Search

Background To evaluate outcomes of laparoscopic retroperitoneal para-aortic lymphadenectomy for stage 1b3-3b cervical cancer.Methods Pathology databases searched for all para-aortic lymphadenectomy cases 2005–2016. Descriptive statistics were used to analyse baseline characteristics, cox models for treatment affect after accounting for variables, and Kaplan Meier curves for survival (STATA v15).Results 191 patients had 1b3-3b cervical cancer of which 110 patients had Para-aortic lymphadenectomy. 8 (7.3%) patients stage 1b3, 82 (74.6%) stage 2b, and 20 (18.1%) stage 3b cervical cancer. Mean lymph node count 11.7 (SD7.6). The intra-operative and post-operative 30 day complication rates were 8.8% (CI: 4.3%, 15.7%) and 5.3% (CI: 1.9%, 11.2%) respectively.Para-aortic nodes were apparently positive on CT/MRI in 5/110 (5%) cases. Cancer was found in 10 (8.9%, CI: 4.3%, 15.7%) cases on histology, all received extended field radiotherapy. Only 2 were identified on pre-operative CT/MRI imaging. 3 of 10 suspected node-positive cases on CT/MRI had negative histology. Para-aortic lymphadenectomy led to alteration in staging and radiotherapy management in 8 (8%, CI: 3.7%, 14.6%) patients. Mean overall survival 42.81 months (SD = 31.79 months). Survival was significantly higher for women undergoing PAN (50.57 (SD 30.7) months) compared to those who didn’t (31.27 (SD 32.5) months)Conclusion Laparoscopic retroperitoneal para-aortic lymphadenectomy is an acceptable procedure which can guide treatment in women with locally advanced cervical cancer.

Early diagnosis and screening of ovarian cancer remain significant challenges to improving patient outcomes. There is an urgent need to implement both established and modern strategies to address the “early detection” conundrum, especially as new research continues to uncover the complexities of the disease. The discussion provided is the result of a unique research conference focused on reviewing early detection modalities and providing insight into future approaches.

Abstract Background Ovarian cancer is the most lethal of all gynecological cancers. Cancer Antigen 125 (CA125) is the best‐performing ovarian cancer biomarker which however is still not effective as a screening test in the general population. Recent literature reports additional biomarkers with the potential to improve on CA125 for early detection when using longitudinal multimarker models. Methods Our data comprised 180 controls and 44 cases with serum samples sourced from the multimodal arm of UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Our models were based on Bayesian change‐point detection and recurrent neural networks. Results We obtained a significantly higher performance for CA125–HE4 model using both methodologies (AUC 0.971, sensitivity 96.7% and AUC 0.987, sensitivity 96.7%) with respect to CA125 (AUC 0.949, sensitivity 90.8% and AUC 0.953, sensitivity 92.1%) for Bayesian change‐point model (BCP) and recurrent neural networks (RNN) approaches, respectively. One year before diagnosis, the CA125–HE4 model also ranked as the best, whereas at 2 years before diagnosis no multimarker model outperformed CA125. Conclusions Our study identified and tested different combination of biomarkers using longitudinal multivariable models that outperformed CA125 alone. We showed the potential of multivariable models and candidate biomarkers to increase the detection rate of ovarian cancer.

Summary: This Viewpoint presents an overview of trials methodology research (TMR) and the case for investing in TMR in India. Randomised controlled trials and other types of clinical research inform evidence-based medicine, but this endeavour is dependent on the quality of such research. TMR is aimed at improving the way in which clinical trials are designed, conducted, analysed, and reported. The evolution of TMR in countries like the UK has been nurtured through dedicated funding support. Similar funding opportunities for TMR in India will help optimise the ethical and methodological rigour of the growing number of trials conducted in India. Such funding could help initiate an interdisciplinary network of key stakeholders in India to lead on TMR priority-setting exercises so that methodological questions of relevance to India are addressed. The establishment of trials methodology hubs will enhance initiatives such as the disease-specific clinical trials networks being set up as part of the National Biopharma Mission in India. We posit that promoting and establishing TMR as a distinct field of study in India will ensure the improvement of our health research ecosystem and call on national and international funding bodies to initiate consultation, consensus building and ringfenced funding for TMR in India.

