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Findings from clinical trials have led to advancement of care for patients with gynecologic malignancies. However, restrictive inclusion of patients into trials has been widely criticized for inadequate representation of the real-world population. Ideally, patients enrolled in clinical trials should represent a broader population to enhance external validity and facilitate translation of outcomes across all relevant groups. Specifically, there has been a systematic lack of data for underrepresented groups, with many studies failing to report or differentiate study participants based on sociodemographic domains, such as race and ethnicity. As such, the impact of treatment in these underrepresented groups is poorly understood, and clinical outcomes according to various sociodemographic factors are infrequently assessed. Inclusion of diverse trial participants, with different racial and ethnic background, is essential for the understanding of factors that may impact clinical outcomes. Therefore, we conducted a multi-national meeting of clinical trial groups and industry with the goal of increasing equity, diversity, and inclusion in gynecologic cancer clinical trials and to address barriers to recruitment, participation, and harmonization of data collection and reporting. These Gynecologic Cancer Intergroup (GCIG) statements present recommendations and strategies for the gynecologic cancer research community to improve equity, diversity, and inclusion in gynecologic cancer clinical trials., Competing Interests: Competing interests: Alison Brand reports grants/contracts from the Australian Government Department of Health and Aged Care Medical Research Future Fund, Australia and New Zealand Gynaecological Oncology Group (ANZGOG); and is Director ANZGOG, Chair GCIG. Michael Bookman reports consultancy fees paid to the institution from Immunogen independent DSMB. Sabrina Chiara Cecere reports travel support from AstraZeneca, Clovis, GSK, MSD; honoraria from AstraZeneca, Clovis, GSK, MSD; participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, Clovis, GSK, MSD. Paul A. Cohen reports grants/contracts from the Australian Government Department of Health and Aged Care Medical Research Future Fund, Cancer Council Western Australia, Australia and New Zealand Gynaecological Oncology Group (ANZGOG); honoraria and educational events from AstraZeneca, MSD; advisory boards with AstraZeneca, Reliis; non-remunerated leadership roles as Director ANZGOG, Chair Research Advisory Committee ANZGOG, Education Committee Chair, International Gynecological Cancer Society, Expert Advisory Group Australian Centre for Prevention of Cervical Cancer, Editorial Board Member International Journal Gynecological Cancer; stock in Reliis Ltd. Jennifer Croke reports honoraria from American Society of Radiation Oncology (Member, Sexual and Gender Minority Affinity Working Group), Canadian Association of Radiation Oncology (Annual Scientific Meeting lead), Merck. Josie Ethier reports consultancy fees from AstraZeneca; honoraria from AstraZeneca, GSK, Merck; advisory board participation with AstraZeneca, Eisai, GSK, Merck. Franziska Geissler reports grants/contracts from International Research Fellowship, Swiss Cancer Research Foundation & Swiss Cancer League and Research Fund for Excellent Junior Researchers University of Basel 2024. Rosalind Glasspool reports grants/contracts from Clovis Oncology; consultancy fees from Clovis Oncology, GSK, Novartis; honoraria from GSK; travel support from GSK, MSD; participation on a Data Safety Monitoring Board or Advisory Board from IDMC Matao trial; leadership or fiduciary roles at IGCS Advocacy committee chair, IGCS board member, Chair of Scottish Gynaecological Cancer Trials Group; receipt of equipment, materials, drugs, medical writing, gifts or other services from AstraZeneca, GSK, Novartis; other financial or non-financial interests with Allarity Therapeutics, AstraZeneca, Immunogen, GSK. Philipp Harter reports grants/contracts from AstraZeneca, Clovis, Genmab, GSK, Immunogen, Novartis, Roche, Seagen; consultancy fees from Miltenyi; honoraria from Amgen, AstraZeneca, Clovis, Daiichi Sankyo, Eisai, Exscientia, GSK, Immunogen, Karyopharm, Mersana, MSD, Roche, Sotio, Stryker, Zai Lab; travel support from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board at AstraZeneca, Clovis, Eisai, GSK, Immunogen, MSD, Miltenyi, Novartis, Roche. Chee Khoon Lee reports grants/contracts from Amgen, AstraZeneca, Merck, Roche; honoraria from Amgen, AstraZeneca, Gilead, GSK, Janssen, Merck, Merck kGA, Novartis, Roche, Takeda. Kristina Lindemann reports grants/contracts from GSK (research funding paid to institution); honoraria, consultancy fees, or advisory board fees from AstraZeneca, Eisai, GSK, MSD, Nycode; part of the Data Safety Monitoring Committee for Karyopharm.Ainhoa Madariaga reports honoraria from AstraZeneca, Clovis, GSK, MSD, Pharma & PharmaMar; travel support from AstraZeneca, GSK, MSD; participation on a Data Safety Monitoring Board or Advisory Board from AbbVie, AstraZeneca, GSK, MSD. Asima Mukhopadhyay reports grants/contracts from the Indian Council of Medical Research for the IPIRIC academic study which endorses the principles of EDIM; honoraria from KGOG; advisory board at CannariaBio; Secretary KolGoTrg, Executive Board Member GCIG; part funding support for the IPIROC trial for drug procurement from BDR Pharma. Amit Oza reports grants/contracts from Amgen, AstraZeneca; consultancy fees from BMS; advisory board participation with AstraZeneca and GSK; other financial or non-financial interests with AstraZeneca, GSK. Elisa Piovano reports travel support from AstraZeneca, GSK. Bhavana Pothuri reports grants/contracts from Agenus, Alkermes, AstraZeneca, Acrivon, Celgene, Celsion/Immunon, Clovis Oncology, Duality Bio, Eisai, Immunogen, Incyte, Imab, InxMed, Karyopharm Therapeutics, Lily, LOXO/Lily, Merck, Mersana, Novocure, Onconova, NRG Oncology, Roche/Genentech, Seagen, Sutro, Takeda, Tesaro/GSK, Toray, VBL Therapeutics, Xencor; consultancy fees from AstraZeneca, Celsion, Duality Bio, Eisai, GOG Foundation, Imvax Inc, Incyte Corporation, InxMed, Lily, Onconova Therapeutics, Regeneron, SeaGen, Signatera, Sutro Biopharma, Tesaro/GSK; honoraria from Albert Einstein-Montefiore, Bioascend, Colorado University, Curio, Lankenau Hospital, OncLive, PERS, PeerView, Vanium, Yale University; travel support from GOG Partners; advisory boards with AstraZeneca, Celsion/Immunon, GOG Foundation, Imab, Imvax, Incyte, InxMed, Lily, Merck, Mersana, Nuvation, Sutro, Tesaro/GSK; leadership or fiduciary roles in GOG Partners, NYOB Society VP, SGO Board of Directors, SGO Clinical Practice Committee Chair, SGO COVID-19 Taskforce co-chair. Jose Alejandro Rauh-Hain reports grants/contracts from NIH, Department of Defense, American Cancer Society; support for the present manuscript from Guidepoint Consulting, Sago. Ora Rosengarten reports consultancy fees from AstraZeneca, Medison, MSD, Neopharm; travel support from AstraZeneca, MSD; lecture honoraria from AstraZeneca. Jalid Sehouli reports grants/contracts from AstraZeneca, Eisai, GSK, Merck, MSD, Novocure, Roche, Tesaro; consultancy fees from AstraZeneca, Clovis, Eisai, GSK, Immunogen, Incyte, MSD, Novocure; honoraria from AstraZeneca, Bristol Myers Squibb, Clovis, Eisai, GSK, Immunogen, Incyte, MSD, Novartis, Novocure; travel support from AstraZeneca, Eisai, GSK, Immunogen, Incyte, MSD, Novocure, Roche; advisory boards with AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, GSK, Immunogen, Incyte, MSD, Novocure, PharmaMar; leadership or fiduciary roles at AGO, ASCO, Deutsche Stiftung Eierstockkrebs, ENGAGE, ESGO, GCIG, Medical writing (MSD). David Tan reports receiving research funding from the National Medical Research Council (NMRC) Clinician Scientist Award Senior Investigator Grant (CSASI21jun-0003), the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, MSD (non-financial interest) for research trials. Institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, Roche; personal fees for advisory board membership from AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Genmab, GSK, MSD, PMV Pharma, Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, Takeda; travel support from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, Takeda; current non-renumerated role as protocol chair of Asia Pacific Gynecologic Oncology Trials Group (APGOT); previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; ownership of stocks/shares of Asian Microbiome Library (AMiLi). Toon Van Gorp reports consultancy fees (via institution) from AbbVie, AstraZeneca, BioNTech, Cancer Communications and Consultancy Ltd, Eisai, GSK, ImmunoGen, Incyte, Karyopharm, MSD/Merck, OncXerna Therapeutics, Seagen, Tubulis, Zentalis; corporate sponsored research (via institution) from Amgen, AstraZeneca, Roche; honoraria for lectures (via institution) from AstraZeneca, Eisai, GSK, ImmunoGen, MSD; travel support from AstraZeneca, ImmunoGen, MSD, PharmaMar; grants/contracts from Amgen, AstraZeneca, Roche; chair of the Belgian and Luxembourg Gynaecological Oncology Group. Stephen Welch reports honoraria from AstraZeneca, Eisai, GSK, Merck; advisory boards with Eisai, Incyte, GSK, Roche, Takeda.All other authors declare no conflict of interest., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism 1 . Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons 2 . However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect 3-5 . This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action., Competing Interests: Competing interests J.M.F. receives royalty payments from the sale of leptin through Rockefeller University, according to the university’s policy for distributing proceeds from inventions to their inventors. All other authors declare no competing interests., (© 2024. The Author(s).)

Brown adipose tissue (BAT) represents an evolutionary innovation enabling placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are surrounded by a dense network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure stimulates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we identify Slit guidance ligand 3 (Slit3) as a new niche factor that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We show that adipocyte progenitors secrete Slit3 which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which activate distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. Moreover, we introduce bone morphogenetic protein-1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this study underscores the essential role of Slit3-mediated neurovascular network expansion in enabling cold-induced BAT adaptation. The co-regulation of neurovascular expansion by Slit3 fragments provides a bifurcated yet harmonized approach to ensure a synchronized response of BAT to environmental challenges. This study presents the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue., Competing Interests: Competing interests M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors declare no conflict of interest.

Endocervical adenocarcinomas (EACs) are a group of malignant neoplasms associated with diverse pathogenesis, morphology, and clinical behavior. As a component of the International Society of Gynecological Pathologists International Endocervical Adenocarcinoma Project, a large international retrospective cohort of EACs was generated in an effort to study potential clinicopathological features with prognostic significance that may guide treatment in these patients. In this study, we endeavored to develop a robust human papillomavirus (HPV)-associated EAC prognostic model for surgically treated International Federation of Gynecology and Obstetrics (FIGO) stage IA2 to IB3 adenocarcinomas incorporating patient age, lymphovascular space invasion (LVSI) status, FIGO stage, and pattern of invasion according to the Silva system (traditionally a 3-tier system). Recently, a 2-tier/binary Silva pattern of invasion system has been proposed whereby adenocarcinomas are classified into low-risk (pattern A/pattern B without LVSI) and high-risk (pattern B with LVSI/pattern C) categories. Our cohort comprised 792 patients with HPV-associated EAC. Multivariate analysis showed that a binary Silva pattern of invasion classification was associated with recurrence-free and disease-specific survival (P < 0.05) whereas FIGO 2018 stage I substages were not. Evaluation of the current 3-tiered system showed that disease-specific survival for those patients with pattern B tumors did not significantly differ from that for those patients with pattern C tumors, in contrast to that for those patients with pattern A tumors. These findings underscore the need for prospective studies to further investigate the prognostic significance of stage I HPV-associated EAC substaging and the inclusion of the binary Silva pattern of invasion classification (which includes LVSI status) as a component of treatment recommendations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3 -/- (Shn3 -/- ) mice with augmented osteoblast activity, we show Shn3 -/- mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3 -/- mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome., (© 2024. The Author(s).)

