Screening for gynecological cancers

An estimated 17% of all new cancers in women worldwide are due to cancers of the cervix, the ovary and the uterus. Together, these cancers account for 14.6% of all female cancer deaths. This is a significant societal and economic burden, which can be limited through cancer screening. In the developed world, marked reductions of 50-90% in disease rates have been observed as a result of cervical cancer screening. By contrast, in developing countries, where more than 85% of all new cases and deaths from this cancer are reported, significant challenges need to be overcome. Although cytology remains a key component of cervical screening, the newer molecular tests offer a more targeted, risk-attuned approach. The situation for the other two gynecological cancers is different. The case for ovarian cancer screening has yet to be made with the results of key screening trials in high-and low-risk populations still pending. Screening for endometrial cancer is traditionally not advocated as women become symptomatic during the earlier, treatable stages of disease. However, consideration of screening options for these two cancers is warranted since endometrial cancer rates are on the increase and in ovarian cancer, the high case:fatality ratio remains unchanged. © 2013 Expert Reviews Ltd

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial.

BACKGROUND: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. METHODS: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). INTERPRETATION: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. FUNDING: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal

Completeness and accuracy of national cancer and death registration for outcome ascertainment in trials—an ovarian cancer exemplar

BACKGROUND: There is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). METHODS: Of the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard). RESULTS: Outcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7-86.2%) and 94.0% (1679/1786; 95% CI 93.2-94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4-91.2%) and 96.7% (1482/1533, 95% CI 95.8-97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4-92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9-95.5%). Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered. CONCLUSION: Follow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses. TRIAL REGISTRATION: ISRCTN: ISRCTN22488978 . Registered on 6 April 2000

Diagnosis of epithelial ovarian cancer using a combined protein biomarker panel

BACKGROUND: An early detection tool for EOC was constructed from analysis of biomarker expression data from serum collected during the UKCTOCS. METHODS: This study included 49 EOC cases (19 Type I and 30 Type II) and 31 controls, representing 482 serial samples spanning seven years pre-diagnosis. A logit model was trained by analysis of dysregulation of expression data of four putative biomarkers, (CA125, phosphatidylcholine-sterol acyltransferase, vitamin K-dependent protein Z and C-reactive protein); by scoring the specificity associated with dysregulation from the baseline expression for each individual. RESULTS: The model is discriminatory, passes k-fold and leave-one-out cross-validations and was further validated in a Type I EOC set. Samples were analysed as a simulated annual screening programme, the algorithm diagnosed cases with >30% PPV 1–2 years pre-diagnosis. For Type II cases (~80% were HGS) the algorithm classified 64% at 1 year and 28% at 2 years tDx as severe. CONCLUSIONS: The panel has the potential to diagnose EOC one-two years earlier than current diagnosis. This analysis provides a tangible worked example demonstrating the potential for development as a screening tool and scrutiny of its properties. Limits on interpretation imposed by the number of samples available are discussed

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies

Objectives: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. / Design: Multicohort study with three sets of analyses. / Setting: United Kingdom, Europe, and the United States. / Participants: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. / Main outcome measures: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. / Results: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted β −0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted β −0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted β −0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. / Conclusions: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms

Apical and basolateral localisation of GLUT2 transporters in human lung epithelial cells

Glucose concentrations of normal human airway surface liquid are ~12.5 times lower than blood glucose concentrations indicating that glucose uptake by epithelial cells may play a role in maintaining lung glucose homeostasis. We have therefore investigated potential glucose uptake mechanisms in non-polarised and polarised H441 human airway epithelial cells and bronchial biopsies. We detected mRNA and protein for glucose transporter type 2 (GLUT2) and glucose transporter type 4 (GLUT4) in non-polarised cells but GLUT4 was not detected in the plasma membrane. In polarised cells, GLUT2 protein was detected in both apical and basolateral membranes. Furthermore, GLUT2 protein was localised to epithelial cells of human bronchial mucosa biopsies. In non-polarised H441 cells, uptake of d-glucose and deoxyglucose was similar. Uptake of both was inhibited by phloretin indicating that glucose uptake was via GLUT-mediated transport. Phloretin-sensitive transport remained the predominant route for glucose uptake across apical and basolateral membranes of polarised cells and was maximal at 5–10 mM glucose. We could not conclusively demonstrate sodium/glucose transporter-mediated transport in non-polarised or polarised cells. Our study provides the first evidence that glucose transport in human airway epithelial cells in vitro and in vivo utilises GLUT2 transporters. We speculate that these transporters could contribute to glucose uptake/homeostasis in the human airway

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Background Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS. Methods In this randomised controlled trial, postmenopausal women aged 50–74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032. Findings Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1–17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (−41·8 to –2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (−21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group. Interpretation The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended. Funding National Institute for Health Research, Cancer Research UK, and The Eve Appeal

The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use

Ketamine was originally synthesised for use as a dissociative anaesthetic, and it remains widely used legitimately for this indication. However, there is increasing evidence of non-medical recreational use of ketamine, particularly in individuals who frequent the night-time economy. The population-level and sub-population (clubbers) prevalence of recreational use of ketamine is not known but is likely to be similar, or slightly lower than, that of other recreational drugs such as cocaine, MDMA, and amphetamine

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings