therapeutics, Editas Medicine, Exelixis, Gilead Sciences, IMV, Lexicon Pharmaceuticals, Moderna, and Regeneron Pharmaceuticals. K.M.M. reports research support from Bristol Myers Squibb. B.A.M. reports consulting fees from Bayer, Astellas, Astra Zeneca, Seattle Genetics, Dendreon, Calithera, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono, and research support to DFCI from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. D.F.M. has received consulting fees from Bristol Myers Squibb, Pfizer, Merck, Alkermes, EMD Serono, Eli Lilly, Iovance, and Eisai, and research support from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes. S.A.S. reports nonfinancial support from Bristol Myers Squibb outside the submitted work. S.A.S. previously advised and has received consulting fees from Neon Therapeutics. S.A.S. reports nonfinancial support from Bristol Myers Squibb, and equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol Myers Squibb, and Lumos Pharma, outside the submitted work. S.S. reported personal fees from Merck, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI, grants from Bristol Myers Squibb, AstraZeneca, Novartis, and Exelixis, and royalties from Biogenex. A.H.S. has patents/pending royalties on the PD-1 pathway from Roche and Novartis. A.H.S. is on advisory boards for Bicara, Janssen Immunology, Surface Oncology, Elstar, SQZ Biotechnologies, Elpiscience, Selecta, and Monopteros, and consults for Novartis. A.H.S. has received research funding from AbbVie, Novartis, Roche, UCB, Ipsen, Quark, and Merck. D.F.M. reports personal fees from Bristol Myers Squibb, Pfizer, Merck, Novartis, Exelixis, Array BioPharm, Genentech, Alkermes, Jounce Therapeutics, X4 Pharma, Peloton, EMD Serono, and Eli Lilly, and research support from Bristol Myers Squibb, Prometheus Laboratories, Merck, Genentech, Pfizer, Exelixis, Novartis, X4 Pharma, Alkermes, and Peloton. T.K.C. reports grants and personal fees from Astra Zeneca; personal fees from Bayer; grants and personal fees from Bristol Myers Squibb; personal fees from Cerulean; grants and personal fees from Eisai; personal fees from Foundation Medicine Inc.; grants and personal fees from Exelixis; grants and personal fees from Genentech; personal fees from Roche; grants and personal fees from GlaxoSmithKline; grants and personal fees from Merck, from Novartis, Peloton, and Pfizer; personal fees from Prometheus Labs; grants and personal fees from Corvus; personal fees from Ipsen; grants from Tracon; and grants from Astellas outside the submitted work. The other authors declare no potential conflicts of interest. C.J.W. is an equity holder of BioNTech., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB., Competing Interests: Declaration of interests M.X.H. has consulted for Amplify Medicines and Ikena Oncology. Z.B. reports research support from Bristol-Meyers Squibb (BMS) and Genentech/imCORE unrelated to this study. D.A.B. reports non-financial support from BMS, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of this work. B.A.M. has consulted for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono. He received research support to Dana-Farber Cancer Institute from BMS, Calithera, Exelixis, and Seattle Genetics. J.L.G. is a consultant for and/or receives sponsored research support from GlaxoSmithKline (GSK), Array BioPharma, Codagenix, Verseau, Kymera, and Eli Lilly. A. Rotem is an employee of AstraZeneca and an equity holder in NucleAI and Celsius Therapeutics. A. Regev is a founder and equity holder of Celsius Therapeutics, holds equity in Immunitas Therapeutics, and, until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific; since August 1, 2020, she has been an employee of Genentech. E.M.V.A. reports advisory/consulting with Tango Therapeutics, Genome Medical, Invitae, Monte Rosa, Enara Bio, Manifold Bio, and Janssen; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Manifold Bio, Monte Rosa, and Enara Bio. T.K.C. reports research support/honoraria from, consulting/advisory relationships with, and/or equity stakes in Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, BMS, Calithera, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, F. Hoffmann-La Roche, Foundation Management, Genentech, GSK, Heron Therapeutics, Infinity Pharma, Janssen Oncology, IQVIA, Ipsen, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon, Surface Oncology, Tempest, Up-to-Date, OncLIve, PVI, and MJH Life Sciences; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; and support from the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The optimal systemic therapy strategy for advanced epithelial ovarian cancer (EOC) remains unclear. We performed a systematic review and meta-analysis to assess oncologic outcomes and toxicity of bevacizumab combination treatment in advanced EOC., Methods: We conducted an electronic search of all phase 2 and 3 clinical trials involving bevacizumab combination therapy in advanced-stage EOC between 2010 and March 2020, using Embase, Medline, Epub Ahead of Print, Cochrane for clinical trials, Cochrane Database of Systematic Reviews, Web of Science and clinicaltrials.gov databases. Progression-free survival (PFS), overall survival (OS), and their hazard ratios (HR) when available were extracted. Pooled HR were calculated for each efficacy endpoint in the meta-analysis using inverse variance weighted method. Bias was assessed using the Cochrane Collaboration Risk of Bias I (ROB1) tool for randomized controlled trials., Results: Thirty-five studies were included in the qualitative analysis and eight studies in the quantitative synthesis. In the first-line setting, bevacizumab combined with chemotherapy revealed a significant improvement in PFS (pooled HR = 0.72, 95% CI 0.65-0.81) when compared to chemotherapy alone but no significant OS benefit (pooled HR = 0.88, 95% CI 0.72-1.06). In the recurrent setting, bevacizumab combinations showed significant PFS (pooled HR = 0.52, 95% CI 0.47-0.58) and OS benefits (pooled HR = 0.88, 95% CI 0.79-0.99) compared with non-bevacizumab regimens. Rate of bowel perforation was low at 1.24% (range 0-4.2%)., Conclusions: Bevacizumab-containing regimens are associated with significant PFS benefit in advanced and recurrent epithelial ovarian cancer. While the difference in OS did not reach statistical significance in the first-line setting, bevacizumab was associated with improved survival in the recurrent setting., Competing Interests: Declaration of Competing Interest The authors have no personal nor financial conflict of interests to disclose. Several of the clinical trials included in this systematic review were conducted at the Princess Margaret Cancer Centre., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Although a common form of family violence, sibling bullying is often viewed as harmless by families and society. Consequently, it has not received as much attention in research compared with peer bullying or other types of family violence, such as interpartner violence, child abuse, and elder abuse. Considering that sibling relationships have lasting effects on children's development, this retrospective study focused on the antecedents and outcomes of sibling bullying. Grounded in family system theory and social learning theory, it explored whether sibling bullying during childhood and adolescence mediated the relationship between negative family dynamics (i.e., sibling rivalry, interparental hostility, and parental hostility) and young adults' well-being (i.e., sense of competence, internalized problems, self-esteem, and satisfaction with life). Data from 216 respondents were analyzed using structural equation modeling. Results revealed that young adults who reported higher levels of sibling rivalry and interparental hostility were more likely to be victims of sibling bullying. In turn, sibling bullying was associated with lower sense of competence, self-esteem, and life satisfaction, as well as more internalized problems. Parents' hostile behaviors toward their children were not associated with sibling bullying but were negatively associated with well-being in early adulthood. Our work underlines the importance of harmonious family dynamics and the need for sibling bullying to be taken more seriously by parents and family members. From a clinical point of view, our findings suggest that clinicians and human service workers should adopt a family-level approach when trying to reduce sibling bullying and its negative outcomes by educating parents about the interdependence of family relationships.