Objectives: In ovarian and other cancers, low muscle mass and density are associated with poorer clinical outcomes. However, screening for cancer-related sarcopenia (typically defined as low muscle mass) is not routinely conducted. The European Working Group on Sarcopenia in Older People (EWGSOP) recommends an algorithm for sarcopenia screening and diagnosis in clinical settings, with sarcopenia based on muscle strength and mass, and severity on physical performance. We explored the application of the EWGSOP2 algorithm to assess sarcopenia in six ovarian cancer patients receiving neoadjuvant chemotherapy., Methods: We assessed sarcopenia risk with the SARC-F screening questionnaire (at risk ≥4 points), muscle strength with a handgrip strength test (cut point <16 kg) and five times sit-to-stand test (cut point >15 s), muscle mass by skeletal muscle index (SMI in cm 2 /m 2 from a single computed tomography [CT] image; cut point <38.5 cm 2 /m 2 ), and physical performance with a 4-m gait speed test (cut point ≤0.8 m/s)., Results: Of six participants, none were identified as "at risk" for sarcopenia based on SARC-F scores. Two participants were severely sarcopenic based on EWGSOP2 criteria (had low muscle strength, mass, and physical performance), and five participants were sarcopenic based on muscle mass only., Discussion: Ovarian cancer patients with low muscle mass during neoadjuvant chemotherapy may not be identified as sarcopenic based on the EWGSOP2 diagnostic algorithm. While lacking a universally accepted definition for cancer-related sarcopenia and cancer-specific recommendations for the screening, diagnosis, and treatment of sarcopenia, ovarian cancer clinicians should focus on the diagnosis and treatment of low muscle mass and density., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

As medical treatment increasingly focuses on improving health-related quality of life, patient-reported outcome measures (PROMs) are an essential component of clinical research. The National Gynae-Oncology Registry (NGOR) is an Australian clinical quality registry. A suitable PROM was required for the NGOR ovarian cancer module to complement clinical outcomes and provide insights into outcomes important to patients. Our narrative review aimed to identify existing ovarian cancer-specific PROMs and ascertain which tool would be most appropriate for implementation into the NGOR ovarian cancer module.A literature review of Cochrane Library, Embase, MEDLINE and PubMed databases was performed to identify existing ovarian cancer-specific PROM tools. A steering committee was convened to (1) determine the purpose of, and criteria for our required PROM; and (2) to review the available tools against the criteria and recommend the most appropriate one for implementation within the NGOR.The literature review yielded five tools: MOST, EORTC QLQ-OV28, FACIT-O, NFOSI-18 and QOL-OVCA. All were developed and validated for use in clinical trials, but none had been validated for use in clinical quality registry. Our expert steering committee pre-determined purpose of a PROM tool for use within the NGOR was to enable cross-service comparison and benchmarking to drive quality improvements. They identified that while there was no ideal, pre-existing, ovarian cancer-specific PROM tool for implementation into the NGOR, on the basis of its psychometric properties, its available translations, its length and its ability to be adapted, the EORTC tool is most fit-for-purpose for integration into the NGOR.This process enabled identification of the tool most appropriate to provide insights into how ovarian cancer treatments impact patients' quality of life and permit benchmarking across health services., (© 2024. The Author(s).)

BACKGROUNDObesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.METHODSWe analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status.RESULTS524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox's regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals.CONCLUSIONObesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype.FUNDINGNIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.

Reducing growth and limiting metabolism are strategies that allow bacteria to survive exposure to environmental stress and antibiotics. During infection, uropathogenic Escherichia coli (UPEC) may enter a quiescent state that enables them to reemerge after the completion of successful antibiotic treatment. Many clinical isolates, including the well-characterized UPEC strain CFT073, also enter a metabolite-dependent, quiescent state in vitro that is reversible with cues, including peptidoglycan-derived peptides and amino acids. Here, we show that quiescent UPEC is antibiotic tolerant and demonstrate that metabolic flux in the tricarboxylic acid (TCA) cycle regulates the UPEC quiescent state via succinyl-CoA. We also demonstrate that the transcriptional regulator complex integration host factor and the FtsZ-interacting protein ZapE, which is important for E. coli division during stress, are essential for UPEC to enter the quiescent state. Notably, in addition to engaging FtsZ and late-stage cell division proteins, ZapE also interacts directly with TCA cycle enzymes in bacterial two-hybrid assays. We report direct interactions between the succinate dehydrogenase complex subunit SdhC, the late-stage cell division protein FtsN, and ZapE. These interactions may enable communication between oxidative metabolism and the cell division machinery in UPEC. Moreover, these interactions are conserved in an E. coli K-12 strain. This work suggests that there is coordination among the two fundamental and essential pathways that regulate overall growth, quiescence, and antibiotic susceptibility., Importance: Uropathogenic Escherichia coli (UPEC) are the leading cause of urinary tract infections (UTIs). Upon invasion into bladder epithelial cells, UPEC establish quiescent intracellular reservoirs that may lead to antibiotic tolerance and recurrent UTIs. Here, we demonstrate using an in vitro system that quiescent UPEC cells are tolerant to ampicillin and have decreased metabolism characterized by succinyl-CoA limitation. We identify the global regulator integration host factor complex and the cell division protein ZapE as critical modifiers of quiescence and antibiotic tolerance. Finally, we show that ZapE interacts with components of both the cell division machinery and the tricarboxylic acid cycle, and this interaction is conserved in non-pathogenic E. coli , establishing a novel link between cell division and metabolism., Competing Interests: The authors declare no conflict of interest.

Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI., Methods: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status., Results: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/ TP53 abnormal (CN-H/ TP53 abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals., Conclusion: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/ TP53 abn EC molecular subtype., Funding: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Long-standing controversial and unresolved issues in the current "International Federation of Gynecology and Obstetrics" staging system for endometrial cancer are well-recognized by pathologists and clinicians alike and exist primarily as a result of limitations to the existing literature. To guide the design of future outcome-based studies specifically aimed at resolving such gaps, the International Society of Gynecologic Pathologists developed a survey of the current perceptions of pathologists (n = 172) and clinicians (n= 135) from the International Society of Gynecological Pathologists and from the International Gynecologic Cancer Society on areas for potential refinement of the current International Federation of Gynecology and Obstetrics staging system. The highest priority issues for pathologists and clinicians alike were the need to determine whether stage IIIA patients (ovarian/fallopian tube involvement) can be reliably separated into favorable versus unfavorable outcome groups to avoid over-treatment of the former group and to determine whether stage IIIC patients (lymph node metastases) can be separated into favorable versus unfavorable outcome groups based on the size of lymph node metastases. The majority of pathologists and clinicians viewed lymphovascular space invasion as an independent prognostic variable and favored incorporating lymphovascular space invasion into staging, though the level of support did not meet the threshold of 75% in support that we used to define a formal consensus. While pathologists did agree on the prognostic value of reporting the extent of lymphovascular space invasion, there was no consensus on the diagnostic criteria to distinguish focal versus substantial involvement. The majority of pathologists and clinicians viewed that a universally accepted protocol for sentinel lymph node ultra-staging is lacking. Both survey groups conveyed a slight preference for incorporating tumor histotype and molecular classification into staging but the support was short of the 75% threshold for formal consensus. Collectively, this survey permits the International Society of Gynecological Pathologists to develop a pathologist and clinician-driven long-term strategy for prioritizing and designing outcome-based studies specifically targeted to resolving controversial and unresolved issues in the International Federation of Gynecology and Obstetrics staging of endometrial cancer., Competing Interests: J.T.R. reports that his spouse receives salary and stock options from Merck & Co. The remaining authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment., (© 2024. The Author(s).)

Surgical decision making is complex and involves a combination of analytic, intuitive, and cognitive processes. Medicolegal, infrastructural, and financial factors may influence these processes depending on the context and setting, but to what extent can they influence surgical decision making in gynecologic oncology? This scoping review evaluates existing literature related to medicolegal, infrastructural, and financial aspects of gynecologic cancer surgery and their implications in surgical decision making. Our objective was to summarize the findings and limitations of published research, identify gaps in the literature, and make recommendations for future research to inform policy., Competing Interests: Competing interests: PAC declares honoraria from Astra Zeneca unrelated to the submitted work., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The study examined whether increased physical activity (PA) in nonmetropolitan cancer survivors was maintained 12 weeks following the PPARCS intervention., Methods: PA outcomes were assessed using an accelerometer at baseline, end of the intervention, and at 24 weeks. Linear mixed models were used to examine between-group changes in PA outcomes., Results: The increased moderate-to-vigorous PA (MVPA) following intervention was maintained with significantly higher MVPA in the intervention group at 24 weeks (vs. controls) compared to baseline nett change of 52.5 min/week (95% CI 11.0-94.0.4)., Conclusions: Distance-based interventions using wearables and health coaching may produce MVPA maintenance amongst nonmetropolitan cancer survivors., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

In this chapter, we update our 2004 review of "The Life of Commensal Escherichia coli in the Mammalian Intestine" (https://doi.org/10.1128/ecosalplus.8.3.1.2), with a change of title that reflects the current focus on "Nutrition of E. coli within the Intestinal Microbiome." The earlier part of the previous two decades saw incremental improvements in understanding the carbon and energy sources that E. coli and Salmonella use to support intestinal colonization. Along with these investigations of electron donors came a better understanding of the electron acceptors that support the respiration of these facultative anaerobes in the gastrointestinal tract. Hundreds of recent papers add to what was known about the nutrition of commensal and pathogenic enteric bacteria. The fact that each biotype or pathotype grows on a different subset of the available nutrients suggested a mechanism for succession of commensal colonizers and invasion by enteric pathogens. Competition for nutrients in the intestine has also come to be recognized as one basis for colonization resistance, in which colonized strain(s) prevent colonization by a challenger. In the past decade, detailed investigations of fiber- and mucin-degrading anaerobes added greatly to our understanding of how complex polysaccharides support the hundreds of intestinal microbiome species. It is now clear that facultative anaerobes, which usually cannot degrade complex polysaccharides, live in symbiosis with the anaerobic degraders. This concept led to the "restaurant hypothesis," which emphasizes that facultative bacteria, such as E. coli , colonize the intestine as members of mixed biofilms and obtain the sugars they need for growth locally through cross-feeding from polysaccharide-degrading anaerobes. Each restaurant represents an intestinal niche. Competition for those niches determines whether or not invaders are able to overcome colonization resistance and become established. Topics centered on the nutritional basis of intestinal colonization and gastrointestinal health are explored here in detail.

