Risk-reducing early salpingectomy and delayed oophorectomy as a two-staged alternative for primary prevention of ovarian cancer in women at increased risk: a commentary.

This is the peer reviewed version of the following article: Gaba, F. , Piek, J. , Menon, U. and Manchanda, R. (2019), Risk reducing early salpingectomy and delayed oophorectomy as a two staged alternative for primary prevention of ovarian cancer in increased risk women: a commentary. BJOG: Int J Obstet Gy. Accepted Author Manuscript. doi:10.1111/1471-0528.15651, which has been published in final form at https://doi.org/10.1111/1471-0528.15651. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Version

Systematic review of acceptability, cardiovascular, neurological, bone health and HRT outcomes following risk reducing surgery in BRCA carriers

© 2020 Primary surgical prevention in the form of risk-reducing salpingo-oophorectomy (RRSO) is the most effective option and the gold standard for ovarian cancer (OC) risk-reduction, particularly given the absence of an effective national OC screening programme. However, premenopausal RRSO leads to premature surgical menopause with detrimental long-term health sequelae particularly in women who do not/are unable to take hormone replacement therapy (HRT). HRT uptake in women undergoing pre-menopausal oophorectomy appears low and is dependent on informed counselling, the safety of HRT and efficacy in mitigating the health sequelae of premature menopause. Acceptance of a central role for the fallopian tube in OC etiopathogenesis, coupled with the detrimental consequences of premature menopause, has led to the attractive proposal of early-salpingectomy with delayed oophorectomy as an alternative OC surgical prevention strategy in premenopausal women who have completed childbearing but decline or wish to delay RRSO. The successful implementation of risk reducing surgery for OC prevention depends on the acceptability of surgery to both, recipients (e.g. BRCA1/BRCA2 carriers) and intervention deliverers (healthcare professionals/researchers). Acceptability is also informed by an understanding of health outcomes following risk reducing surgery and the safety of HRT. It is therefore vital to understand the effects of surgery on important health outcomes such as cardiovascular health, neurological function and bone health. We present a comprehensive review of acceptability, the selected health outcomes mentioned above and HRT safety following risk reducing surgery

Population Based Testing for Primary Prevention: A Systematic Review

Working paperThe current clinical model for genetic-testing is based on clinical-criteria/family-history(FH) and a pre-defined mutation probability threshold.  It requires people to develop cancer before identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intense and misses >50% of individuals/mutation carriers at risk. Population genetic-testing can overcome these limitations. It is technically feasible to test populations on a large scale; genetic-testing costs are falling and the acceptability/awareness is rising. MEDLINE/EMBASE/Pubmed/CINAHL/PsychINFO databases were searched using a free-text and MeSH terms; reference lists of publications retrieved screened; additionally web-based platforms, Google, and clinical-trial registries were searched. Quality of studies were evaluated using appropriate check-lists. A number of studies have evaluated population-based BRCA-testing in the Jewish-population. This has been found to be acceptable, feasible, clinically-effective, safe, associated with high satisfaction rates and extremely cost-effective. Data support change in guidelines to population-based BRCA-testing in the Jewish-population. Population panel-testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast/ovarian cancers than current clinical-criteria based approaches. A few ongoing studies are evaluating population-based genetic-testing for multiple cancer susceptibility genes in the general-population but more implementation studies are needed. A future population-testing programme could also target other chronic diseases

A commentary on population genetic testing for primary prevention: changing landscape and the need to change paradigm

BRCA1/BRCA2 genes were discovered in early 1990s and clinical testing for these has been available since the mid-1990s. National Institute of Health and Care Excellence (NICE) and other international guidelines recommend genetic-testing at a ~10% probability threshold of carrying a BRCA-mutation. A detailed three generation family-history (FH) of cancer is used within complex mathematical models (e.g. BOADICEA, BRCAPRO, Manchester-Scoring-System) or through standardized clinical-criteria to identify individuals who fulfil this probability threshold and can be offered genetic-testing. Identification of unaffected carriers is important given the high risk of cancer in these women and the effective options available for clinical management which can reduce cancer risk, improve outcomes and minimise burden of disease. This article is protected by copyright. All rights reserved

