Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Utility Scores for Risk-Reducing Mastectomy and Risk-Reducing Salpingo-Oophorectomy: Mapping to EQ-5D.

BACKGROUND: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are the most effective breast and ovarian cancer preventive interventions. EQ-5D is the recommended tool to assess the quality of life and determine health-related utility scores (HRUSs), yet there are no published EQ-5D HRUSs after these procedures. These are essential for clinicians counselling patients and for health-economic evaluations. METHODS: We used aggregate data from our published systematic review and converted SF-36/SF-12 summary scores to EQ-5D HRUSs using a published mapping algorithm. Study control arm or age-matched country-specific reference values provided comparison. Random-effects meta-analysis provided adjusted disutilities and utility scores. Subgroup analyses included long-term vs. short-term follow-up. RESULTS: Four studies (209 patients) reported RRM outcomes using SF-36, and five studies (742 patients) reported RRSO outcomes using SF-12/SF-36. RRM is associated with a long-term (>2 years) disutility of -0.08 (95% CI -0.11, -0.04) (I2 31.4%) and a utility of 0.92 (95% CI 0.88, 0.95) (I2 31.4%). RRSO is associated with a long-term (>1 year) disutility of -0.03 (95% CI -0.05, 0.00) (I2 17.2%) and a utility of 0.97 (95% CI 0.94, 0.99) (I2 34.0%). CONCLUSIONS: We present the first HRUSs sourced from patients following RRM and RRSO. There is a need for high-quality prospective studies to characterise quality of life at different timepoints.

BRCA awareness and testing experience in the UK Jewish population: a qualitative study.

BACKGROUND: 1 in 40 UK Jewish individuals carry a pathogenic variant in BRCA1/BRCA2. Traditional testing criteria miss half of carriers, and so population genetic testing is being piloted for Jewish people in England. There has been no qualitative research into the factors influencing BRCA awareness and testing experience in this group. This study aimed to explore these and inform improvements for the implementation of population genetic testing. METHODS: Qualitative study of UK Jewish adults who have undergone BRCA testing. We conducted one-to-one semistructured interviews via telephone or video call using a predefined topic guide, until sufficient information power was reached. Interviews were audio-recorded, transcribed verbatim and interpreted using applied thematic analysis. RESULTS: 32 individuals were interviewed (28 carriers, 4 non-carriers). We interpreted five themes intersecting across six time points of the testing pathway: (1) individual differences regarding personal/family history of cancer, demographics and personal attitudes/approach; (2) healthcare professionals' support; (3) pathway access and integration; (4) nature of family/partner relationships; and (5) Jewish community factors. Testing was largely triggered by connecting information to a personal/family history of cancer. No participants reported decision regret, although there was huge variation in satisfaction. Suggestions were given around increasing UK Jewish community awareness, making information and support services personally relevant and proactive case management of carriers. CONCLUSIONS: There is a need to improve UK Jewish community BRCA awareness and to highlight personal relevance of testing for individuals without a personal/family history of cancer. Traditional testing criteria caused multiple issues regarding test access and experience. Carriers want information and support services tailored to their individual circumstances.

Screening and prevention of ovarian cancer.

Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer. Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer.

Importance: Pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed. Objective: To estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs. Design, Setting, and Participants: In this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed. Exposures: CSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention. Main Outcomes and Measures: The incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated. Results: In the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were -£1942/QALY (-$2680/QALY), -£89/QALY (-$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs. Conclusions and Relevance: In this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

The UEMS experience in continuous medical education accreditation process: a 'quo vadis' analysis of our global database.