Background: Physical activity (PA) is important for cancer survivors. Trials of remotely delivered interventions are needed to assist in reaching under-served non-metropolitan cancer survivors. The objective of this study was to ascertain whether wearable technology, coupled with health coaching was effective in increasing PA in breast and colorectal cancer survivors living in regional and remote areas in Australia., Methods: Cancer survivors from 5 states were randomized to intervention and control arms. Intervention participants were given a Fitbit Charge 2 TM and received up to 6 telephone health coaching sessions. Control participants received PA print materials. Accelerometer assessments at baseline and 12 weeks measured moderate-to-vigorous PA (MVPA), light PA, and sedentary behavior., Results: Eighty-seven participants were recruited (age = 63 ± 11 years; 74 (85%) female). There was a significant net improvement in MVPA of 49.8 min/week, favoring the intervention group (95% confidence interval (95%CI): 13.6-86.1, p = 0.007). There was also a net increase in MVPA bouts of 39.5 min/week (95%CI: 11.9-67.1, p = 0.005), favoring the intervention group. Both groups improved light PA and sedentary behavior, but there were no between-group differences., Conclusion: This is the first study to demonstrate that, when compared to standard practice (i.e., PA education), a wearable technology intervention coupled with distance-based health coaching, improves MVPA in non-metropolitan cancer survivors. The results display promise for the use of scalable interventions using smart wearable technology in conjunction with phone-based health coaching to foster increased PA in geographically disadvantaged cancer survivors., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour 1 , and has become an intriguing therapeutic target for conditions such as autism and schizophrenia 2 . Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis 1,3 , suggesting that it may also have therapeutic potential for metabolic disease 1,4 . It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of β-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Our primary aim was to compare muscle morphology (skeletal muscle mass and density) between patients who underwent primary cytoreductive surgery versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer. Secondarily, we explored the associations of muscle morphology with survival outcomes., Methods: We retrospectively analysed computed tomography (CT) images for 88 ovarian cancer patients (aged 38-89 years) to calculate skeletal muscle index (cm 2 /m 2 ) and skeletal muscle density (Hounsfield units (HU)). A skeletal muscle index of <38.5 cm 2 /m 2 and skeletal muscle density of <33.7 HU were classified as low. Analyses included repeated measures analysis of covariance and multivariable Cox proportional hazards regression., Results: At baseline, 44.3% of patients had low skeletal muscle index and 50.6% had low skeletal muscle density, with interval surgery patients having significantly lower mean skeletal muscle density than primary surgery patients (32.2±8.9 vs 37.3±8.6 HU, p=0.014). Although both groups had similar reductions in skeletal muscle index following treatment (p=0.49), primary surgery patients had a greater reduction in skeletal muscle density compared with interval surgery patients (-2.4 HU, 95% CI -4.3 to -0.5, p=0.016). Patients who experienced skeletal muscle density loss >2% during treatment (HR 5.16, 95% CI 1.33 to 20.02) and had low skeletal muscle density post-treatment (HR 58.87, 95% CI 3.70 to 935.68) had significantly worse overall survival., Conclusion: Low skeletal muscle index and skeletal muscle density were prevalent at ovarian cancer diagnosis. While both groups experienced muscle mass loss, greater reductions in skeletal muscle density occurred in patients undergoing primary surgery. In addition, skeletal muscle density loss during treatment and low skeletal muscle density post-treatment were associated with poorer overall survival. Supportive care involving resistance exercise targeting muscle hypertrophic drive, and nutrition counseling during and after ovarian cancer treatment may help preserve/enhance muscle mass and density., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Poly-ADP ribose polymerase inhibitors (PARPi) have expanded the management armamentarium against high grade serous tubo-ovarian cancer (HGSOC) in patients with germline and somatic BRCA pathogenic variants (PVs). Germline testing has been available in Western Australia (WA) since July 2015, whilst somatic BRCA testing was previously only available through interstate laboratories. We hypothesized that due to complexity of referral, testing rates for somatic BRCA would be low. We aimed to demonstrate that improving education and information systems would improve testing rates in our service., Methods: Retrospective data were collected for all patients with HGSOC reviewed between June - November 2021. BRCA testing for this period was discussed at multi-disciplinary tumor board. Patients eligible to commence PARPi that had not received somatic testing were referred. Changes were implemented to patient outcome reports, the results application was adjusted to flag clinicians, departmental guidelines were developed, and teaching sessions conducted. Testing rates from March - August 2022 were compared., Results: From June - November 2021, 98% of patients had germline BRCA testing performed. PVs in BRCA1/2 were detected in 18% of patients. Of those without germline PVs, further somatic BRCA testing was referred in 42% of patients. One somatic PV was detected. From March - August 2022, 99% of patients had germline BRCA testing and 17% had PVs detected. Further somatic BRCA testing was referred in 72% of patients. No somatic PVs were detected., Conclusion: Testing rates for germline BRCA variants in patients with HGSOC in WA are high. Focused education and information systems improved somatic BRCA testing rates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background and Aims: Adequate postoperative analgesia and prevention of post-op nausea and vomiting (PONV) are core components of modern day anaesthesia and peri-operative care. As well as contributing to overall morbidity, postoperative pain and PONV are frequently cited as one of the most unpleasant and distressing aspects of surgery for patients. Variation in healthcare delivery is known to exist but has often been poorly described. A first step to understanding the consequences of variation is to describe the extent of variation. We aimed to assess variation in pharmacological strategies to prevent postoperative pain, nausea and vomiting in patients undergoing elective major abdominal surgery at a tertiary hospital in Perth, Western Australia, over a three-month period., Methods: Retrospective cross-sectional study., Results: We observed considerable variation in prescribing of postoperative analgesia and PONV prophylaxis and suggest that despite adequate evidence based guidelines, they are often overlooked in practice., Conclusion: Measurement of the consequences of variation requires randomised clinical trials that evaluate differences in outcome and cost, associated with the strategies that exist within the spectrum of variation., Competing Interests: P. A. Cohen declares honoraria from Seqirus and Astra Zeneca unrelated to the submitted work. The remaining authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom). Data on invasive EOC diagnosed in women aged 15 to 99 years during 1995 to 2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995 and 2014 among women aged 65 to 99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma "not otherwise specified" with estimates ranging between 4.4% and 7.4% in women aged 15 to 64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival., (© 2022 International Agency for Research on Cancer. International Agency for Research on Cancer retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Objectives: In ovarian cancer (OC), suboptimal muscle morphology (i.e., low muscle mass and density) is associated with poor clinical outcomes, yet little is known about the effect of interventions aimed at improving these measures. We investigated the effect of resistance exercise after first-line treatment on muscle mass and density, muscle strength and physical function, health-related quality of life (QoL), and pelvic-floor function in advanced-stage OC survivors., Methods: Fifteen OC survivors participated in supervised resistance exercise twice weekly for 12 weeks (in-clinic or by telehealth). Assessments included muscle mass and density (dual-energy X-ray absorptiometry, peripheral quantitative computed tomography), muscle strength (1-repetition maximum [1RM] chest press, 5RM leg press, handgrip strength), physical function (400-m walk, timed up-and-go [TUG]), QoL (QLQ-C30 questionnaire), and self-reported pelvic floor function (Australian Pelvic Floor Questionnaire)., Results: The median age was 64 (range 33-72) years, 10 women underwent neoadjuvant chemotherapy and five underwent adjuvant chemotherapy. All participants completed the intervention (median attendance = 92%; range 79-100%). Post-intervention improvements were observed for whole-body lean mass (1.0 ± 1.4 kg, p = 0.015), appendicular lean mass (0.6 ± 0.9 kg, p = 0.013), muscle density (p = 0.011), upper and lower body strength (p ≤ 0.001), 400-m walk (p = 0.001), TUG (p = 0.005), and social and cognitive QoL domains (p = 0.002 and 0.007), with no change to pelvic floor symptoms (p > 0.05)., Conclusion: In this study, supervised resistance exercise effectively improved muscle mass and density, muscle strength, and physical functioning without deleterious effects on the pelvic floor. Considering the prognostic value of these outcomes, larger studies are needed to confirm the benefits of resistance exercise in OC supportive care., (© 2023. The Author(s).)