International Variations in Surgical Morbidity and Mortality Post Gynaecological Oncology Surgery: A Global Gynaecological Oncology Surgical Outcomes Collaborative Led Study (GO SOAR1)

Gynaecological malignancies affect women in low and middle income countries (LMICs) at disproportionately higher rates compared with high income countries (HICs) with little known about variations in access, quality, and outcomes in global cancer care. Our study aims to evaluate international variation in post-operative morbidity and mortality following gynaecological oncology surgery between HIC and LMIC settings. Study design consisted of a multicentre, international prospective cohort study of women undergoing surgery for gynaecological malignancies (NCT04579861). Multilevel logistic regression determined relationships within three-level nested-models of patients within hospitals/countries. We enrolled 1820 patients from 73 hospitals in 27 countries. Minor morbidity (Clavien-Dindo I-II) was 26.5% (178/672) and 26.5% (267/1009), whilst major morbidity (Clavien-Dindo III-V) was 8.2% (55/672) and 7% (71/1009) for LMICs/HICs, respectively. Higher minor morbidity was associated with pre-operative mechanical bowel preparation (OR = 1.474, 95%CI = 1.054-2.061, p = 0.023), longer surgeries (OR = 1.253, 95%CI = 1.066-1.472, p = 0.006), greater blood loss (OR = 1.274, 95%CI = 1.081-1.502, p = 0.004). Higher major morbidity was associated with longer surgeries (OR = 1.37, 95%CI = 1.128-1.664, p = 0.002), greater blood loss (OR = 1.398, 95%CI = 1.175-1.664, p ≤ 0.001), and seniority of lead surgeon, with junior surgeons three times more likely to have a major complication (OR = 2.982, 95%CI = 1.509-5.894, p = 0.002). Of all surgeries, 50% versus 25% were performed by junior surgeons in LMICs/HICs, respectively. We conclude that LMICs and HICs were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention

Risk-Reducing Salpingo-Oophorectomy and the Use of Hormone Replacement Therapy Below the Age of Natural Menopause: Scientific Impact Paper No. 66

This paper deals with the use of hormone replacement therapy (HRT) after the removal of fallopian tubes and ovaries to prevent ovarian cancer in premenopausal high risk women. Some women have an alteration in their genetic code, which makes them more likely to develop ovarian cancer. Two well-known genes which can carry an alteration are the BRCA1 and BRCA2 genes. Examples of other genes associated with an increased risk of ovarian cancer include RAD51C, RAD51D, BRIP1, PALB2 and Lynch syndrome genes. Women with a strong family history of ovarian cancer and/or breast cancer, may also be at increased risk of developing ovarian cancer. Women at increased risk can choose to have an operation to remove the fallopian tubes and ovaries, which is the most effective way to prevent ovarian cancer. This is done after a woman has completed her family. However, removal of ovaries causes early menopause and leads to hot flushes, sweats, mood changes and bone thinning. It can also cause memory problems and increases the risk of heart disease. It may reduce libido or impair sexual function. Guidance on how to care for women following preventative surgery who are experiencing early menopause is needed. HRT is usually advisable for women up to 51 years of age (average age of menopause for women in the UK) who are undergoing early menopause and have not had breast cancer, to minimise the health risks linked to early menopause. For women with a womb, HRT should include estrogen coupled with progestogen to protect against thickening of the lining of the womb (called endometrial hyperplasia). For women without a womb, only estrogen is given. Research suggests that, unlike in older women, HRT for women in early menopause does not increase breast cancer risk, including in those who are BRCA1 and BRCA2 carriers and have preventative surgery. For women with a history of receptor-negative breast cancer, the gynaecologist will liaise with an oncology doctor on a case-by-case basis to help to decide if HRT is safe to use. Women with a history of estrogen receptor-positive breast cancer are not normally offered HRT. A range of other therapies can be used if a woman is unable to take HRT. These include behavioural therapy and non-hormonal medicines. However, these are less effective than HRT. Regular exercise, healthy lifestyle and avoiding symptom triggers are also advised. Whether to undergo surgery to reduce risk or not and its timing can be a complex decision-making process. Women need to be carefully counselled on the pros and cons of both preventative surgery and HRT use so they can make informed decisions and choices