Background: The authors systematically appraise a large database of continuous professional development (CPD) and continuous medical education (CME) events against the European Accreditation Council for Continuous Medical Education (EACCME) framework. Methods: The authors performed a retrospective observational study of all CPD or CME events within the European Union of Medical Specialists (UEMS) database between 2017 and 2019, including 91 countries and 6034 events. Assessment of event design, quality and outcomes was evaluated against a validated, expert-derived accreditation framework, using thematic analysis to extract distinct themes, and subsequent quantitative analysis. Results: The authors included 5649 live educational events (LEEs) and 385 e-learning materials (ELMs). Three thousand seven hundred sixty-two [3762 (62.3%)] of the events did not report clear justification in their needs assessment process. Most accreditation applications claimed covering a single educational need [1603/2277 (70.3%)]. Needs assessments were reported to be similar across conferences, courses and other types of events (P<0.01); 5642/6034 events (93.5%) had clearly documented expected learning outcomes; only 978/6034 (16.2%) reported a single expected learning outcome while the rest report 2-10 outcomes. Providers who declared more than one educational need also declared multiple learning outcomes (ρ=0.051, P<0.01). Conclusions: Despite EACCME providing a robust framework for the CPD/CME accreditation process, reporting quality can still be improved, as more than 1 in 2 events fail to provide a clear description of their needs assessment. To the authors' knowledge, this is the largest educational LEE/ELM database, which can be a starting to revisit the CME/CPD accreditation process.

Assessing Radiological Response to Immunotherapy in Lung Cancer: An Evolving Arena.

In the past decade, immune checkpoint inhibitors (ICIs) have entered the treatment landscape of non-small-cell lung cancer, signalling a paradigm shift within the field characterized by significant survival benefits for patients with advanced and metastatic disease, and especially those with non-targetable genetic oncogenic driver mutations. However, the shift towards immune-based treatments has created new challenges in oncology. Atypical immunotherapy response patterns, including pseudo-progression and hyperprogressive disease, as well as immune-related adverse events have generated the need for new methods to predict patient response to treatment. Hence, new versions of the traditional Response Evaluation Criteria for Solid Tumors (RECIST) have emerged to help characterise with better accuracy radiological findings concerning patient response classification to immunotherapy. This review discusses response evaluation criteria relevant to unique radiological findings observed in patients treated with immunotherapy for non-small-cell lung cancer.

Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study.

OBJECTIVE: To evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis. DESIGN: Cohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857). SETTING: North-East London Cancer Network (NELCN) population. POPULATION/SAMPLE: Women with high-grade non-mucinous epithelial OC. METHODS: A more detailed DA was developed using patient and stakeholder input following the principles/methodology of IPDAS (International Patients Decision Aids Standards). Unselected patients attending oncology clinics evaluated both a pre-existing short and a new long DA version and then underwent mainstreaming genetic testing by a cancer clinician. Appropriate inferential descriptive and regression analyses were undertaken. MAIN OUTCOME MEASURES: Satisfaction, readability, understanding, emotional well-being and preference for long/short DA. RESULTS: The mean age of patients was 66 years (interquartile range 11), and 85% were White British ethnicity. Of the participants, 74% found DAs helpful/useful in decision-making. Women reported higher levels of satisfaction (86% versus 58%, p < 0.001), right amount of information provided (76.79% versus49.12%, p < 0.001) and improved understanding (p < 0.001) with the long DA compared with the short DA. There was no statistically significant difference in emotional outcomes (feeling worried/concerned/reassured/upset) between 'short' and 'long' DA; 74% of patients preferred the long DA and 24% the short DA. Patients undergoing treatment (correlation coefficient (coef) = 0.603; 95% CI 0.165-1.041, p = 0.007), those with recurrence (coef = 0.493; 95% CI 0.065-0.92, p = 0.024) and older women (coef = 0.042; 95% CI 0.017-0.066, p = 0.001) preferred the short DA. Ethnicity did not affect outcomes or overall preference for long/short DA. CONCLUSIONS: A longer DA in OC patients has higher satisfaction without increasing emotional distress. Older women and those undergoing treatment/recurrence prefer less extensive information, whereas those in remission preferred a longer DA.

Pulmonary benign metastasizing uterine leiomyoma (PBML): a case report and review of the literature.

Benign metastasizing leiomyoma (BML) is a rare disorder characterized by the presence of benign smooth muscle tumours in extrauterine sites, typically the lungs. It classically involves perimenopausal women with a history of uterine surgery. The condition follows an indolent course but may cause clinical symptoms with large or widespread lesions. Case presentation: The authors report the case of a 47-year-old female who presented with a 6-month history of irregular vaginal bleeding and severe hot flushes. The patient had no previous history of gynaecological surgery. Ultrasonography and subsequent MRI identified a suspicious 105×65 mm mass involving the right uterine cornu and broad ligament. Computed tomography identified bilateral lung nodules, suspicious for metastases. Histological assessment of the final uterine surgical specimen identified a benign dissecting leiomyoma involving the broad ligament and cervix. BML was diagnosed after thoracoscopic resection of a lung lesion which revealed a histologically identical tumour with entrapped normal lung alveoli. Clinical discussion: This case shows that there is a minority of patients without previous uterine surgery who still go on to develop pulmonary BML. In our case, a combined treatment approach was adopted, involving substitution of hormone replacement therapy to a non-hormonal alternative, thoracoscopic resection of lung lesions and interval surveillance imaging of the chest. Conclusions: BML is a rare condition but should be considered as a differential in women with pulmonary nodules and a history of uterine leiomyomata. Its diagnosis and subsequent counselling can be challenging; therefore cases should be treated by multidisciplinary teams in tertiary specialized centres.

Quality of life after risk-reducing surgery for breast and ovarian cancer prevention: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the impact of risk-reducing surgery for breast cancer and ovarian cancer prevention on quality of life. We considered risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, and risk-reducing early salpingectomy and delayed oophorectomy. DATA SOURCES: We followed a prospective protocol (International Prospective Register of Systematic Reviews: CRD42022319782) and searched MEDLINE, Embase, PubMed, and Cochrane Library from inception to February 2023. STUDY ELIGIBILITY CRITERIA: We followed a PICOS (population, intervention, comparison, outcome, and study design) framework. The population included women at increased risk of breast cancer or ovarian cancer. We focused on studies reporting quality of life outcomes (health-related quality of life, sexual function, menopause symptoms, body image, cancer-related distress or worry, anxiety, or depression) after risk-reducing surgery, including risk-reducing mastectomy for breast cancer and risk-reducing salpingo-oophorectomy or risk-reducing early salpingectomy and delayed oophorectomy for ovarian cancer. METHODS: We used the Methodological Index for Non-Randomized Studies (MINORS) for study appraisal. Qualitative synthesis and fixed-effects meta-analysis were performed. RESULTS: A total of 34 studies were included (risk-reducing mastectomy: 16 studies; risk-reducing salpingo-oophorectomy: 19 studies; risk-reducing early salpingectomy and delayed oophorectomy: 2 studies). Health-related quality of life was unchanged or improved in 13 of 15 studies after risk-reducing mastectomy (N=986) and 10 of 16 studies after risk-reducing salpingo-oophorectomy (N=1617), despite short-term deficits (N=96 after risk-reducing mastectomy and N=459 after risk-reducing salpingo-oophorectomy). Sexual function (using the Sexual Activity Questionnaire) was affected in 13 of 16 studies (N=1400) after risk-reducing salpingo-oophorectomy in terms of decreased sexual pleasure (-1.21 [-1.53 to -0.89]; N=3070) and increased sexual discomfort (1.12 [0.93-1.31]; N=1400). Hormone replacement therapy after premenopausal risk-reducing salpingo-oophorectomy was associated with an increase (1.16 [0.17-2.15]; N=291) in sexual pleasure and a decrease (-1.20 [-1.75 to -0.65]; N=157) in sexual discomfort. Sexual function was affected in 4 of 13 studies (N=147) after risk-reducing mastectomy, but stable in 9 of 13 studies (N=799). Body image was unaffected in 7 of 13 studies (N=605) after risk-reducing mastectomy, whereas 6 of 13 studies (N=391) reported worsening. Increased menopause symptoms were reported in 12 of 13 studies (N=1759) after risk-reducing salpingo-oophorectomy with a reduction (-1.96 [-2.81 to -1.10]; N=1745) in the Functional Assessment of Cancer Therapy - Endocrine Symptoms. Cancer-related distress was unchanged or decreased in 5 of 5 studies after risk-reducing mastectomy (N=365) and 8 of 10 studies after risk-reducing salpingo-oophorectomy (N=1223). Risk-reducing early salpingectomy and delayed oophorectomy (2 studies, N=413) led to better sexual function and menopause-specific quality of life. CONCLUSION: Risk-reducing surgery may be associated with quality of life outcomes. Risk-reducing mastectomy and risk-reducing salpingo-oophorectomy reduce cancer-related distress, and do not affect health-related quality of life. Women and clinicians should be aware of body image problems after risk-reducing mastectomy, and of sexual dysfunction and menopause symptoms after risk-reducing salpingo-oophorectomy. Risk-reducing early salpingectomy and delayed oophorectomy may be a promising alternative to mitigate quality of life-related risks of risk-reducing salpingo-oophorectomy.