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC., Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated., Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss., Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose ( 18 F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and β-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia. NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.

Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features., Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55)., Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%)., Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Overparenting (O-P), or "helicopter" parenting, has warranted increased attention across the past decade. It is characterized as being overly involved, protective, and low on granting autonomy, and is associated with deleterious psychosocial outcomes outside of the concussion literature. This study examined the association of overparenting and patient emotional distress and clinical outcomes (i.e., symptoms, neurocognitive test scores, recovery time) post-concussion. Adolescents/young adult concussion patients (injury < 30 days) and parents (N = 101 child-parent dyads) participated. Patient participants completed measures of depression, anxiety, stress, and concussion clinical outcomes while parents concurrently completed an overparenting measure. Results of a general linear model found that overparenting was associated with higher anxiety and stress report of the child. Overparenting had a significant positive correlation with concussion recovery, although of a small magnitude. Emotional distress level, but not overparenting, was moderately associated with worse performance on clinical outcomes, including neurocognitive testing, vestibular/ocular motor dysfunction, and concussion symptom severity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology., Competing Interests: Declaration of interests F.E.M. and N.V.B. and are currently employees of Calico Life Sciences, LLC. T.B. is currently an employee of Roche Diagnostics. E.T.C. is a founder, equity holder, and consultant for Matchpoint Therapeutics and Aevum Therapeutics. B.M.S. is a founder, equity holder, and consultant for Aevum Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adip ocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α-2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology., Competing Interests: CC, WB, SZ, CM, AP, MK, ZL, SS, FM, AC, TC, HM, PC No competing interests declared, (© 2022, Choi et al.)

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRN Vglut3 ) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRN Vglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRN Vglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRN Vglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders., (© 2022. The Author(s).)

Background: Use of patient-reported outcome measures in clinical settings facilitate the delivery of better health care to improve patient health outcomes. Previously collected qualitative data indicated themes that could inform items for a health-related quality of life measure. This study investigated the content validity of items for inclusion in a new health-related quality of life measure suitable for patients with ovarian cancer., Methods: Cognitive interviewing techniques were used with fourteen women diagnosed with ovarian cancer and at different times since diagnosis, to evaluate items derived from the previously collected qualitative dataset. A set of draft items was administered via telephone, Zoom and WhatsApp app together with questions on item meaning and wording. Interviews were transcribed and thematically analysed., Results: Four broad themes emerged in relation to the questionnaire construction and comprehension of items: intent and clarity, wording, relevance and context, and overall questionnaire construct. All draft items were adjusted based on the interview findings. A final set of 38 health-related quality of life items comprised 7 items describing physical health and functioning, 21 describing emotional wellbeing and 10 items describing social wellbeing; each rated on a five-point frequency response scale., Conclusion: The items reflected a range of personal experiences associated with the patient clinical journey, creating a health-related quality of life tool specific to women diagnosed with ovarian cancer. The cognitive interviewing process established content validity for the tool, thereby, preparing it for field testing and evaluation of its psychometric properties. This study highlighted the fundamental role of cognitive interviewing during health-related quality of life questionnaire development to ensure that item content is grounded in patient feelings, functioning and meaning., (© 2022. The Author(s).)

In a randomized crossover study in humans, high fructose feeding reduced glucose uptake in brown fat without affecting the tissue's oxidative capacity. These effects were independent of alterations in the gut microbiome., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction. As a tumor suppressor, germline and somatic inactivation of BRCA1 associated protein 1 gene ( BAP1 ) is a common finding in mesothelioma, melanocytic tumors, clear cell renal cell carcinoma and several other epithelial, mesenchymal and neural tumors. Incidence of BAP1 genetic alterations and subsequent expression loss has not been well established in non-small cell lung carcinoma (NSCLC) by large-scale studies. Design. After IRB approval, a total of 356 NSCLC cases of our institution between July 2016 and June 2020 were reviewed. The study cohort consisted of 214 (60%) adenocarcinomas, 89 (25%) squamous cell carcinomas, and 53 (15%) diagnosed as "non-small cell lung carcinoma" without specified subtype. All tumors underwent comprehensive target cancer gene next generation sequencing (Oncomine Assay). The protein expression status of BAP1 was subsequently evaluated by immunohistochemistry. Results. BAP1 somatic mutations were detected in 8 NSCLC tumors (incidence: 2.2%). Tumors harboring BAP1 mutations were all diagnosed at advanced stage and carried at least one additional genetic alteration. Immunohistochemically, four tumors showed complete loss of BAP1 protein expression, including two adenocarcinomas which harbored different missense BAP1 mutations and another two with bioinformatically predicated deleterious frameshifting mutations. Conclusion. Compared with known BAP1 loss associated other malignancies, such as mesothelioma, inactivation of BAP1 by somatic mutation is a rare occurrence in NSCLC. BAP1 mutations and loss of expression in NSCLC are accompanied by other complex genetic alternations, suggesting BAP1 mutation maybe a late event NSCLC carcinogenesis.