Vaginal metastasis of a Ewing sarcoma five years after resection of the primary tumor

A 35-year-old female presented with pain and swelling of the distal left radius. A diagnosis of Ewing sarcoma was made and she underwent neoadjuvant chemotherapy and surgery. Macroscopic viable areas remained on the map of the surgical specimen; as such, she was classified as a poor responder and received high dose adjuvant chemotherapy. She remained disease-free for five years, until age 40. A vaginal polyp was then detected during a routine gynaecologic examination. It was removed and histopathology revealed metastatic Ewing sarcoma

Impact of SARS-CoV-2 on training and mental well-being of surgical gynecological oncology trainees

Introduction: The SARS-CoV-2 global pandemic has caused a crisis disrupting health systems worldwide. While efforts are being made to determine the extent of the disruption, the impact on gynecological oncology trainees/training has not been explored. We conducted an international survey of the impact of SARS-CoV-2 on clinical practice, medical education, and mental well-being of surgical gynecological oncology trainees. Methods: In our cross-sectional study, a customized web-based survey was circulated to surgical gynecological oncology trainees from national/international organizations from May to November 2020. Validated questionnaires assessed mental well-being. The Wilcoxon rank-sum test and Fisher's exact test were used to analyse differences in means and proportions. Multiple linear regression was used to evaluate the effect of variables on psychological/mental well-being outcomes. Outcomes included clinical practice, medical education, anxiety and depression, distress, and mental well-being. Results: A total of 127 trainees from 34 countries responded. Of these, 52% (66/127) were from countries with national training programs (UK/USA/Netherlands/Canada/Australia) and 48% (61/127) from countries with no national training programs. Altogether, 28% (35/125) had suspected/confirmed COVID-19, 28% (35/125) experienced a fall in household income, 20% (18/90) were self-isolated from households, 45% (57/126) had to re-use personal protective equipment, and 22% (28/126) purchased their own. In total, 32.3% (41/127) of trainees (16.6% (11/66) from countries with a national training program vs 49.1% (30/61) from countries with no national training program, p=0.02) perceived they would require additional time to complete their training fellowship. The additional training time anticipated did not differ between trainees from countries with or without national training programs (p=0.11) or trainees at the beginning or end of their fellowship (p=0.12). Surgical exposure was reduced for 50% of trainees. Departmental teaching continued throughout the pandemic for 69% (87/126) of trainees, although at reduced frequency for 16.1% (14/87), and virtually for 88.5% (77/87). Trainees reporting adequate pastoral support (defined as allocation of a dedicated mentor/access to occupational health support services) had better mental well-being with lower levels of anxiety/depression (p=0.02) and distress (p<0.001). Trainees from countries with a national training program experienced higher levels of distress (p=0.01). Mean (SD) pre-pandemic mental well-being scores were significantly higher than post-pandemic scores (8.3 (1.6) vs 7 (1.8); p<0.01). Conclusion: SARS-CoV-2 has negatively impacted the surgical training, household income, and psychological/mental well-being of surgical gynecological oncology trainees. The overall clinical impact was worse for trainees in countries with no national training program than for those in countries with a national training program, although national training program trainees reported greater distress. COVID-19 sickness increased anxiety/depression. The recovery phase must focus on improving mental well-being and addressing lost training opportunities

Attitudes towards risk-reducing early salpingectomy with delayed oophorectomy for ovarian cancer prevention: a cohort study

OBJECTIVE: To determine risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) acceptability and effect of surgical prevention on menopausal sequelae/satisfaction/regret in women at increased ovarian cancer (OC) risk. DESIGN: Multicentre, cohort, questionnaire study (IRSCTN:12310993). SETTING: United Kingdom (UK). POPULATION: UK women without OC ≥18 years, at increased OC risk, with/without previous RRSO, ascertained through specialist familial cancer/genetic clinics and BRCA support groups. METHODS: Participants completed a 39-item questionnaire. Baseline characteristics were described using descriptive statistics. Logistic/linear regression models analysed the impact of variables on RRESDO acceptability and health outcomes. MAIN OUTCOMES: RRESDO acceptability, menopausal sequelae, satisfaction/regret. RESULTS: In all, 346 of 683 participants underwent risk-reducing salpingo-oophorectomy (RRSO). Of premenopausal women who had not undergone RRSO, 69.1% (181/262) found it acceptable to participate in a research study offering RRESDO. Premenopausal women concerned about sexual dysfunction were more likely to find RRESDO acceptable (odds ratio [OR] = 2.9, 95% CI 1.2-7.7, P = 0.025). Women experiencing sexual dysfunction after premenopausal RRSO were more likely to find RRESDO acceptable in retrospect (OR = 5.3, 95% CI 1.2-27.5, P < 0.031). In all, 88.8% (143/161) premenopausal and 95.2% (80/84) postmenopausal women who underwent RRSO, respectively, were satisfied with their decision, whereas 9.4% (15/160) premenopausal and 1.2% (1/81) postmenopausal women who underwent RRSO regretted their decision. HRT uptake in premenopausal individuals without breast cancer (BC) was 74.1% (80/108). HRT use did not significantly affect satisfaction/regret levels but did reduce symptoms of vaginal dryness (OR = 0.4, 95% CI 0.2-0.9, P = 0.025). CONCLUSION: Data show high RRESDO acceptability, particularly in women concerned about sexual dysfunction. Although RRSO satisfaction remains high, regret rates are much higher for premenopausal women than for postmenopausal women. HRT use following premenopausal RRSO does not increase satisfaction but does reduce vaginal dryness. TWEETABLE ABSTRACT: RRESDO has high acceptability among premenopausal women at increased ovarian cancer risk, particularly those concerned about sexual dysfunction

An upstream ORF with non-AUG start codon is translated in vivo but dispensable for translational control of GCN4 mRNA

Genome-wide analysis of ribosome locations in mRNAs of Saccharomyces cerevisiae has revealed the translation of upstream open reading frames that initiate with near-cognate start codons in many transcripts. Two such non-translation initiation codon (AUG)-initiated upstream open reading frames (uORFs) (nAuORFs 1 and 2) occur in GCN4 mRNA upstream of the four AUG-initiated uORFs (uORFs 1–4) that regulate GCN4 translation. We verified that nAuORF2 is translated in vivo by demonstrating β-galactosidase production from lacZ coding sequences fused to nAuORF2, in a manner abolished by replacing its non-AUG initiation codon (AUA) start codon with the non-cognate triplet AAA, whereas translation of nAuORF1 was not detected. Importantly, replacing the near-cognate start codons of both nAuORFs with non-cognate triplets had little or no effect on the repression of GCN4 translation in non-starved cells, nor on its derepression in response to histidine limitation, nutritional shift-down or treatment with rapamycin, hydrogen peroxide or methyl methanesulfonate. Additionally, we found no evidence that initiation from the AUA codon of nAuORF2 is substantially elevated, or dependent on Gcn2, the sole eIF2α kinase of yeast, in histidine-deprived cells. Thus, although nAuORF2 is translated in vivo, it appears that this event is not stimulated by eIF2α phosphorylation nor significantly influences GCN4 translational induction under various starvation or stress conditions