Impact of Multiple COVID-19 Waves on Gynaecological Cancer Services in the UK.

BACKGROUND: This study aimed to assess the impact of multiple COVID-19 waves on UK gynaecological-oncology services. METHODS: An online survey was distributed to all UK-British-Gynaecological-Cancer-Society members during three COVID-19 waves from 2020 to2022. RESULTS: In total, 51 hospitals (including 32 cancer centres) responded to Survey 1, 42 hospitals (29 centres) to Survey 2, and 39 hospitals (30 centres) to Survey 3. During the first wave, urgent referrals reportedly fell by a median of 50% (IQR = 25-70%). In total, 49% hospitals reported reduced staffing, and the greatest was noted for trainee doctors, by a median of 40%. Theatre capacity was reduced by a median of 40%. A median of 30% of planned operations was postponed. Multidisciplinary meetings were completely virtual in 39% and mixed in 65% of the total. A median of 75% of outpatient consultations were remote. By the second wave, fewer hospitals reported staffing reductions, and there was a return to pre-pandemic urgent referrals and multidisciplinary workloads. Theatre capacity was reduced by a median of 10%, with 5% of operations postponed. The third wave demonstrated worsening staff reductions similar to Wave 1, primarily from sickness. Pre-pandemic levels of urgent referrals/workload continued, with little reduction in surgical capacity. CONCLUSION: COVID-19 led to a significant disruption of gynaecological-cancer care across the UK, including reduced staffing, urgent referrals, theatre capacity, and working practice changes. Whilst disruption eased and referrals/workloads returned to normal, significant staff shortages remained in 2022, highlighting persistent capacity constraints.

