No signs of subclinical atherosclerosis after risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers

Background: BRCA1/2 mutation carriers are generally exposed to early menopause due to risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 years. This risk-reducing intervention is based on a 10–40% life-time risk of ovarian cancer in this population. Although effective, premature and acute menopause induces non-cancer related morbidity in both the short and long term. Little is known about the impact of RRSO on the cardiovascular system. Methods: This cross-sectional study explored the relationship between time since RRSO and signs of subclinical atherosclerosis, as measured by carotid intima-media thickness (CIMT) and pulse wave velocity (PWV), in 165 BRCA1/2 mutation carriers. All participants, aged 40 to 63 years, underwent RRSO before the age of 45 years, and at least 5 years ago. Cardiovascular risk factors were assessed by questionnaires and a single screening visit. Data were analyzed using linear regression models. Results: Mean CIMT was 692.7 μm (SD 87.0), and mean central PWV 6.40 m/s (SD 1.42). After adjustment for age and several relevant cardiovascular risk factors, time since RRSO was not associated with CIMT (β=0.68 μm; 95% CI –4.02, 5.38) and PWV (β=44 mm/s; 95% CI –32, 120). Compared to women of a reference group from the general population, lower systolic blood pressure [mean difference 12 mmHg; 95% confidence interval (CI) 10, 14] was found in BRCA1/2 mutation carriers. Conclusions: We found that, in BRCA1/2 mutation carriers, at 5 to 24 years follow-up, time since RRSO is not related to development of subclinical atherosclerosis. However, the follow-up period in these relatively young women might have been too short

Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer:A systematic review

The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely, based on different criteria, such as age of onset, family history of breast and/or ovarian cancer and histological type of EOC. The overall probability of a germline BRCA1/2 mutation in women with EOC is above 10%, and a substantial part of the germline BRCA1/2 mutation carriers is missed when applying these criteria for referral. Therefore, we strongly recommend referral of all women with EOC for genetic counselling and DNA analysis. (C) 2016 Elsevier Ltd. All rights reserved

High demoralization in a minority of oophorectomized BRCA1/2 mutation carriers influences quality of life

Introduction: Demoralization is a relatively neglected issue in which low morale and poor coping result from a stressor such as familial cancer risk. Female BRCA1/2 mutation carriers are highly susceptible for developing breast and ovarian cancer. The aim of this study was to evaluate demoralization in oophorectomized BRCA1/2 mutation carriers and its relation to quality of life. Methods: This cross-sectional study examined 288 oophorectomized BRCA1/2 mutation carriers using the following standardized self-report measures: Demoralization Scale, EORTC Quality of Life Questionnaire-C30, State-Trait Anxiety Inventory and the Cancer Worry Scale. Results: The mean score on the Demoralization Scale was 17.8 (SD 14.0). A clinically significant level of demoralization, defined as a score ≥30, was found in 45 BRCA1/2 mutation carriers (16%). Being highly demoralized was associated with a significantly lower quality of life, and higher levels of physical problems, anxiety and cancer worries. No demographic or clinical factors could predict higher levels of demoralization. Conclusions: Our findings established that a clear proportion of oophorectomized BRCA1/2 mutation carriers experience demoralization impacting on their well-being. Further research is needed to explore the natural trajectory of demoralization and the resultant need for support in these women

Added Value of Family History in Counseling About Risk of BRCA1/2 Mutation in Early-Onset Epithelial Ovarian Cancer

Contains fulltext : 125202.pdf (publisher's version ) (Closed access)OBJECTIVES: Epithelial ovarian cancer in women 40 years or younger is rare; diagnosis at this age justifies referral for genetic testing. We evaluated clinical data, family history, and risk of identifying BRCA1/2 mutations in women with early-onset epithelial ovarian cancer. MATERIALS/METHODS: Women 40 years or younger with epithelial ovarian cancer tested for BRCA1/2 mutation at our department of human genetics between 1996 and 2012 were included. The rate of BRCA1/2 mutation was obtained; carriers were compared to noncarriers regarding clinical data. RESULTS: Ten (19%) of 52 women had a BRCA1/2 mutation. This mutation was detected in 67% of women with and in 9% of the women without first-degree relatives with breast and/or ovarian cancer (P < 0.001; Fisher exact test). The median age at diagnosis was lower in the noncarriers compared to the carriers (30 vs 38 years; P = 0.014). Among the BRCA1/2 mutation carriers, 60% had serous tumors, 80% had moderately to poorly differentiated tumors, and 70% had International Federation of Gynecology and Obstetrics stage III/IV compared to 55%, 43%, and 45%, respectively, in the noncarriers. CONCLUSIONS: The risk of finding a BRCA1/2 mutation in women 40 years or younger is comparable to women of all ages with epithelial ovarian cancer. Prior probability of finding a BRCA1/2 mutation in these young women is largely determined by their family history, which can help caregivers in informing ahead of genetic counseling and testing

Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study

Background: Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80-96 % but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. Methods: A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40-45 (BRCA1) or 45-50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed. Discussion: The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL

Association of Salpingectomy with Delayed Oophorectomy Versus Salpingo-oophorectomy with Quality of Life in BRCA1/2 Pathogenic Variant Carriers: A Nonrandomized Controlled Trial