Introduction: In situ simulation (ISS) consists of performing a simulation in the everyday working environment with the usual team members. The feasibility of ISS in emergency medicine is an important research question, because ISS offers the possibility for repetitive, regular simulation training consistent with specific local needs. However, ISS also raises the issue of safety, since it might negatively impact the care of other patients in the emergency department (ED). Our hypothesis is that ISS in an academic high-volume ED is feasible, safe and associated with benefits for both staff and patients., Methods: A mixed-method, including a qualitative method for the assessment of feasibility and acceptability and a quantitative method for the assessment of patients' safety and participants' psychosocial risks, will be used in this study.Two distinct phases are planned in the ED of the CHU de Québec-Université Laval (Hôpital de l'Enfant-Jésus) between March 2021 and October 2021. Phase 1: an ISS programme will be implemented with selected ED professionals to assess its acceptability and safety and prove the validity of our educational concept. The number of cancelled sessions and the reasons for cancellation will be collected to establish feasibility criteria. Semistructured interviews will evaluate the acceptability of the intervention. We will compare unannounced and announced ISS. Phase 2: the impact of the ISS programme will be measured with validated questionnaires for the assessment of psychosocial risks, self-confidence and perceived stress among nonselected ED professionals, with comparison between those exposed to ISS and those that were not., Ethics and Dissemination: The CHU de Québec-Université Laval Research ethics board has approved this protocol (#2020-5000). Results will be presented to key professionals from our institution to improve patient safety. We also aim to publish our results in peer-reviewed journals and will submit abstracts to international conferences to disseminate our findings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Importance: Whether sentinel lymph node biopsy (SLNB) can replace lymphadenectomy for surgical staging in patients with high-grade endometrial cancer (EC) is unclear., Objective: To examine the diagnostic accuracy of, performance characteristics of, and morbidity associated with SLNB using indocyanine green in patients with intermediate- and high-grade EC., Design, Setting, and Participants: In this prospective, multicenter cohort study (Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging [SENTOR] study), accrual occurred from July 1, 2015, to June 30, 2019, with early stoppage because of prespecified accuracy criteria. The study included patients with clinical stage I grade 2 endometrioid or high-grade EC scheduled to undergo laparoscopic or robotic hysterectomy with an intent to complete staging at 3 designated cancer centers in Toronto, Ontario, Canada., Exposures: All patients underwent SLNB followed by lymphadenectomy as the reference standard. Patients with grade 2 endometrioid EC underwent pelvic lymphadenectomy (PLND) alone, and patients with high-grade EC underwent PLND and para-aortic lymphadenectomy (PALND)., Main Outcomes and Measures: The primary outcome was sensitivity of the SLNB algorithm. Secondary outcomes were additional measures of diagnostic accuracy, sentinel lymph node detection rates, and adverse events., Results: The study enrolled 156 patients (median age, 65.5 years; range, 40-86 years; median body mass index [calculated as weight in kilograms divided by height in meters squared], 27.5; range, 17.6-49.3), including 126 with high-grade EC. All patients underwent SLNB and PLND, and 101 patients (80%) with high-grade EC also underwent PALND. Sentinel lymph node detection rates were 97.4% per patient (95% CI, 93.6%-99.3%), 87.5% per hemipelvis (95% CI, 83.3%-91.0%), and 77.6% bilaterally (95% CI, 70.2%-83.8%). Of 27 patients (17%) with nodal metastases, 26 patients were correctly identified by the SLNB algorithm, yielding a sensitivity of 96% (95% CI, 81%-100%), a false-negative rate of 4% (95% CI, 0%-19%), and a negative predictive value of 99% (95% CI, 96%-100%). Only 1 patient (0.6%) was misclassified by the SLNB algorithm. Seven of 27 patients with node-positive cancer (26%) were identified outside traditional PLND boundaries or required immunohistochemistry for diagnosis., Conclusions and Relevance: In this prospective cohort study, SLNB had acceptable diagnostic accuracy for patients with high-grade EC at increased risk of nodal metastases and improved the detection of node-positive cases compared with lymphadenectomy. The findings suggest that SLNB is a viable option for the surgical staging of EC.

Objectif: Cette directive passe en revue l'évaluation clinique et la prise en charge des maladies gestationnelles trophoblastiques, notamment les traitements chirurgicaux et médicamenteux des tumeurs bénignes, prémalignes et malignes. L'objectif de la présente directive clinique est d'aider les fournisseurs de soins de santé à rapidement diagnostiquer les maladies gestationnelles trophoblastiques, à normaliser les traitements et le suivi et à assurer des soins spécialisés précoces aux patientes dont l'atteinte est maligne ou métastatique. PROFESSIONNELS CONCERNéS: Gynécologues généralistes, obstétriciens, médecins de famille, sages-femmes, urgentologues, anesthésistes, radiologistes, anatomopathologistes, infirmières autorisées, infirmières praticiennes, résidents, gynécologues-oncologues, oncologues médicaux, radio-oncologues, chirurgiens, omnipraticiens en oncologie, infirmières en oncologie, pharmaciens, auxiliaires médicaux et autres professionnels de la santé qui traitent des patientes atteintes d'une maladie gestationnelle trophoblastique. La présente directive vise également à fournir des renseignements aux parties intéressées qui prodiguent des soins de suivi à ces patientes après le traitement., Population Cible: Femmes en âge de procréer atteintes d'une maladie gestationnelle trophoblastique., Options: Les femmes ayant reçu un diagnostic de maladie gestationnelle trophoblastique doivent être orientées vers un gynécologue afin qu'il réalise une évaluation initiale, envisage une intervention chirurgicale primaire (évacuation ou hystérectomie) et effectue un suivi. Il y a lieu d'orienter les femmes ayant reçu un diagnostic de tumeur trophoblastique gestationnelle vers un gynécologue-oncologue afin qu'il effectue la stadification tumorale, établisse le score de risque et envisage l'intervention chirurgicale primaire ou un traitement systémique (mono- ou polychimiothérapie) et la nécessité d'éventuels traitements supplémentaires. Il est recommandé de discuter de chaque cas de néoplasie gestationnelle trophoblastique lors d'une réunion multidisciplinaire de cas oncologiques et de l'inscrire dans une base de données centralisée (régionale et/ou nationale). DONNéES PROBANTES: Des recherches ont été effectuées au moyen des bases de données Embase et MEDLINE, du Cochrane Central Register of Controlled Trials et de la Cochrane Database of Systematic Reviews afin de trouver les études publiées depuis 2002 utilisant un ou plusieurs des mots clés suivants : trophoblastic neoplasms, choriocarcinoma, trophoblastic tumor, placental site, gestational trophoblastic disease, hydatidiform mole, drug therapy, surgical therapy, radiotherapy, cure, complications, recurrence, survival, prognosis, pregnancy outcome, disease outcome, treatment outcome et remission. La recherche initiale a été effectuée en avril 2017; une mise à jour a été faite en mai 2019. Les données probantes pertinentes ont été sélectionnées aux fins d'inclusion selon l'ordre suivant : méta-analyses, revues systématiques, directives cliniques, essais cliniques randomisés, études de cohortes prospectives, études observationnelles, revues non systématiques, études de séries de cas et rapports. D'autres articles pertinents ont été trouvés en recoupant les revues répertoriées. Le nombre total d'études relevées était de 673, dont 79 études sont citées dans la présente revue. MéTHODES DE VALIDATION: Le contenu et les recommandations ont été rédigés et acceptés par les auteurs. La direction et le conseil d'administration de la Société de gynéco-oncologie du Canada ont passé en revue le contenu de la version préliminaire et ont soumis des commentaires à prendre en considération. Le conseil d'administration de la Société des obstétriciens et gynécologues du Canada a approuvé la version définitive aux fins de publication. La qualité des données probantes a été évaluée au moyen des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation). Consulter les tableaux dans l'annexe en ligne pour connaître les critères de notation et d'interprétation des recommandations. BéNéFICES, RISQUES, COûTS: Les présentes recommandations aideront les médecins à diagnostiquer rapidement les maladies gestationnelles trophoblastiques et à orienter de façon urgente les patientes ayant reçu un diagnostic de maladie gestationnelle trophoblastique en gynécologie oncologique pour une prise en charge spécialisée. Le traitement des néoplasies gestationnelles trophoblastiques en centre spécialisé combiné à l'utilisation de bases de données centralisées permet de recueillir et de comparer des données sur les résultats thérapeutiques des patientes atteintes de ces tumeurs rares et d'optimiser les soins aux patientes. DÉCLARATIONS SOMMAIRES (CLASSEMENT GRADE ENTRE PARENTHèSES): RECOMMANDATIONS (CLASSEMENT GRADE ENTRE PARENTHèSES)., (Copyright © 2019. Published by Elsevier Inc.)

Objective: This guideline reviews the clinical evaluation and management of gestational trophoblastic diseases, including surgical and medical management of benign, premalignant, and malignant entities. The objective of this guideline is to assist health care providers in promptly diagnosing gestational trophoblastic diseases, to standardize treatment and follow-up, and to ensure early specialized care of patients with malignant or metastatic disease., Intended Users: General gynaecologists, obstetricians, family physicians, midwives, emergency department physicians, anaesthesiologists, radiologists, pathologists, registered nurses, nurse practitioners, residents, gynaecologic oncologists, medical oncologists, radiation oncologists, surgeons, general practitioners in oncology, oncology nurses, pharmacists, physician assistants, and other health care providers who treat patients with gestational trophoblastic diseases. This guideline is also intended to provide information for interested parties who provide follow-up care for these patients following treatment., Target Population: Women of reproductive age with gestational trophoblastic diseases., Options: Women diagnosed with a gestational trophoblastic disease should be referred to a gynaecologist for initial evaluation and consideration for primary surgery (uterine evacuation or hysterectomy) and follow-up. Women diagnosed with gestational trophoblastic neoplasia should be referred to a gynaecologic oncologist for staging, risk scoring, and consideration for primary surgery or systemic therapy (single- or multi-agent chemotherapy) with the potential need for additional therapies. All cases of gestational trophoblastic neoplasia should be discussed at a multidisciplinary cancer case conference and registered in a centralized (regional and/or national) database., Evidence: Relevant studies from 2002 onwards were searched in Embase, MEDLINE, the Cochrane Central Register of Controlled Trials, and Cochrane Systematic Reviews using the following terms, either alone or in combination: trophoblastic neoplasms, choriocarcinoma, trophoblastic tumor, placental site, gestational trophoblastic disease, hydatidiform mole, drug therapy, surgical therapy, radiotherapy, cure, complications, recurrence, survival, prognosis, pregnancy outcome, disease outcome, treatment outcome, and remission. The initial search was performed in April 2017 and updated in May 2019. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 673, with 79 studies cited in this review., Validation Methods: The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of Directors of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of Directors for the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework. See the online appendix tables for key to grading and interpretation of recommendations., Benefits: These guidelines will assist physicians in promptly diagnosing gestational trophoblastic diseases and urgently referring patients diagnosed with gestational trophoblastic neoplasia to gynaecologic oncology for specialized management. Treating gestational trophoblastic neoplasia in specialized centres with the use of centralized databases allows for capturing and comparing data on treatment outcomes of patients with these rare tumours and for optimizing patient care., Summary Statements (grade Ratings in Parentheses): RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES)., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Minimally invasive radical hysterectomy is associated with decreased survival in patients with early cervical cancer. The objective of this study was to determine whether the use of an intra-uterine manipulator at the time of laparoscopic or robotic radical hysterectomy is associated with inferior oncologic outcomes., Methods: A retrospective cohort study was carried out of all patients with cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) International Federation of Gynecology and Obstetrics 2009 stages IA1 (with positive lymphovascular space invasion) to IIA who underwent minimally invasive radical hysterectomy at two academic centers between January 2007 and December 2017. Treatment, tumor characteristics, and survival data were retrieved from hospital records., Results: A total of 224 patients were identified at the two centers; 115 had surgery with the use of an intra-uterine manipulator while 109 did not; 53 were robotic and 171 were laparoscopic. Median age was 44 years (range 38-54) and median body mass index was 25.8 kg/m 2 (range 16.6-51.5). Patients in whom an intra-uterine manipulator was not used at the time of minimally invasive radical hysterectomy were more likely to have residual disease at hysterectomy (p<0.001), positive lymphovascular space invasion (p=0.02), positive margins (p=0.008), and positive lymph node metastasis (p=0.003). Recurrence-free survival at 5 years was 80% in the no intra-uterine manipulator group and 94% in the intra-uterine manipulator group. After controlling for the presence of residual cancer at hysterectomy, tumor size and high-risk pathologic criteria (positive margins, parametria or lymph nodes), the use of an intra-uterine manipulator was no longer significantly associated with worse recurrence-free survival (HR 0.4, 95% CI 0.2 to 1.0, p=0.05). The only factor which was consistently associated with recurrence-free survival was tumor size (HR 2.1, 95% CI 1.5 to 3.0, for every 10 mm increase, p<0.001)., Conclusion: After controlling for adverse pathological factors, the use of an intra-uterine manipulator in patients with early cervical cancer who underwent minimally invasive radical hysterectomy was not an independent factor associated with rate of recurrence., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: CD73-adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5'-nucleotidase ( NT5E ), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 ( ENTPD1 )) and A2 adenosine receptor (A2AR; ADORA2A ) transcript levels with markers of angiogenesis and antitumor immune response., Methods: Patients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73 negative (CS=0), CD73 low or CD73 high (< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and high NT5E , ENTPD1 and ADORA2A gene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared between NT5E , ENTPD1 and ADORA2A expression groups., Results: Among the 138 patients eligible for inclusion, 'any' CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73 high tumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73 negative group (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008). NT5E and ENTPD1 expression correlated with higher regulatory T cell (Treg) signature, while ADORA2A expression was associated with increased Treg and angiogenesis signatures., Conclusions: High CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73-adenosine pathway in RCC., Competing Interests: Competing interests: AT: advisory role for Foundation Medicine, Pfizer; research funding to institution from EMD Serono, Bayer, Clovis Oncology, Aravive Inc, WindMIL therapeutics, Corvus Pharmaceuticals; EL, WX, AF, JAS, ESG, GB, JHF, CG, CM and LT: none; NM-C: support for research travel from Pfizer and Ipsen, and consulting fees from BMS and Bayer; XXW: research funding to institution from Bristol-Myers Squibb (BMS); MG: research funding from BMS and Merck; BAM: payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai and EMD Serono, and received research support to Dana Farber Cancer Institute (DFCI) from BMS, Calithera, Exelixis, Seattle Genetics. TKC: supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Research (institutional and personal): AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda. Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly Oncology. Consulting or advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest, Lilly Ventures. Stock ownership: Pionyr, Tempest. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee), KidneyCan Advisory board, Kidney cancer Research Summit co-chair (2019-). Patents, royalties or other intellectual properties: related to biomarkers of immune checkpoint blockers. Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others).The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. CV provided upon request for scope of clinical practice and researchMentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. NA: consultancy to Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to my institution: Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. DFM: Honorarium for consultancy from BMS, Pfizer, Merck, Alkermes Inc, EMD Serono, Eli Lilly, Iovance and Eisai. Research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes. SS: reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. LCH: Reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, BMS, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, ASIM CME, and Ology Medical Education. Research funding from Bayer, Sotio, BMS, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis). Support for research travel from Bayer and Genentech. Currently employed by Surface Oncology., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: The preoperative neutrophil-to-lymphocyte ratio has been found to be an independent prognostic indicator for perioperative complications and survival outcomes in patients undergoing oncologic surgery for several malignancies. The objective of this study was to evaluate the role of the preoperative neutrophil-to-lymphocyte ratio in predicting 30-day postoperative morbidity and overall survival in advanced-stage high-grade serous ovarian cancer patients after primary surgery., Methods: A retrospective study was conducted on consecutive patients who underwent primary surgery for high-grade serous ovarian cancer between January 2008 and December 2016 at a single tertiary academic institution in Toronto, Canada. Optimal thresholds for preoperative neutrophil-to-lymphocyte ratio were determined using receiver-operator characteristic curve analysis. Cox-proportional hazard models, Kaplan-Meier, and logistic regression analyses were performed., Results: Of 505 patients with ovarian cancer during the study period, 199 met the inclusion criteria. Receiver-operator characteristic curve analysis generated optimal preoperative neutrophil-to-lymphocyte ratio thresholds of 2.3 and 2.9 for 30-day postoperative morbidity and survival outcomes, respectively. A neutrophil-to-lymphocyte ratio ≥2.3 was predictive of a composite outcome of 30-day postoperative complications (odds ratio 7.3, 95% confidence interval 2.44 to 21.81; p=0.0004), after adjusting for longer operative time and intraoperative complications. Postoperative complications included superficial surgical site infections (p=0.007) and urinary tract infections (p=0.004). A neutrophil-to-lymphocyte ratio ≥29 was associated with worse 5-year overall survival (57.8% vs 77.7%, p=0.003), and suggested no statistically significant difference in progression-free survival (33.8% vs 40.7%, p=0.054). On multivariable analysis, the neutrophil-to-lymphocyte ratio remained an independent predictor for overall survival (p=0.02) when adjusting for suboptimal cytoreduction (p≤0.0001)., Discussion: A preoperative neutrophil-to-lymphocyte ratio ≥2.3 and ≥2.9 is associated with greater risk of 30-day postoperative morbidity and worse overall survival, respectively. This marker may be used in conjunction with other risk assessment strategies to preoperatively identify high-risk patients. Further prospective study is required to investigate its role in clinical decision-making., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There remains uncertainty about the prognostic significance of residual lung lesion on imaging after completion of treatment of low- or high-risk gestational trophoblastic neoplasia (GTN). Here, we determine if such residual lung lesions are associated with an increased risk of relapse., Methods: We retrospectively screened our electronic database to identify patients with low- or high-risk GTN and lung metastases between 2004 and 18. Recurrences among patients with or without residual lung lesions on imaging were compared. Chi square analysis and Kaplan-Meier survival curves were constructed. As the numbers of cases were low, we combined this data with our previously published and non-overlapping patient cohort (1995-2004)., Results: Of 1304 GTN patients treated at our centre between 2004 and 18, 99 had lung metastases without other distant sites. There were 40 patients (40.4%) with residual lung lesions. Whilst an increased rate of relapse was observed among patients with residual lung lesions (4/40; 10.0%) compared to without such lesions (3/59; 5.1%), this difference was not statistically significant (p = .35). By combining the data with our previous cohort, there was an increase in relapse rate of patients with residual lung lesions (5/63; 7.9%) compared to those without such lesions (4/112; 3.6%). However, this difference was also not statistically significant (p = .21)., Conclusion: Residual lung lesions on imaging after completion of GTN treatment are common. However, this finding did not statistically increase relapse rate. Due to low number of recurrent events, a multi-centre, larger dataset would be needed to provide more definitive evidence., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Real-time intraoperative assessment of anastomotic perfusion with indocyanine green fluorescence angiography (ICG-FA) is a recent technique that is found to assist intraoperative decision-making and decrease risk of anastomotic leak in the General Surgery literature. No studies to date evaluate its use in Gynecologic Oncology. Our objectives were to assess the safety and feasibility of ICG-FA use and to describe the intraoperative assessment of anastomotic perfusion with ICG-FA., Methods: A retrospective study of a prospectively-collected database of patients with a gynecologic malignancy who underwent a bowel resection at Princess Margaret Cancer Centre in Toronto, Canada, between November 1, 2017 and December 15, 2019 was conducted. ICG-FA was administered intravenously, and a near infrared imaging system (Pinpoint, Novadaq, Canada; SPY-PHI, Stryker, USA) was used to objectively assess bowel perfusion., Results: ICG-FA was used to assess a total of 100 bowel anastomoses in 82 consecutive surgeries: 56 low anterior resections, 19 small bowel resections, 15 right hemi-colectomies, 6 left hemi-colectomies, 3 transverse colectomies, and 1 total colectomy. Fifty-five end-to end, 44 side-to-side and 1 end-to-side anastomoses were assessed. ICG angiography was successful in all patients, allowing complete visualization of anastomotic perfusion in all cases. Hypoperfusion detected by ICG-FA resulted in change in operative plan for three patients (two anastomotic revisions and one diverting ileostomy). There were no adverse reactions to ICG. In this cohort, there was one postoperative anastomotic leak., Conclusions: ICG-FA enables objective and accurate intraoperative evaluation of anastomotic perfusion in surgeries for gynecologic malignancies. Its implementation and routine use were found to be safe and well-tolerated without side effects in our study cohort. ICG-FA can be used with other risk-assessment strategies to guide operative decision-making in Gynecologic Oncology., Competing Interests: Declaration of competing interest There are no conflicts of interests to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).