Health worker education during the COVID-19 pandemic: global disruption, responses and lessons for the future-a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis identified early evidence quantifying the disruption to the education of health workers by the COVID-19 pandemic, ensuing policy responses and their outcomes. METHODS: Following a pre-registered protocol and PRISMA/AMSTAR-2 guidelines, we systematically screened MEDLINE, EMBASE, Web of Science, CENTRAL, clinicaltrials.gov and Google Scholar from January 2020 to July 2022. We pooled proportion estimates via random-effects meta-analyses and explored subgroup differences by gender, occupational group, training stage, WHO regions/continents, and study end-year. We assessed risk of bias (Newcastle-Ottawa scale for observational studies, RοB2 for randomized controlled trials [RCT]) and rated evidence certainty using GRADE. RESULTS: Of the 171 489 publications screened, 2 249 were eligible, incorporating 2 212 observational studies and 37 RCTs, representing feedback from 1 109 818 learners and 22 204 faculty. The sample mostly consisted of undergraduates, medical doctors, and studies from institutions in Asia. Perceived training disruption was estimated at 71.1% (95% confidence interval 67.9-74.2) and learner redeployment at 29.2% (25.3-33.2). About one in three learners screened positive for anxiety (32.3%, 28.5-36.2), depression (32.0%, 27.9-36.2), burnout (38.8%, 33.4-44.3) or insomnia (30.9%, 20.8-41.9). Policy responses included shifting to online learning, innovations in assessment, COVID-19-specific courses, volunteerism, and measures for learner safety. For outcomes of policy responses, most of the literature related to perceptions and preferences. More than two-thirds of learners (75.9%, 74.2-77.7) were satisfied with online learning (postgraduates more than undergraduates), while faculty satisfaction rate was slightly lower (71.8%, 66.7-76.7). Learners preferred an in-person component: blended learning 56.0% (51.2-60.7), face-to-face 48.8% (45.4-52.1), and online-only 32.0% (29.3-34.8). They supported continuation of the virtual format as part of a blended system (68.1%, 64.6-71.5). Subgroup differences provided valuable insights despite not resolving the considerable heterogeneity. All outcomes were assessed as very-low-certainty evidence. CONCLUSION: The COVID-19 pandemic has severely disrupted health worker education, inflicting a substantial mental health burden on learners. Its impacts on career choices, volunteerism, pedagogical approaches and mental health of learners have implications for educational design, measures to protect and support learners, faculty and health workers, and workforce planning. Online learning may achieve learner satisfaction as part of a short-term solution or integrated into a blended model in the post-pandemic future.

Variation in outcome reporting in studies of fertility-sparing surgery for cervical cancer: A systematic review.

BACKGROUND: Cervical cancer affects 3197 women in the UK, and 604 000 women worldwide annually, with peak incidence seen in women between 30 and 34 years of age. For many, fertility-sparing surgery is an appealing option where possible. However, absence of large-scale data, along with a notable variation in reported outcomes in relevant studies, may undermine future efforts for consistent evidence synthesis. OBJECTIVES: To systematically review the reported outcomes measured in studies that include women who underwent fertility-sparing surgery for cervical cancer and identify whether variation exists. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL from inception to February 2019. SELECTION CRITERIA: Randomised controlled trials, cohort and observational studies, and case studies of more than ten participants from January 1990 to date. DATA COLLECTION AND ANALYSIS: Study characteristics and all reported treatment outcomes. MAIN RESULTS: A total of 104 studies with a sum of 9535 participants were identified. Most studies reported on oncological outcomes (97/104), followed by fertility and pregnancy (86/104), postoperative complications (74/104), intra-operative complications (72/104) and quality of life (5/104). There was huge variation and heterogeneity in reported outcomes, with only 12% being good quality and 87% being of poor quality. CONCLUSIONS: There is significant heterogeneity in the reported outcomes. An agreed Core Outcome Set is necessary for future studies to effectively harmonise reported outcomes that are measurable and relevant to patients, clinicians and researchers. This systematic review sets the groundwork for the development of a Core Outcome Set for fertility-sparing surgery in cervical cancer.

Quality of Life after Risk-Reducing Hysterectomy for Endometrial Cancer Prevention: A Systematic Review.

