BackgroundVital 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.Methods and FindingsA 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.ConclusionsAnalysis 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.

Ovarian cancer risk is known to be reduced amongst women who have had children, but reported associations with breastfeeding are varied. Few studies have had sufficient power to explore reliably these associations by tumour histotype. In a prospective study of 1.1 million UK women, 8719 developed ovarian cancer during follow‐up. Cox regression yielded adjusted relative risks (RRs) overall and by tumour histotype amongst women with different childbearing patterns. Nulliparous women had a 24% greater ovarian cancer risk than women with one child, with significant heterogeneity by histotype (p = 0.01). There was no significant increase in serous tumours, a modest increase in mucinous tumours, but a substantial increase in endometrioid (RR = 1.49, 95% CI: 1.18‐1.89) and clear‐cell tumours (RR = 1.68, 1.29‐2.20). Among parous women, each additional birth was associated with an overall 6% reduction in ovarian cancer risk; this association also varied by histotype (p = 0.0006), with the largest reduction in risk for clear‐cell tumours (RR per birth = 0.75, 0.65‐0.85, p < 0.001) and weak, if any, effect for endometrioid, high‐grade serous, or mucinous tumours. We found little association with age at first or last birth. There was about a 10% risk reduction per 12‐months breastfeeding (RR = 0.89, 0.84‐0.94, p < 0.001), with no significant heterogeneity by histotype, but statistical power was limited. In this large prospective study, ovarian cancer risk associated with parity varied substantially by tumour histotype. Nulliparity was associated with a substantially greater overall risk than expected from the effect of a single birth, especially for clear cell and endometrioid tumours, perhaps suggesting that infertility is associated with these histotypes.

Histopathological and molecular studies suggest that different histological subtypes (histotypes) of ovarian cancer have different aetiologies. Few studies have been large enough to explore reliably the effect of tubal ligation (sterilization), which has been associated with a reduced overall risk of ovarian cancer, on different tumour histotypes. In a prospective study of 1.1 million UK women without prior cancer or bilateral oophorectomy, 8,035 ovarian cancers occurred during mean follow‐up of 13.8 years. Using a Cox proportional hazards model, we estimated adjusted relative risks of ovarian cancer associated with tubal ligation. Overall, there was substantial heterogeneity in tumour risk associated with tubal ligation for the four main histotypes, serous, endometrioid, mucinous and clear cell (heterogeneity: p < 0.0001). For serous tumours, the most common histotype (n = 3,515), risks differed significantly between high‐grade (RR: 0.77, 95% CI: 0.67–0.89) and low‐grade tumours (RR: 1.13, 95% CI: 0.89–1.42); heterogeneity: p = 0.007. Relative risks were almost halved for endometrioid (n = 690, RR: 0.54, 95% CI: 0.43–0.69) and clear cell tumours (n = 401, RR: 0.55, 95% CI: 0.39–0.77), but there was no association between tubal ligation and mucinous tumours (n = 836, RR: 0.99, 95% CI: 0.84–1.18). For the main tumour histotypes we found little variation of risk by timing of tubal ligation. The significant differences by tumour histotype are unlikely to be due to confounding and are consistent with hypotheses that high‐grade and low‐grade serous tumours have different origins, and that some endometrioid and clear cell tumours might arise from cells and/or carcinogens travelling through the fallopian tubes.

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.

A systematic review of the incidence of STICs in HGSOCs identifies significant methodological inconsistencies.

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.

Associations between behavioural and other personal factors and colorectal cancer risk have been reported to vary by tumour characteristics, but evidence is inconsistent. In a large UK‐based prospective study we examined associations of 14 postulated risk factors with colorectal cancer risk overall, and across three anatomical sites and four morphological subtypes. Among 1.3 million women, 18,518 incident colorectal cancers were identified during 13.8 (SD 3.4) years follow‐up via record linkage to national cancer registry data. Cox regression yielded adjusted relative risks. Statistical significance was assessed using correction for multiple testing. Overall, colorectal cancer risk was significantly associated with height, body mass index (BMI), smoking, alcohol intake, physical activity, parity and menopausal hormone therapy use. For smoking there was substantial heterogeneity across morphological types; relative risks around two or greater were seen in current smokers both for signet ring cell and for neuroendocrine tumours. Obese women were also at higher risk for signet ring cell tumours. For adenocarcinomas, the large majority of colorectal cancers in the cohort, all risk factor associations were weak. There was little or no heterogeneity in risk between tumours of the right colon, left colon and rectum for any of the 14 factors examined. These epidemiological findings complement an emerging picture from molecular studies of possible different developmental pathways for different tumour types.

Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40 kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p < 2−16), which was not found in patients without cancer (n = 108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n = 100), and common in BRCA1-BRCA2 mutation carriers (n = 71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.