Background: Cancer is the leading cause of death for Southeast Asian women in the U.S. Southeast Asian women have significantly high rates of breast and cervical cancers, yet are least likely to obtain regular mammography and Pap testing of all racial/ethnic groups in the U.S. Objectives: The purpose of this study is to compare a tailored navigation intervention delivered by bilingual and bicultural Community Health Advisors to information and reminder only to increase age-appropriate breast and cervical cancer screening completion among Southeast Asian women. Methods: The Southeast Asian Women's Health Project study will enroll 232 Cambodian, Filipino, Lao, and Vietnamese women who are not up to date with their breast and cervical cancer screenings. Women randomized to navigation will receive the intervention for 10 weeks. Women in the information group will be mailed information on mammography and Pap testing only. All participants will be contacted post-enrollment to assess screening completion. Discussion: We will examine intervention efficacy, predictors of each intervention group, and the influence of intergenerational exchange of breast and cervical cancer screening information between mothers and daughters. We will disseminate study results locally to the community, nationally at conferences, and through peer-reviewed journals.

Abstract Background Despite the dramatic increase in opioid-related deaths in recent years, global access to treatment remains poor. A major barrier to people accessing Medication-assisted treatment of the opioid use disorder (MOUD) is the lack of providers who can prescribe and monitor MOUD. According to the World Drug Report, more young people are using drugs compared with previous generations and people in need of treatment cannot get it, women most of all. Nurse prescribers have the potential to enhance both access and treatment outcomes. Nurse prescribing practices do, however, vary greatly internationally. The aim of this scoping review is to explore nurse prescribing practices for MOUD globally with a view to informing equitable access and policies for people seeking MOUD. Methods This scoping review was informed by the preferred reporting items for systematic reviews and meta-analysis extension for scoping reviews (PRISMA-ScR). Electronic searches from 2010 to date were conducted on the following databases: PsycInfo, PubMed, Embase, and CINAHL. Only studies that met the eligibility criteria and described nurse prescribing policies and/or behaviours for MOUD were included. Results A total of 22 articles were included in the review which found several barriers and enablers to nurse prescribing of MOUD. Barriers included legislation constraints, lack of professional education and training and the presence of stigmatizing attitudes. Enablers included the presence of existing supportive services, prosocial messaging, and nurse prescriber autonomy. Conclusion The safety and efficacy of nurse prescribing of MOUD is well established, and its expansion can provide a range of advantages to people who are dependent on opiates. This includes increasing access to treatment. Nurse prescribing of MOUD can increase the numbers of people in treatment from ‘hard to reach’ cohorts such as rural settings, or those with less financial means. It holds significant potential to reduce a wide range of harms and costs associated with high-risk opiate use. To reduce drug-related death and the global burden of harm to individuals, families, and communities, there is an urgent need to address the two key priorities of nurse prescriber legislation and education. Both of which are possible given political and educational commitment.

Abstract Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q

Nené et al. construct machine learning models based on serum protein biomarker data to detect pancreatic ductal adenocarcinoma in a nested case-control study from the UKCTOCS cohort. Their ensemble modelling approach outperforms existing combinations of biomarkers.

Abstract Background Sexual wellbeing is a critical yet often overlooked aspect of overall wellbeing for women across cancer diagnoses. Objective We identified profiles of women cancer survivors by sexual and psychosocial outcomes and compared groups for differences in relevant outcomes and individual characteristics. Methods Partnered women treated for cancer (n = 226; M age = 51.1 (12.6); 54% breast cancer; 86% White) completed a cross-sectional survey assessing sexual and psychosocial wellbeing. K-means cluster analysis modeled subgroups (clusters) with similar response patterns on measures of sexual wellbeing (sexual function, distress, sexual communication, and self-efficacy for communication), psychosocial wellbeing (quality of life (QOL), anxiety and depressive symptoms), and time since treatment. ANOVAs with Tukey post-hoc analyses and chi-square analyses tested cluster mean differences. Results Three distinct clusters of women differed by levels of adjustment in sexual and psychosocial wellbeing: higher-adjustment (32.7%), intermediate (37.6%), and lower-adjustment (29.6%). Significant differences among the clusters were found for all outcomes, with largest effect sizes for sexual distress (η2 p = 0.66), sexual communication (η2 p = 0.51), sexual satisfaction (η2 p = 0.44), and anxiety and self-efficacy for communication (η2 p = 0.32). The intermediate adjustment group was characterized by lower adjustment on measures of sexual and relationship function, and better adjustment on measures of QOL and mood. Conclusions Findings suggest that for women cancer survivors, measures of sexual and psychosocial wellbeing can model distinct profiles to inform targeted interventions to meet women’s needs. Evidence-based targeted interventions could lead to better sexual function, and ultimately to better QOL and overall wellbeing. Implications for practice A stepped intervention approach to sexual health care for women with cancer, where content and format depend on degree of sexual and psychosocial adjustment after cancer, may be most appropriate. Interdisciplinary teams may address sexual, emotional, and relationship functioning.