BACKGROUND: Risk-reducing hysterectomy (RRH) is the gold-standard prevention for endometrial cancer (EC). Knowledge of the impact on quality-of-life (QoL) is crucial for decision-making. This systematic review aims to summarise the evidence. METHODS: We searched major databases until July 2022 (CRD42022347631). Given the paucity of data on RRH, we also included hysterectomy as treatment for benign disease. We used validated quality-assessment tools, and performed qualitative synthesis of QoL outcomes. RESULTS: Four studies (64 patients) reported on RRH, 25 studies (1268 patients) on hysterectomy as treatment for uterine bleeding. There was moderate risk-of-bias in many studies. Following RRH, three qualitative studies found substantially lowered cancer-worry, with no decision-regret. Oophorectomy (for ovarian cancer prevention) severely impaired menopause-specific QoL and sexual-function, particularly without hormone-replacement. Quantitative studies supported these results, finding low distress and generally high satisfaction. Hysterectomy as treatment of bleeding improved QoL, resulted in high satisfaction, and no change or improvements in sexual and urinary function, although small numbers reported worsening. CONCLUSIONS: There is very limited evidence on QoL after RRH. Whilst there are benefits, most adverse consequences arise from oophorectomy. Benign hysterectomy allows for some limited comparison; however, more research is needed for outcomes in the population of women at increased EC-risk.

Cost-Effectiveness of Risk-Reducing Surgery for Breast and Ovarian Cancer Prevention: A Systematic Review.

Policymakers require robust cost-effectiveness evidence of risk-reducing-surgery (RRS) for decision making on resource allocation for breast cancer (BC)/ovarian cancer (OC)/endometrial cancer (EC) prevention. We aimed to summarise published data on the cost-effectiveness of risk-reducing mastectomy (RRM)/risk-reducing salpingo-oophorectomy (RRSO)/risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) for BC/OC prevention in intermediate/high-risk populations; hysterectomy and bilateral salpingo-oophorectomy (BSO) in Lynch syndrome women; and opportunistic bilateral salpingectomy (OBS) for OC prevention in baseline-risk populations. Major databases were searched until December 2021 following a prospective protocol (PROSPERO-CRD42022338008). Data were qualitatively synthesised following a PICO framework. Twenty two studies were included, with a reporting quality varying from 53.6% to 82.1% of the items scored in the CHEERS checklist. The incremental cost-effectiveness ratio/incremental cost-utility ratio and cost thresholds were inflated and converted to US$2020, using the original currency consumer price index (CPI) and purchasing power parities (PPP), for comparison. Eight studies concluded that RRM and/or RRSO were cost-effective compared to surveillance/no surgery for BRCA1/2, while RRESDO was cost-effective compared to RRSO in one study. Three studies found that hysterectomy with BSO was cost-effective compared to surveillance in Lynch syndrome women. Two studies showed that RRSO was also cost-effective at ≥4%/≥5% lifetime OC risk for pre-/post-menopausal women, respectively. Seven studies demonstrated the cost-effectiveness of OBS at hysterectomy (n = 4), laparoscopic sterilisation (n = 4) or caesarean section (n = 2). This systematic review confirms that RRS is cost-effective, while the results are context-specific, given the diversity in the target populations, health systems and model assumptions, and sensitive to the disutility, age and uptake rates associated with RRS. Additionally, RRESDO/OBS were sensitive to the uncertainty concerning the effect sizes in terms of the OC-risk reduction and long-term health impact. Our findings are relevant for policymakers/service providers and the design of future research studies.

IL-10 in cancer: an essential thermostatic regulator between homeostatic immunity and inflammation - a comprehensive review.

Cytokines are soluble proteins that mediate intercellular signaling regulating immune and inflammatory responses. Cytokine modulation represents a promising cancer immunotherapy approach for immune-mediated tumor regression. However, redundancy in cytokine signaling and cytokines' pleiotropy, narrow therapeutic window, systemic toxicity, short half-life and limited efficacy represent outstanding challenges for cytokine-based cancer immunotherapies. Recently, there has been interest in the paradoxical role of IL-10 in cancer, its controversial prognostic utility and novel strategies to enhance its therapeutic profile. Here, the authors review the literature surrounding the role of IL-10 within the tumor microenvironment, its prognostic correlates to cancer patient outcomes and its pro- and antitumor effects, and they assess the legitimacy of potential therapeutic strategies harnessing IL-10 by outlining the notable preclinical and clinical evidence to date.

