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Ovarian cancer is the fifth leading cause of cancer mortality in UK women. Ovarian cancer survival varies by disease stage at diagnosis, but evidence is mixed on the effect of tumour histological type (histotype) and other factors. 1.3 million UK women completed a detailed health questionnaire in 1996–2001 and were followed for incident cancers and deaths via linkage to national databases. Using Cox regression models, we estimated adjusted relative risks (RRs) of death from ovarian cancer, by stage at diagnosis, tumour histotype, and 16 other personal characteristics of the women. During 17.7 years’ average follow-up, 13,222 women were diagnosed with ovarian cancer, and 8697 of them died from the disease. Stage at diagnosis was a major determinant of survival (stage IV vs I, RR=10.54, 95% CI: 9.16–12.13). Histotype remained a significant predictor after adjustment for stage and other factors, but associations varied over the follow-up period. Histotype-specific survival was worse for high-grade than low-grade tumours. Survival appeared worse with older age at diagnosis (per 5 years: RR=1.19, 95% CI: 1.15–1.22), higher BMI (per 5-unit increase: RR=1.06, 95% CI: 1.02–1.11), and smoking (current vs never: RR=1.17, 95% CI: 1.07–1.27), but there was little association with 13 other pre-diagnostic reproductive, anthropometric, and lifestyle factors. Stage at diagnosis is a strong predictor of ovarian cancer survival, but tumour histotype and grade remain predictors of survival even after adjustment for stage and other factors, contributing further evidence of biological dissimilarity between the ovarian cancer histotypes. Obesity and smoking represent potentially-modifiable determinants of survival, but the stronger association with stage suggests that improving earlier diagnosis would have a greater impact on increasing ovarian cancer survival. •This study investigated ovarian cancer survival in a cohort of 1.3 million UK women.•After 18 years of follow-up, the study included 13,222 incident ovarian cancers.•Stage, age and histotype were significantly associated with ovarian cancer survival.•Survival was also worse with higher BMI and smoking, but with less impact than stage.

The availability of protein measurements and whole exome sequence data in the UK Biobank enables investigation of potential observational and genetic protein-cancer risk associations. We investigated associations of 1463 plasma proteins with incidence of 19 cancers and 9 cancer subsites in UK Biobank participants (average 12 years follow-up). Emerging protein-cancer associations were further explored using two genetic approaches, cis -pQTL and exome-wide protein genetic scores (exGS). We identify 618 protein-cancer associations, of which 107 persist for cases diagnosed more than seven years after blood draw, 29 of 618 were associated in genetic analyses, and four had support from long time-to-diagnosis ( > 7 years) and both cis -pQTL and exGS analyses: CD74 and TNFRSF1B with NHL, ADAM8 with leukemia, and SFTPA2 with lung cancer. We present multiple blood protein-cancer risk associations, including many detectable more than seven years before cancer diagnosis and that had concordant evidence from genetic analyses, suggesting a possible role in cancer development. Plasma proteins are a potential diagnostic tool to detect multiple diseases, including cancer. Here, the authors leverage multi-omics data to identify 1,463 proteins associated with 19 common cancers in UK Biobank participants. Reviewer Recognition:

Background/Objectives: To evaluate the clinicopathological features, treatment, and survival outcomes and to identify independent prognosticators for recurrence and mortality in patients with endometrioid ovarian cancer. Methods: The medical records of patients diagnosed with endometrioid ovarian carcinoma between January 2010 and December 2022 were reviewed retrospectively. Demographic and disease-related data were evaluated. Kaplan–Meier survival analysis using log rank test and Cox regression was performed. Results: Seventy-six patients were included in the study. The median age at diagnosis was 54 years (range 31–86). A total of 85.5% of the patients were diagnosed with early-stage disease and 88.1% of the tumours represented low-grade carcinomas. Synchronous endometrioid endometrial cancer was confirmed in 19.7% of the cases. All patients underwent surgical management and 65.8% received adjuvant chemotherapy. Median follow-up time was 67.5 months. The 5-year disease-free survival and overall survival were 92.1% and 93.4%, respectively. The risk of cancer-related death was higher in advanced stages (HR = 13.86; 95% CI 2.16–57.17; p < 0.001) and in the presence of residual disease (HR = 15.18; 95% CI 2.36–87.17; p < 0.002). Residual disease and advanced stages were also identified as independent risk factors for disease relapse with HR = 16.04 (95% CI 2.61–93.7; p < 0.002) and HR = 11.73 (95% CI 1.92–41.6; p < 0.001), respectively. Conclusions: Endometrioid ovarian carcinoma usually affects younger patients with the majority of the cases representing low-grade carcinomas diagnosed at early stages. Residual disease and advanced stages are independently associated with inferior survival outcomes. There was no significance of lymph node dissection and adjuvant chemotherapy in the overall and recurrence-free survival rates. Further research focusing on molecular profiling should aim to define the prevalence and the prognostic value of major molecular alterations and develop precise stratification models to plan personalised treatment for optimal care.

Breast cancer can be categorised into a number of histological types, based on microscopic appearances. There is some evidence that the different breast cancer histological types are associated with different patient and tumour characteristics, but few previous studies have been large enough to investigate this systematically, especially for rare histological types. National cancer registration data were used to describe trends in the incidence of specific histological types of invasive breast cancer in women diagnosed when aged 18–89 years in England from January 1988 to December 2016, and to investigate associations between breast cancer histological types and patient and tumour characteristics. There were 838,776 women diagnosed with a first primary invasive breast cancer in this 29‐year period, including 614,698 (73%) cases of ductal carcinoma NST [no special type (NST)], 90,028 (11%) cases of lobular carcinoma, and more than 16,000 (2%) cases each of tubular and mucinous carcinomas. Rarer histological types included medullary, papillary, metaplastic, and cribriform carcinomas, with >1000 cases of each type. Data quality and completeness improved substantially during the study period. The different histological types of breast cancer showed different patterns in incidence by calendar period of diagnosis, age at diagnosis, and screen‐detection status, as well as different associations with tumour characteristics such as grade, stage at diagnosis, and molecular subtype. This large nationwide study provides an overview of the changing incidence of the different histological types of invasive breast cancer in England over almost 30 years. It also gives an opportunity to investigate the characteristics of rare histological types, which smaller studies have been unable to explore. In addition, the results demonstrate the continuing value of histological types defined by microscopic morphology, alongside newer molecular classifications.

Background: Tubal ligation is known to be associated with a reduction in ovarian cancer risk. Associations with breast, endometrial and cervical cancers have been suggested. We investigated associations for 26 site-specific cancers in a large UK cohort. Methods: Study participants completed a questionnaire on reproductive and lifestyle factors in 1996–2001, and were followed for cancer and death via national registries. Using Cox regression models, we estimated adjusted relative risks (RRs) for 26 site-specific cancers among women with vs without tubal ligation. Results: In 1 278 783 women without previous cancer, 167 430 incident cancers accrued during 13.8 years’ follow-up. Significantly reduced risks were found in women with tubal ligation for cancers of the ovary (RR=0.80, 95% CI: 0.76–0.85; P <0.001; n =8035), peritoneum (RR=0.81, 0.66–0.98; P =0.03; n =730), and fallopian tube (RR=0.60, 0.37–0.96; P =0.04; n =168). No significant associations were found for endometrial, breast, or cervical cancers. Conclusions: The reduced risks of ovarian, peritoneal and fallopian tube cancers are consistent with hypotheses of a common origin for many tumours at these sites, and with the suggestion that tubal ligation blocks cells, carcinogens or other agents from reaching the ovary, fallopian tubes and peritoneal cavity.

Vital registration and cause of death reporting is incomplete in the countries in which the HIV epidemic is most severe. A reliable tool that is independent of HIV status is needed for measuring the frequency of AIDS deaths and ultimately the impact of antiretroviral therapy on mortality. A verbal autopsy questionnaire was administered to caregivers of 381 adults of known HIV status who died between 1998 and 2003 in Manicaland, eastern Zimbabwe. Individuals who were HIV positive and did not die in an accident or during childbirth (74%; n = 282) were considered to have died of AIDS in the gold standard. Verbal autopsies were randomly allocated to a training dataset (n = 279) to generate classification criteria or a test dataset (n = 102) to verify criteria. A rule-based algorithm created to minimise false positives had a specificity of 66% and a sensitivity of 76%. Eight predictors (weight loss, wasting, jaundice, herpes zoster, presence of abscesses or sores, oral candidiasis, acute respiratory tract infections, and vaginal tumours) were included in the algorithm. In the test dataset of verbal autopsies, 69% of deaths were correctly classified as AIDS/non-AIDS, and it was not necessary to invoke a differential diagnosis of tuberculosis. Presence of any one of these criteria gave a post-test probability of AIDS death of 0.84. Analysis of verbal autopsy data in this rural Zimbabwean population revealed a distinct pattern of signs and symptoms associated with AIDS mortality. Using these signs and symptoms, demographic surveillance data on AIDS deaths may allow for the estimation of AIDS mortality and even HIV prevalence.

The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal–epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development. The Human Endometrial Cell Atlas integrates single-cell transcriptomic datasets from women with and without endometriosis. Novel and known cell types are registered using spatial transcriptomics to provide a comprehensive map of the human endometrium in controls and endometriosis cases.

ObjectivesTo investigate associations between daily physical activity, activity intensity and step counts with incident cancer risk.MethodsProspective analysis of UK Biobank participants who wore wrist-based accelerometers for 7 days, followed for cancer incidence (mean follow-up 5.8 years, SD 1.3). Time-series machine-learning models derived total physical activity, sedentary behaviour (SB), light-intensity physical activity (LIPA), moderate-vigorous-intensity physical activity (MVPA) and step counts. The outcome was a composite of 13 cancers previously associated with low physical activity in questionnaire-based studies. Cox proportional hazard models estimated HRs and 95% CIs, adjusted for demographic, health and lifestyle factors. We also explored associations of LIPA, MVPA and SB with cancer risk.ResultsAmong 85 394 participants (median age 63 (IQR 56–68)), 2633 were diagnosed with cancer during follow-up. Compared with individuals in the lowest quintile of total physical activity (<21.6 milligravity units), those in the highest (34.3+) had a 26% lower cancer risk (HR=0.74 (95% CI 0.65 to 0.84)). After mutual adjustment, LIPA (HR=0.94 (95% CI 0.90 to 0.98)) and MVPA (HR=0.87 (95% CI 0.79 to 0.94)) were associated with lower risk, but SB was not. Similar associations were observed for substituting 1 hour/day of SB with LIPA or MVPA. Daily step counts were inversely associated with cancer, with the dose-response beginning to plateau at around 9 000 steps/day (HR=0.89 (95% CI 0.83 to 0.96) 7000 vs 5000 steps; HR=0.84 (95% CI 0.76 to 0.93) 9000 vs 5000 steps). There was no significant association between stepping intensity (peak 30-minute cadence) and cancer after adjusting for step count.ConclusionTotal physical activity, LIPA, MVPA and step counts were inversely associated with incident cancer.

Background: Vulval cancer predominantly affects postmenopausal women. A smaller proportion of vulval cancers, particularly at older ages, are now thought to be associated with human papillomavirus infection than previously reported, but other risk factors have not been well examined in prospective cohort studies. Methods: A total of 1.3 million women aged 49–65 years were followed for incident vulval cancer (ICD-10 C51). Adjusted Cox regression models were used to examine the relationship between reproductive and lifestyle factors and risk of vulval cancer. Results: There were 898 vulval cancers registered in the cohort over an average of 14 years of follow-up; 70% were squamous cell carcinomas. Past registration of cervical carcinoma in situ (RR 2.68; 95% CI 1.71–4.18; P <0.001), obesity (RR 1.71; 95% CI 1.44–2.04; P <0.0001), and menopause before the age of 50 years (RR 1.52; 95% CI 1.22–1.89; P <0.001) were associated with a significantly increased risk of subsequent vulval cancer. Conclusion: Past cervical pre-cancer, obesity, and earlier age at menopause are associated with an increased risk of vulval cancer at older ages.

Introduction/BackgroundThis report details the cases of two women – one in her 70s and one in her 80s - who developed unexplained cerebellar symptoms, which eventually led to the investigation and discovery of underlying gynaecologic malignancy in one, while the investigations for the second are still ongoing.Paraneoplastic Neurological Syndromes (PNS) describe a wide variety of conditions where neurological symptoms are indirectly caused by an underlying malignancy via immune-medicated pathogenesis. This is a rare presentation of malignancy and is extremely susceptible to misdiagnosis. One such PNS is paraneoplastic cerebellar ataxia, which is most often a result of gynaecologic cancer.MethodologyTwo patients were referred from their local or community hospitals to the neurology department of a large tertiary centre with ongoing neurological symptoms of unknown cause. They underwent surgical and histological investigation for underlying malignancyResultsOne patient was found to have Stage 1a serous type tubal malignancy. The second patient has been so far only found to have incidental hyperplasia with no malignancy.ConclusionPNS is a rare and often debilitating disorder caused by underlying malignancy, which may not have yet been diagnosed. Prompt recognition of PNS may lead to improved outcomes for patients due to early identification of malignancy. Further work is needed to promote understanding of PNS among clinicians and to develop guidelines to aid with diagnosis and correlation of the underlying malignancy.DisclosuresNone.