Purpose: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives., Patients and Methods: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver., Results: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before., Conclusion: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects., Competing Interests: Belinda CreightonEmployment: Cancer Specialists 1/84 Bridge Rd, Richmond VIC 3121 AustraliaConsulting or Advisory Role: Bristol Myers Squibb, Eisai Dinuka AriyaratneResearch Funding: AstraZeneca Elizabeth ChristieHonoraria: AstraZeneca Sian FeredayConsulting or Advisory Role: Geneseq Biosciences Pty LtdResearch Funding: AstraZeneca (Inst), AstraZeneca (Inst) Nadia TraficanteResearch Funding: AstraZeneca (Inst) Bryony ThompsonConsulting or Advisory Role: Genetic Technologies Kenneth DoigStock and Other Ownership Interests: CSL Limited Christopher LoveEmployment: Geneseq Biosciences Yeh Chen LeeConsulting or Advisory Role: GlaxoSmithKlineResearch Funding: AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca Rachel WilliamsHonoraria: AstraZeneca Andrew N. StephensConsulting or Advisory Role: Invion Pty Ltd (Inst)Research Funding: Invion Pty Ltd (Inst) Adeline TanEmployment: Sonic HealthcareStock and Other Ownership Interests: Sonic Healthcare Stephen B. FoxConsulting or Advisory Role: Novartis (Inst), BMS (Inst), AstraZeneca (Inst), MSD (Inst), Pfizer (Inst), Roche (Inst)Research Funding: AstraZeneca (Inst), Amgen (Inst), Roche (Inst), BMS (Inst)Expert Testimony: AstraZeneca (Inst), MSD (Inst)Travel, Accommodations, Expenses: Ventana Medical Systems, AstraZeneca, MSD Mary-Anne YoungUncompensated Relationships: Illumina (Inst) Jane HillOther Relationship: Medicines Australia Paul A. CohenEmployment: St John of God HealthcareStock and Other Ownership Interests: Clinic IQHonoraria: AstraZenecaConsulting or Advisory Role: Clinic IQResearch Funding: ANZGOG, St John of God Foundation Penelope M. WebbResearch Funding: AstraZeneca (Inst) Michael FriedlanderHonoraria: AstraZeneca, MSD, Lilly, Takeda, Novartis, GlaxoSmithKlineConsulting or Advisory Role: AstraZeneca, MSD, AbbVie, Lilly, Takeda, Novartis, GlaxoSmithKlineSpeakers' Bureau: AstraZeneca, ACT GenomicsResearch Funding: BeiGene (Inst), AstraZeneca (Inst), Novartis (Inst)Travel, Accommodations, Expenses: AstraZeneca David BowtellHonoraria: AstraZenecaConsulting or Advisory Role: Exo TherapeuticsResearch Funding: Roche/Genentech, AstraZeneca, BeiGenePatents, Royalties, Other Intellectual Property: AstraZeneca Genentech Roche Kathryn AlsopResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported.

Study Objective: To study the progression of benign ovarian lesions to mucinous borderline ovarian tumors (mBOTs); analyze the clinicopathologic features, diagnosis, and management of mBOTs in pediatric and adolescent girls; and provide a review of the literature on mBOTs in this population., Design: Retrospective chart review of female adolescents younger than 18 years diagnosed with mBOTs between July 2017 and February 2021., Setting: Yale New Haven Hospital, New Haven, Connecticut; and Yale New Haven Health Bridgeport Hospital, Bridgeport, Connecticut., Participants: Three female patients diagnosed with mBOTs between ages 12 and 17 years., Interventions: None., Main Outcome Measures: Clinical presentation, preoperative characteristics, surgical technique, histology, tumor stage, treatment, progression, outcome, and rate of recurrence., Results: Three adolescent patients were identified to have mBOTs. All three patients presented with a chief complaint of abdominal pain. One of the 3 patients was premenarchal at presentation. Two of the 3 patients were initially diagnosed with a mucinous cystadenoma and had recurrences of an ovarian cyst in the same ovary within 5 and 17 months, respectively. Pathology of the recurrent cyst was consistent with mBOT. Two of the 3 patients initially underwent cystectomy, and all ultimately had a unilateral salpingo-oophorectomy. Subsequent surveillance over 2 to 4 years found no evidence of disease recurrence., Conclusion: mBOTs are rare in the pediatric and adolescent population and could arise from benign ovarian tumors., (Copyright © 2021. Published by Elsevier Inc.)

Adverse drug reactions (ADRs) for all drugs in Europe are described in the legally approved Summary of Product Characteristics (SmPC). An overview of all ADRs of the patients' drug list can support healthcare staff to link patient symptoms to possible ADRs. We review the possibilities and challenges to extract ADR information from SmPCs and present the development of our semi-automated procedure for extraction of ADRs from the tabulated section of the SmPCs to create a database, named Bikt, which is regularly updated and used at point of care in Sweden. The existence of five major table formats for ADRs used in the SmPCs required the development of different parsing scripts. Manual checks for correctness for all content has to be performed. The quality of extraction was investigated for all SmPCs by measuring precision, recall and F1 scores (i.e. the weighted harmonic mean of precision and recall) and compared with other methods published. We conclude that it is possible to semi-automatically extract ADR information from SmPCs. However, clear technical and content guidelines and standards for ADR tables and terms from drug registration authorities would lead to improved extraction and usability of ADR information at point of care.