Importance: Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. Objective: To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. Design, Setting, and Participants: A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. Interventions: Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. Main Outcomes and Measures: Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. Results: A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P <.001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P <.001) compared with RRS. Conclusions and Relevance: Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02321228

Association of Salpingectomy with Delayed Oophorectomy Versus Salpingo-oophorectomy with Quality of Life in BRCA1/2 Pathogenic Variant Carriers A Nonrandomized Controlled Trial

IMPORTANCE Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. OBJECTIVE To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. DESIGN, SETTING, AND PARTICIPANTS A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. INTERVENTIONS Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. MAIN OUTCOMES AND MEASURES Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. RESULTS A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P <.001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P <.001) compared with RRS. CONCLUSIONS AND RELEVANCE Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy

Systematic review and individual participant data meta-analysis of randomized controlled trials assessing mindfulness-based programs for mental health promotion

Acknowledgements: We are very grateful to those in our professional and public stakeholder groups for their keen involvement. This publication presents independent research funded by the UK National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the UK National Health Service (NHS), the NIHR, or the Department of Health and Social Care. All research from the Department of Psychiatry at the University of Cambridge is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and the NIHR East of England Applied Research Centre. J.G. is funded by an NIHR post-doctoral fellowship for this research project (PDF-2017-10-018, salary and all project costs). C.F.’s salary for this research project was funded by a Cambridgeshire and Peterborough NHS Foundation Trust grant awarded to J.G. I.R.W. was supported by the UK Medical Research Council Programme MC_UU_00004/06. T.D. was supported by the UK Medical Research Council (SUAG/043 G101400), the Wellcome Trust (104908/Z/14/Z, 107496/Z/15/Z), and the NIHR Cambridge Biomedical Research Centre. P.B.J. is supported by the Wellcome Trust (095844/Z/11/Z), the UK Medical Research Council (MR/N019067/1), and the NIHR ARC East of England. S.B.G. was supported by the National Center for Complementary and Integrative Health of the National Institutes of Health under Award Number K23AT010879 and by the Hope for Depression Research Foundation ‘Defeating Depression’ Award. Funders for the trials with data shared for inclusion in the IPD meta-analysis were as follows: the University of Newcastle and the University of Phayao64; the NIH National Center for Complementary and Alternative Medicine and the Clinical and Translational Science Award Program of the NIH National Center for Research Resources 104–110; the National Institutes of Health and National Center for Complementary and Alternative Medicine111–116; the National Center for Complementary and Integrative Health of the National Institutes of Health117–119; Fundación Científica y Tecnológica de la Asociación Chilena de Seguridad120; the University of Cambridge and the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England39, 121–123; the Health Promotion Administration and the Ministry of Health and Welfare124; the Teachers Health Foundation125; the National Center for Complementary and Integrative Health and the National Institute of Mental Health (NIMH) and the Fetzer Institute; the John Templeton Foundation and the Waisman Center from the National Institute of Child Health and Human Development65, 126–128; the Alberta Children’s Hospital Foundation and the Alberta Center for Child, Family and Community Research and the Alberta Family Wellness Initiative66, 129; the Foundation Alpe d’Huzes and the Dutch Cancer Society30, 130, 131; the Horizon 2020 Marie Sklodowska-Curie Innovative Training Networks grant and with additional support from MIND Netherland and Karakter Child and Adolescent Psychiatry67, 132; and the Departments of Psychiatry and of Primary and Community Care and the Health Academy of the Radboudumc71, 133. The funders had no role in the study design or data collection.Funder: Cambridgeshire & Peterborough NHS Foundation TrustFunder: Hope for Depression Research Foundation (Depression Research Foundation); doi: https://doi.org/10.13039/100006346AbstractMindfulness-based programs (MBPs) are widely used to prevent mental ill health. Evidence suggests beneficial average effects but wide variability. We aimed to confirm the effect of MBPs and to understand whether and how baseline distress, gender, age, education, and dispositional mindfulness modify the effect of MBPs on distress among adults in non-clinical settings. We conducted a systematic review and individual participant data (IPD) meta-analysis (PROSPERO CRD42020200117). Databases were searched in December 2020 for randomized controlled trials satisfying a quality threshold and comparing in-person, expert-defined MBPs with passive-control groups. Two researchers independently selected, extracted and appraised trials using the revised Cochrane Risk-of-Bias tool. IPD of eligible trials were sought from authors. The primary outcome was psychological distress (unpleasant mental or emotional experiences including anxiety and depression) at 1 to 6 months after program completion. Data were checked and imputed if missing. Pairwise, random-effects, two-stage IPD meta-analyses were conducted. Effect modification analyses followed a within-studies approach. Stakeholders were involved throughout this study. Fifteen trials were eligible; 13 trialists shared IPD (2,371 participants representing 8 countries. In comparison with passive-control groups, MBPs reduced average distress between 1 and 6 months post-intervention with a small to moderate effect size (standardized mean difference, −0.32; 95% confidence interval, −0.41 to −0.24; P &lt; 0.001; no heterogeneity). Results were robust to sensitivity analyses and similar for the other timepoint ranges. Confidence in the primary outcome result is high. We found no clear indication that this effect is modified by the pre-specified candidates. Group-based teacher-led MBPs generally reduce psychological distress among volunteering community adults. More research is needed to identify sources of variability in outcomes at an individual level.</jats:p

Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study

Background: Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80-96 % but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. Methods: A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40-45 (BRCA1) or 45-50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed. Discussion: The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL