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Simple Summary: Accurate pre-operative surgical risk predictions form the foundation of pre-operative counseling and informed consent. There are currently no validated risk calculators that are able to accurately predict post-operative complications for women undergoing gynecological cancer surgery in both high- and low-middle-income healthcare settings. Using the dataset from the international GO SOAR database, we present a novel artificial intelligence surgical risk calculator capable of accurately predicting the risk of complications associated with gynecological cancer surgery. The GO SOAR surgical risk calculator uses readily available pre-operative data available across all-income healthcare settings, ensuring benefits to women globally. The medical complexity of surgical patients is increasing, and surgical risk calculators are crucial in providing high-value, patient-centered surgical care. However, pre-existing models are not validated to accurately predict risk for major gynecological oncology surgeries, and many are not generalizable to low- and middle-income country settings (LMICs). The international GO SOAR database dataset was used to develop a novel predictive surgical risk calculator for post-operative morbidity and mortality following gynecological surgery. Fifteen candidate features readily available pre-operatively across both high-income countries (HICs) and LMICs were selected. Predictive modeling analyses using machine learning methods and linear regression were performed. The area-under-the-receiver-operating characteristic curve (AUROC) was calculated to assess overall discriminatory performance. Neural networks (AUROC 0.94) significantly outperformed other models (p < 0.001) for evaluating the accuracy of prediction across three groups, i.e., minor morbidity (Clavien–Dindo I-II), major morbidity (Clavien–Dindo III-V), and no morbidity. Logistic-regression modeling outperformed the clinically established SORT model in predicting mortality (AUROC 0.66 versus 0.61, p < 0.001). The GO SOAR surgical risk prediction model is the first that is validated for use in patients undergoing gynecological surgery. Accurate surgical risk predictions are vital within the context of major cytoreduction surgery, where surgery and its associated complications can diminish quality-of-life and affect long-term cancer survival. A model that requires readily available pre-operative data, irrespective of resource setting, is crucial to reducing global surgical disparities. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery to prevent breast and ovarian cancer is very effective, but there is limited research into the quality of life afterwards, particularly with reference to quality-of-life scores known as utility scores. These are important for patients at increased cancer risk who are considering surgery and are essential for health-economic evaluations. This article used data from a systematic review of different quality-of-life questionnaires given to patients following these surgeries. We converted these data into utility scores, as recommended by the national guidelines. This shows that surgery to prevent breast cancer is associated with a long-term utility score of 0.92 and surgery to prevent ovarian cancer has a score of 0.97, indicating a mild–moderate impact. These are the first utility scores sourced from patients who have undergone these procedures, and they are important to doctors counselling patients about cancer prevention options and to researchers. Higher-quality studies are still needed, using the recommended quality-of-life questionnaire (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. [ABSTRACT FROM AUTHOR]

Simple Summary: Little is known about factors contributing to early post-operative morbidity and mortality in low and middle income countries with a paucity of data limiting global efforts to improve gynaecological cancer care. In this multicentre, international prospective cohort study of women undergoing gynaecological oncology surgery, we show that low and middle versus high income countries were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Women with BRCA1 or BRCA2 gene mutations are at increased risk of breast and ovarian cancer and often undergo operations to remove both their ovaries in order to prevent ovarian cancer. The impact of this operation on breast cancer risk is uncertain; thus, we performed a systematic review and meta-analysis to determine it. We found that this operation was not linked with a reduced risk of developing breast cancer when considering both BRCA1 and BRCA2 carriers together but was linked with a reduced risk of breast cancer when considering BRCA2 carriers alone. If a woman had this operation after developing breast cancer, it was not related to a reduced chance of developing cancer in the other breast. However, it was associated with increased survival following breast cancer when considering BRCA1 and BRCA2 carriers together and BRCA1 carriers alone. These findings may have important implications for counselling for women in the clinic. Background: Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. Methods: We conducted a systematic review (CRD42018077613) of BRCA1/BRCA2 carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status. Results: RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59–1.21) or CBC risk (RR = 0.95, 95%CI: 0.65–1.39) in BRCA1 and BRCA2 carriers combined but was associated with reduced BC-specific mortality in BC-affected BRCA1 and BRCA2 carriers combined (RR = 0.26, 95%CI: 0.18–0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68–1.17) or CBC risk (RR = 0.85, 95%CI: 0.59–1.24) in BRCA1 carriers nor a reduction in the CBC risk in BRCA2 carriers (RR = 0.35, 95%CI: 0.07–1.74) but was associated with a reduction in the PBC risk in BRCA2 carriers (RR = 0.63, 95%CI: 0.41–0.97) and BCSM in BC-affected BRCA1 carriers (RR = 0.46, 95%CI: 0.30–0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in BRCA2 carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers, respectively. Conclusions: RRSO was not associated with PBC or CBC risk reduction in BRCA1 and BRCA2 carriers combined but was associated with improved BC survival in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers and a reduced PBC risk in BRCA2 carriers. [ABSTRACT FROM AUTHOR]

Background: An accurate and simple risk prediction model that would facilitate earlier detection of pancreatic adenocarcinoma (PDAC) is not available at present. In this study, we compare different algorithms of risk prediction in order to select the best one for constructing a biomarker-based risk score, PancRISK.Methods: Three hundred and seventy-nine patients with available measurements of three urine biomarkers, (LYVE1, REG1B and TFF1) using retrospectively collected samples, as well as creatinine and age, were randomly split into training and validation sets, following stratification into cases (PDAC) and controls (healthy patients). Several machine learning algorithms were used, and their performance characteristics were compared. The latter included AUC (area under ROC curve) and sensitivity at clinically relevant specificity.Results: None of the algorithms significantly outperformed all others. A logistic regression model, the easiest to interpret, was incorporated into a PancRISK score and subsequently evaluated on the whole data set. The PancRISK performance could be even further improved when CA19-9, commonly used PDAC biomarker, is added to the model.Conclusion: PancRISK score enables easy interpretation of the biomarker panel data and is currently being tested to confirm that it can be used for stratification of patients at risk of developing pancreatic cancer completely non-invasively, using urine samples. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipid kinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-driven breast cancer was never elucidated.Methods: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling was analysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays.Results: Our findings show for the first time that human primary breast tumours and associated lymph node metastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77, respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significant increase in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negative breast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition and gene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathways downstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and may function as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferation was abrogated by SK1-specific small interfering RNA (siRNA).Conclusions: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signalling and expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance of this pathway in ER-negative breast cancer. [ABSTRACT FROM AUTHOR]

Background: The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40-48 years on breast cancer mortality.Methods: We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39-41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151.Findings: 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8-24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58-0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79-1·22]; p=0·86).Interpretation: Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality.Funding: National Institute for Health Research Health Technology Assessment programme. [ABSTRACT FROM AUTHOR]