Background: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies., Primary Objectives: To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment., Study Hypothesis: We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective., Trial Design: Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1., Major Inclusion/exclusion Criteria: Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy., Primary Endpoints: Emotional wellbeing at 12 months., Sample Size: 150 patients., Estimated Dates for Completing Accrual and Presenting Results: July 2023. Results expected in 2025, 24 months after the last participant is enrolled., Trial Registration: ACTRN12620000332921., Competing Interests: Competing interests: PAC reports honoraria from Seqirus and Astra Zeneca unrelated to the submitted work. AO reports grants, personal fees, and other funding from SurgicalPerformance PTY Ltd, and grants from Medtronic, not directly related to the subject of this manuscript; consultancy fees from Baxter Healthcare Australia and New Zealand and Astra Zeneca Australia, not directly related to the subject of this manuscript; and a trademark licensed to SurgicalPerformance Pty Ltd. PB reports honoraria from GSK. MF reports grants from Astra Zeneca, Novartis, and Beigene; consulting fees from Astra Zeneca, Novartis, GSK, MSF, Takeda, and Lilly; honoraria from Astra Zeneca, GSK, and ACT Genomics; and support for travel from Astra Zeneca, unrelated to the submitted work. MK, MF, PMW, RC, and PAC developed the MOST-S26., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Fear of recurrence is common following treatment for cancer. Our aim was to assess the feasibility of mindfulness-based cognitive therapy (MBCT) to treat fear of cancer recurrence (FCR) in ovarian cancer survivors., Methods: Investigator initiated, single-arm, open-label, pilot study. Women were eligible after completing adjuvant treatment. The intervention was an 8-week MBCT course of weekly 2-h group sessions. The primary outcome was FCR measured by the FCR inventory. Secondary outcomes were depression and anxiety measured by the Hospital Anxiety and Depression Scale (HADS). The study is registered with the Australian and New Zealand Clinical Trials Registry ACTRN12615000213549., Results: Between May 8, 2015, and May 6, 2019, 33 participants were enrolled. Ten women withdrew. Data were evaluable for 19 participants. There was a significant decrease in FCR at 8 weeks (FCR inventory mean 63.00, SD 27.90) compared to pre-intervention (FCR inventory mean 71.03, SD 31.01) but not at 6 months (FCR inventory mean 63.65, SD 30.08). No differences in depression were observed at baseline (HADS mean 3.42, SD 2.41), 8 weeks (HADS mean 3.10, SD 1.79) and 6 months (HADS mean 2.73, SD 1.88). Anxiety decreased from baseline (HADS mean 8.72, SD 3.99) at both 8 weeks (HADS mean 6.89, SD 2.98) and 6 months (HADS mean 7.06, SD 3.87)., Conclusions: MBCT may be effective as a treatment for FCR and anxiety in women following diagnosis and treatment of ovarian cancer. A randomised controlled trial is required to assess the efficacy of MBCT for FCR but may not be feasible due to high rates of withdrawal., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to measure the prevalence of menopausal symptoms in patients attending a multidisciplinary model of care clinic at their initial clinic visit and their subsequent follow-up consultation using a validated patient-reported outcome measure to assess whether menopausal symptoms after cancer had improved., Methods: A retrospective review was conducted of patients attending the clinic in a 12-month period in 2017 (n = 189). Recorded variables included patient demographics, details of index cancer, previous treatments, and menopausal symptom management strategies. Severity of menopausal symptoms was evaluated using the Greene Climacteric Scale. The extent to which patients were bothered by symptoms was combined into two categories and dichotomized (present/absent). Differences in symptom prevalence between the initial consultation and first follow-up visit were examined using McNemar's test., Results: The majority of patients attending the clinic had a history of breast cancer (72%). Fifty-five percent of patients were prescribed a non-hormonal therapy at their initial visit, most commonly gabapentin. Significantly fewer patients reported being bothered by hot flushes, fatigue, sleep difficulties, and loss of interest in sex, anxiety, or troubles concentrating at the first follow-up visit compared to their initial consultation (p < 0.01)., Conclusion: In this study, there was an improvement in self-reported menopausal symptoms in a significant proportion of cancer survivors attending a multidisciplinary menopause clinic between their initial and first subsequent follow-up consultations., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid β-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Adipose tissue is not simply a collection of lipid storing fat cells, but is now recognized to be a complex tissue with a central role in whole body energy homeostasis. In order to understand how adipocytes and associated cell types interact in normal physiology and in pathological states like obesity, it is critical to obtain a holistic view of cells and structures in three dimensions. To that end, we have adapted the iDISCO/iDISCO+ tissue clearing protocol to facilitate the delipidation of fat tissues, while still maintaining their architecture. We describe here this method, that we refer to as Adipo-Clear, highlighting key steps in the protocol as well as important technical considerations. This versatile approach can provide entirely new insights into adipose tissue biology in health and disease., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Although arteries and atherosclerotic plaques are three-dimensional structures, the evaluation of plaque size and morphology in preclinical models of atherosclerosis is typically performed in two dimensions by histological analysis. Here, we describe a method to visualize arteries and atherosclerotic plaques in three dimensions. This method combines AdipoClear, a procedure that achieves whole tissue immunolabeling and clearing, and light-sheet fluorescence microscopy, which generates a three-dimensional reconstruction of vessel architecture including atherosclerotic lesions if present. This approach reveals the volume, geometry, acellular component and surface of atherosclerotic plaques as well as the spatial position of the lesion in relation to the affected artery., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)