Objectives: Heated intraperitoneal chemotherapy (HIPEC) has not been universally adopted at the time of interval cytoreductive surgery for primary epithelial ovarian cancer (EOC) despite evidence of a 12-month overall survival (OS) benefit in a recent landmark randomized trial. We performed a systematic review and meta-analysis to assess oncologic outcomes and perioperative morbidity following HIPEC among primary EOC patients., Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from inception to August 2019, for observational and randomized studies of primary EOC patients undergoing HIPEC. We assessed risk of bias using the Institute of Health Economics Quality Appraisal Checklist for single-arm cohort studies, Newcastle-Ottawa Scale for comparative cohort studies, and Cochrane Collaboration's Tool for randomized trials. We qualitatively summarized survival outcomes and calculated the pooled proportion of 30-day grade III-IV morbidity and postoperative death., Results: We identified 35 articles including 2252 primary EOC patients; one study was a randomized trial, and only six studies included a comparator group of surgery alone. The timing, temperature, and chemotherapeutic agents used for HIPEC differed across studies. Reported OS was highly variable (3-year OS range: 46-77%); three comparative cohort studies and the sole randomized trial reported statistically significant survival benefits for HIPEC over surgery alone, while two comparative cohort studies did not. The pooled proportions for grade III-IV morbidity and postoperative death at 30 days were 34% (95% CI 20-52) and 0% (95% CI 0-5) respectively., Conclusion: One randomized trial suggests that HIPEC at time of interval cytoreductive surgery should be considered in patients with primary EOC. However, there is significant heterogeneity in literature with respect to an appropriate HIPEC regimen, short- and long-term outcomes. High-quality prospective randomized trials are urgently needed to clarify the role of HIPEC in the first-line treatment of primary EOC., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway., Result: To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior., Conclusion: These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

Objective: Gynecologic Oncology patients are traditionally admitted for 2-3 days following ileostomy closure. Our aim was to assess feasibility and safety of same-day discharge (SDD), by comparing 30-day clinical outcomes after SDD and standard admission., Methods: Retrospective study of patients who underwent ileostomy closure at two academic tertiary centres in Toronto, Canada, between January 2010 and October 2017., Results: In total 117 patients underwent ileostomy closure: 23 had SDD and 94 were admitted for a median of 3 days. There were no significant differences between groups in terms of age, body mass index, comorbidities, primary malignancy, tumor stage, indication for ileostomy, previous radiation therapy, chemotherapy, interval between ileostomy formation and closure, and intraoperative complications. Median operative time was shorter (47 versus 60 min, p = 0.0001) and there was a longer median interval between last chemotherapy cycle to ileostomy closure (145 versus 106 days, p = 0.01) in the SDD group. SDD was not associated with an increased risk of adverse events (13% versus 24.5%, p= 0.24), as assessed by a composite outcome which included small bowel obstruction, anastomotic leak, surgical site infection, clostridium difficile infection, sepsis, and thromboembolic events, when compared to standard admission. Moreover, SDD did not lead to more emergency room visits (17.4% versus 16%, p = 0.87) or readmissions within 30 days of surgery (17.4% versus 8.5%, p= 0.21)., Conclusions: SDD is a safe alternative to routine hospitalization that has the potential to improve healthcare resource utilization, without increasing readmissions or emergency room visits. Careful patient selection is warranted., Competing Interests: Declaration of competing interest There are no conflicts of interests to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Drug screening studies typically involve assaying the sensitivity of a range of cancer cell lines across an array of anti-cancer therapeutics. Alongside these sensitivity measurements high dimensional molecular characterizations of the cell lines are typically available, including gene expression, copy number variation and genomic mutations. We propose a sparse multitask regression model which learns discriminative latent characteristics that predict drug sensitivity and are associated with specific molecular features. We use ideas from Bayesian nonparametrics to automatically infer the appropriate number of these latent characteristics. The resulting analysis couples high predictive performance with interpretability since each latent characteristic involves a typically small set of drugs, cell lines and genomic features. Our model uncovers a number of drug-gene sensitivity associations missed by single gene analyses. We functionally validate one such novel association: that increased expression of the cell-cycle regulator C/EBPδ decreases sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat., Competing Interests: The authors have declared that no competing interests exist.

Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with 18 FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 ( GFPT2 ), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including GFPT2 , with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma. Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445-57. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Measuring expression profiles of inflammatory biomarkers is important in monitoring the polarization of immune responses; therefore, results should be independent of quantitation methods if they are to be accepted as validated clinical pathology biomarkers. To evaluate effects of differing quantitation methods, the seven major circulating Th1/Th2/Th17 cytokines interleukin 2 (IL-2), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), IL-4, IL-6, IL-10 and IL-17A were quantified in plasma of lipopolysaccharide (LPS)-treated mice with two different multiplex platforms., Methods: Female C57BL6 mice were treated orally with vehicle or dexamethasone, followed by LPS intravenously. Plasma samples were analyzed 0.5, 1, 2, 4, and 6 h post-LPS challenge with assays at Myriad-RBM and compared to assays performed on a BD Accuri C6 flow cytometer., Results: IL-17A response to LPS was limited but sustained, and the response for the remaining cytokines were early and transient; dexamethasone reduced expression of all 7 cytokines. TNF-α and IL-6 levels were similar across both assays, and IL-4 levels were generally very low. Plasma levels of remaining cytokines were variably lower with BD assays than Myriad-RBM assays., Conclusions: The present findings demonstrate that quantitation of circulating biomarkers of inflammation can be achieved using multiplexed flow cytometry, but careful consideration must be taken for assay validation when cross-referencing with another multiplexed assay., Competing Interests: All study procedures were reviewed and approved by Sinclair Research Center’s Institutional Animal Care and Use Committee.Not applicable.The authors are employees of Sinclair Research Center, a private research organization. The Sinclair Research Center did not have any influence on the outcome the study or the interpretation of the data.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This study aims to achieve a better understanding of the later stages of the family life cycle by exploring couples' marital quality during the empty-nest years of their relationships, using the actor-partner interdependence mediation model. The empty nest is the family stage that begins with the departure of children from home. In the hypothesized model of marital quality, husbands' and wives' satisfaction at having raised successful children serve as predictor variables, whereas their levels of perceived stress act as mediators. A sample of 344 participants, forming 172 heterosexual couples, participated in the study. The results of path analyses indicated that the model provided an acceptable fit for the data. Closer examination suggested that wives' and husbands' perceived stress fully mediate the relationships between husbands' tendency to view their children as successful adults and both spouses' marital quality. The article discusses interdependence and gender differences between spouses concerning their empty-nest experience.

The soil is a complex ecosystem where interactions between biotic and abiotic factors determine the survival and fate of microbial inhabitants of the system. Having previously shown that Escherichia coli requires the general stress response regulator, RpoS, to survive long term in soil, it was important to determine what specific conditions in this environment necessitate a functional RpoS. This study investigated the susceptibility of soil-persistent E. coli to predation by the single-celled eukaryotes Acanthamoeba polyphaga and Tetrahymena pyriformis, and the role RpoS plays in resisting this predation. Strain-specific differences were observed in the predation of E. coli strains, with soil-persistent strain COB583 being the most resistant to predation by both protozoans. RpoS and curli, proteinaceous fibres used for attachment to biotic and abiotic surfaces, increased the ability of E. coli to resist predation by A. polyphaga and T. pyriformis. Furthermore, soil moisture content impacted the survival of E. coli BW25113 but wild-type COB583 had similar survival irrespective of soil moisture content. Overall, this study confirmed that RpoS contributes to the resistance of E. coli to protozoan predation and that RpoS is crucial for the increased fitness of soil-persistent E. coli against predation and reduced moisture in soil., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Sentinel lymph node (SLN) biopsy is becoming a reasonable alternative to pelvic lymphadenectomy in early-stage cervical cancer. It is therefore imperative that centres without prior experience are able to successfully implement the procedure. The objectives of the current study were to (1) describe the process of implementing an SLN biopsy program with a novel peer mentorship component and (2) assess post-program quality improvement metrics, including SLN detection rate (DR) and diagnostic parameters., Methods: An institutional SLN biopsy protocol was developed collaboratively by gynaecologic oncology, nuclear medicine, and pathology departments at University Health Network, Toronto, Ontario. All decisions were based on the best evidence available. Newly diagnosed, early-stage cervical cancer patients undergoing primary surgery were then recruited prospectively for SLN biopsy with combined technique, followed by pelvic lymphadenectomy to evaluate key quality indicators, including SLN DR, sensitivity, and negative predictive value. Surgeons with previous SLN biopsy experience mentored surgeons unfamiliar with the technique. Interim analyses and multidisciplinary rounds were regularly carried out to identify failures of technique or protocol., Results: Thirty-nine patients (median age 42) were enrolled in the study between August 2010 and February 2014. The median number of SLNs and total pelvic lymph nodes removed per patient were 3 and 19, respectively. SLN DRs were 92% per patient (36/39), 88.5% per hemipelvis (69/78), and 85% bilaterally (33/39). SLN biopsy correctly identified seven of eight hemipelvises with nodal metastases, yielding a sensitivity of 88% (95% CI 0.47 to 1.00) and a false negative rate of 12% (95% CI 0 to 0.53). Surgeons undergoing peer mentorship (n = 3) performed as effectively (DR 100%) as surgeons (n = 2) with prior experience (DR 85%)., Conclusions: This study provides a model upon which other centres can adopt and validate cervical SLN biopsy. High SLN DRs and accurate identification of lymph node metastases can be achieved by focusing on multidisciplinary collaboration, knowledge translation with creation of evidence-based protocols, peer mentorship, and ongoing quality control., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

The use of miniature swine as a non-rodent species in safety assessment has continued to expand for over a decade and their use has become routine, particularly in pharmacology as a model for human integumentary diseases. Translational preclinical swine study data are now favorably compared and contrasted to human data, and miniature swine models provide important information in dermal safety assessment and skin pharmacology. For example, the miniature swine model has been well-accepted for cutaneous absorption and toxicity studies due to swine integument being morphologically and functionally similar to human skin. Subsequently, this model is important to dermal drug development programs, and it is the animal model of choice for assessment of dermal absorption, local tolerance and systemic toxicity following dermal exposures. In conclusion, the miniature swine model has an important role to play in the safety assessment of pharmaceutical products and in multiple aspects of human dermal drug development.

Purpose: Radiotherapy increases the level of inflammatory cytokines, some of which are known to promote metastasis. In a mouse model of triple negative breast cancer (TNBC), we determined whether irradiation of the mammary tumor increases the level of key cytokines and favors the development of lung metastases., Materials and Methods: D2A1 TNBC cells were implanted in the mammary glands of a Balb/c mouse and then 7 days old tumors were irradiated (4 × 6 Gy). The cytokines IL-1β, IL-4, IL-6, IL-10, IL-17 and MIP-2 were quantified in plasma before, midway and after irradiation. The effect of tumor irradiation on the invasion of cancer cells, the number of circulating tumor cells (CTC) and lung metastases were also measured., Results: TNBC tumor irradiation significantly increased the plasma level of IL-1β, which was associated with a greater number of CTC (3.5-fold) and lung metastases (2.3-fold), compared to sham-irradiated animals. Enhancement of D2A1 cell invasion in mammary gland was associated with an increase of the matrix metalloproteinases-2 and -9 activity (MMP-2, -9). The ability of IL-1β to stimulate the invasiveness of irradiated D2A1 cells was confirmed by in vitro invasion chamber assays., Conclusion: Irradiation targeting a D2A1 tumor and its microenvironment increased the level of the inflammatory cytokine IL-1β and was associated with the promotion of cancer cell invasion and lung metastasis development.

A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.

Background: The prognosis of triple-negative breast cancer (TNBC) is still difficult to establish. Some TNBC benefit from radiotherapy (RT) and are cured, while in other patients metastases appear during the first 3 years after treatment. In this study, an animal model of TNBC was used to determine whether the expression of the cell membrane protease MT1-MMP in cancer cells was associated with radiation-stimulated development of lung metastases., Methods: Using invasion chambers, irradiated fibroblasts were used as chemoattractants to assess the invasiveness of TNBC D2A1 cell lines showing downregulated expression of MT1-MMP, which were compared with D2A1-wt (wild-type) and D2A1 shMT1-mock (empty vector) cell lines. In a mouse model, a mammary gland was irradiated followed by the implantation of the downregulated MT1-MMP D2A1, D2A1-wt or D2A1 shMT1-mock cell lines. Migration of D2A1 cells in the mammary gland, number of circulating tumour cells and development of lung metastases were assessed., Results: The reduction of MT1-MMP expression decreased the invasiveness of D2A1 cells and blocked the radiation enhancement of cancer cell invasion. In BALB/c mice, irradiation of the mammary gland has stimulated the invasion of cancer cells, which was associated with a higher number of circulating tumour cells and of lung metastases. These adverse effects of radiation were prevented by downregulating the MT1-MMP., Conclusions: This study shows that the MT1-MMP is necessary for the radiation enhancement of lung metastasis development, and that its expression level and/or localisation could be evaluated as a biomarker for predicting the early recurrence observed in some TNBC patients.

Objectives: The prognostic significance of endometrioid ovarian cancer is unclear. In this study we compared rates of overall survival (OS) and disease-free survival between patients with endometrioid and serous ovarian cancers using long-term follow-up data., Methods: We included patients with endometrioid or serous ovarian cancers diagnosed at a single regional cancer centre between 1988 and 2006. Data on baseline and treatment characteristics were collected retrospectively. We used multivariate Cox proportional hazard models to determine the independent effect of histology on death or recurrence, adjusting for age, tumour grade, primary cytoreductive surgery, year of diagnosis, adjuvant treatment, and stage., Results: Five hundred and thirty-three women with ovarian cancer were included in the study cohort; 98 (18.4%) had endometrioid histology and 435 (81.6%) serous histology. The five-year OS rate for women with endometrioid cancer was 80.6%, and for women with serous ovarian cancer, it was 35.0%. The 10-year OS rates were 68.4% and 18.4% for endometrioid and serous histology, respectively. After adjusting for confounders excluding stage, there was a significantly lower risk of death from endometrioid cancer compared to serous ovarian cancer (hazard ratio [HR] 0.41, 95% CI 0.26 to 0.66). However, the difference was no longer significant after adding tumour stage to the model (HR 0.74, 95% CI 0.45 to 1.24). We found similar results for the risk of recurrence (HR 0.41, 95% CI 0.27 to 0.62 with stage not included, compared to HR 0.77, 95% CI 0.49 to 1.21 with stage included)., Conclusion: In this large cohort, in comparison with women with serous ovarian cancer, women with endometrioid ovarian cancer presented at a younger age, had earlier stage disease, and had disease almost always confined to the pelvis. The earlier stage of presentation of endometrioid ovarian cancer resulted in improved five-year and 10-year OS rates compared to serous ovarian cancer., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objectives: Women with uterine clear cell carcinoma (UCCC) are at high risk of relapse. Adjuvant chemotherapy (CT) is often recommended, although its effectiveness remains controversial. Our objective was to evaluate treatment-related outcomes of patients with UCCC, particularly those treated with adjuvant CT., Methods: In this retrospective cohort study, patients diagnosed with UCCC at 2 academic cancer centers from 2000 to 2014 were included. Clinical, surgical, and pathological data were collected. Survival estimates were obtained using the Kaplan-Meier method and compared by log rank test. Multivariable analysis was used to determine the effect of CT and radiation therapy (RT) on overall survival (OS) and progression-free survival (PFS)., Results: We included 146 patients with UCCC, with a median follow-up of 27 months (range, 1-160). Ninety-five (65%) patients presented with stage I to II disease and 51 (35%) with stage III to IV disease. Forty-six percent of patients with clinical stage I were upstaged after surgery: 29% were upstaged to stages III and IV. Thirty-one percent of patients with early-stage disease and 70% with advanced-stage received CT. Among recurrences, the majority had distant relapse in both early-stage (61.5%) and advanced-stage (96.3%) diseases. In both patients with early-stage and advanced-stage diseases, adjuvant CT did not improve OS or PFS. On multivariate analysis, CT was not a significant factor associated with improved PFS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.69-2.71; P = 0.37) or OS (HR, 0.58; 95% CI, 0.24-1.38; P = 0.22), whereas RT was associated with improved PFS (HR, 0.51; 95% CI, 0.29-0.90; P = 0.02) and OS (HR, 0.19; 95% CI, 0.09-0.42; P < 0.001)., Conclusions: The high rate of upstaging after surgery highlights the importance of lymph node assessment. The high rate of distant recurrence questions the effectiveness of current CT regimens and warrants the development of novel systemic approaches. The role of adjuvant RT deserves further study.

Objectives: Growing teratoma syndrome (GTS) after adjuvant chemotherapy for ovarian germ cell tumors is uncommon, with approximately 60 cases reported in the English literature. The objective of this study was to report clinical parameters including outcomes of patients with a diagnosis of GTS after adjuvant chemotherapy for ovarian immature teratoma (IT)., Methods and Materials: Patients with a condition diagnosed as ovarian IT between 1999 and 2014 at 2 tertiary-care academic centers were evaluated for the development of GTS. Patients' demographics, surgical and pathology data, adjuvant treatment, tumor markers, and survival data were collected retrospectively., Results: Twenty-six patients were treated for ovarian IT with a median follow-up of 69 months (9-166 months). Of the 15 patients who received adjuvant chemotherapy, 6 developed GTS (crude incidence, 40%; 2- and 5-year cumulative actuarial rates, 40% and 50%, respectively). The median age at diagnosis of ovarian IT was 24 years (17-38 years). The median interval from diagnosis of IT to development of GTS was 20 months (8-42 months). These 6 patients underwent 1 to 4 additional surgeries for management of GTS and were alive without evidence of malignancy after a median follow-up of 90 months (range, 24-166 months)., Conclusions: The development of GTS after adjuvant chemotherapy for ovarian IT seems to be more common than previously reported in the literature. Clinicians need to be cognizant that the occurrence of rapidly growing masses during or after chemotherapy for ovarian IT raises the possibility of GTS. This highlights the importance of prolonged follow-up with tumor markers and imaging studies in patients with ovarian IT.

Objective: To report three cases of embryonal rhabdomyosarcoma (ERMS) of the cervix in young women successfully treated with fertility-sparing surgery and chemotherapy., Methods: Between January 2014 and December 2015, three cases of ERMS of the cervix were confirmed in young women at a single tertiary cancer center. All cases were managed by a pediatric oncologist and a gynecologic oncologist with a combination of surgery and chemotherapy. Fertility-sparing surgeries (cervical conization or robotic-assisted radical trachelectomy) were offered to patients depending on the tumor size., Results: All patients were nulliparous and aged 14, 20 and 21 years and all presented with abnormal uterine bleeding. The first patient was managed with radical trachelectomy followed by adjuvant chemotherapy. The second patient underwent primary hysteroscopic resection of the tumor followed by completion cervical conization and adjuvant chemotherapy. The third patient received neoadjuvant chemotherapy followed by loop electrosurgical excision procedure (LEEP) with positive residual margins. She then underwent completion radical trachelectomy. None of the patients experienced perioperative complications. None of the women received radiation. All patients are alive with no evidence of disease., Conclusion: Fertility-sparing surgery and chemotherapy in well-selected patients with ERMS of the cervix result in low complication rates and excellent oncologic outcomes. This treatment option may be considered in young patients who wish to preserve fertility by avoiding hysterectomy. A collaborative effort between pediatric oncologists and gynecologic oncologists is imperative to facilitate innovative approaches to these rare tumors in young adults.