A systematic review and meta-analysis of the diagnostic effectiveness of human papillomavirus methylation biomarkers for detection of cervical cancer.

Background: The aim of this systematic review and meta-analysis was to assess the evidence for the diagnostic effectiveness of human papillomavirus (HPV) methylation biomarkers for detection of cervical cancer. Methods: PubMed, Embase and Web of Science were searched. Nine articles focusing on HPV methylation for detection of precancerous and cancerous cervical lesions were included. The QUADAS-2 tool was used for quality assessment. The receiver operating characteristic (ROC) was the main diagnostic performance parameter extracted. Results: Of the nine articles included in this study, seven were of moderate quality and two were of high quality. A meta-analysis of the ROC for 27 HPV methylation biomarkers revealed an overall pooled ROC of 0.770 (95% CI: 0.720-0.819; I2: 98.4%; Q: 1537.4; p < 0.01). Four methylation biomarkers had strong diagnostic ability (ROC > 0.900), 17 were moderate (ROC: 0.7000-0.8999) and six were poor (ROC < 0.700). Conclusion: HPV methylation biomarkers hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

This study reviewed the literature to assess the available evidence for the ability of biomarkers based on human papillomavirus (HPV) methylation (i.e., the detection of methyl groups in HPV DNA in cervical specimens) to screen for cervical precancerous and cancerous lesions. Scientific databases were searched, and abstracts screened for relevance. The quality of the included articles was assessed using a quality assessment tool called QUADAS-2. The main diagnostic performance parameter extracted from the included articles was the receiver operating characteristic (ROC), a measure of the ability of a biomarker to detect all true cases (true positives) while excluding all true non-cases (true negatives). After screening, nine articles were included, of which seven were of moderate quality and two were of high quality. ROC data were extracted for 27 biomarkers, of which four methylation biomarkers had high diagnostic ability (i.e., ROC > 0.900), 17 had moderate diagnostic ability (ROC: 0.7000­0.8999) and six had low diagnostic ability (ROC < 0.700). An umbrella meta-analysis (i.e., a weighted-average ROC for all HPV methylation biomarkers) revealed an ROC consistent with moderate diagnostic ability (0.770). The main conclusion from this study was that HPV methylation biomarkers, especially ones with high diagnostic ability, hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma.

Brain tumours are the leading cause of paediatric cancer-associated death worldwide. High-grade glioma (HGG) represents a main cause of paediatric brain tumours and is associated with poor prognosis despite surgical and chemoradiotherapeutic advances. The molecular genetics of paediatric HGG (pHGG) are distinct from those in adults, and therefore, adult clinical trial data cannot be extrapolated to children. Compared to adult HGG, pHGG is characterised by more frequent mutations in PDGFRA, TP53 and recurrent K27M and G34R/V mutations on histone H3. Ongoing trials are investigating novel targeted therapies in pHGG. Promising results have been achieved with BRAF/MEK and PI3K/mTOR inhibitors. Combination of PI3K/mTOR, EGFR, CDK4/6, and HDAC inhibitors are potentially viable options. Inhibitors targeting the UPS proteosome, ADAM10/17, IDO, and XPO1 are more novel and are being investigated in early-phase trials. Despite preclinical and clinical trials holding promise for the discovery of effective pHGG treatments, several issues persist. Inadequate blood-brain barrier penetration, unfavourable pharmacokinetics, dose-limiting toxicities, long-term adverse effects in the developing child, and short-lived duration of response due to relapse and resistance highlight the need for further improvement. Future pHGG management will largely depend on selecting combination therapies which work synergistically based on a sound knowledge of the underlying molecular target pathways. A systematic investigation of multimodal therapy with chemoradiotherapy, surgery, target agents and immunotherapy is paramount. This review provides a comprehensive overview of pHGG focusing on molecular genetics and novel targeted therapies. The diagnostics, genetic discrepancies with adults and their clinical implications, as well as conventional treatment approaches are discussed.