Abstract Introduction Genomic/precision medicine offers a remarkable opportunity to improve health and address health disparities. Genomic medicine is the study of genes and their interaction with health. Precision medicine is an approach to disease prevention and treatment that considers individual variability in genes, environment and lifestyle. Conclusions from studies lacking diversity may hinder generalizability as genomic variation occurs within and between populations. Historical factors, such as medical mistrust, ethical issues related to decision making, and data sharing pose complex challenges that may further widen inequities in genomic/precision medicine if not appropriately addressed. Although few biomedical studies integrate priorities of community partners into their conceptual framework, effective implementation of genomic/precision medicine research calls for the involvement of diverse stakeholders to expand traditional unidirectional models of engagement in clinical research towards authentic bidirectional collaboration. Methods A multipronged approach was used integrating an evidence‐based literature review and best practices in developing and evaluating the engagement of diverse stakeholders in genomic and precision medicine research. This was combined with expert consensus building to adapt a conceptual model from a community engagement framework to addressing genomics to be scalable to engagement science, which is challenging to genomic/precision medicine research. Results The final enhanced conceptual framework is composed of four overarching dimensions now inclusive of domains in trust, exploitation, discrimination, privacy risk, stigmatization, prior harms/injustices, failure to recognize coexisting governments, intersectionality and research transformation. This conceptual framework proposes effective participant research engagement strategies for upstream relationship building, distinct from downstream recruitment strategies in which the goal is enrolment. Conclusion To further shape the evolution of genomic/precision medicine research, it is important to leverage existing partnerships, engage participants beyond recruitment and embrace diverse perspectives. Patient or Public Contribution In preparation of this manuscript, the perspectives of the community partners on the impact of engaging in genomic/precision medicine research beyond research participation were integrated into this conceptual framework from various guided listening sessions held in diverse communities.

Background and Objective: High-quality prenatal care promotes adequate care throughout pregnancy by increasing patients’ desires to return for follow-up visits. Almost 15% of women in the United States receive inadequate prenatal care, with 6% receiving late or no prenatal care. Only 63% of pregnant women in Florida receive adequate prenatal care, and little is known about their perceptions of high-quality prenatal care.Therefore, the objective of this study was to assess women’s perceptions of the quality of their prenatal care and to describe their preferences for seeking prenatal care that meets their needs. Methods: From April to December 2019, a qualitative study was conducted with postpartum women (n = 55) who received no or late prenatal care and delivered in Tampa, Florida, USA. Eligible women completed an open-ended qualitative survey and a semi-structured in-depth interview. The interview contextualized the factors influencing prenatal care quality perceptions.The qualitative data analysis was based on Donabedian’s quality of care model. Results: The qualitative data analysis revealed three key themes about women’s perceptions and preferences for prenatal care that meets their needs. First, clinical care processes included provision of health education and medical assessments. Second, structural conditions included language preferences, clinic availability, and the presence of ancillary staff. Finally, interpersonal communication encompassed interactions with providers and continuity of care. Overall, participants desired patient-centered care and care that was informative, tailored to their needs, and worked within the constraints of their daily lives. Conclusion and Global Health Implications: Women seeking and receiving prenatal care prefer a welcoming, patient-centered health care environment. These findings should prompt health care providers and organizations to improve existing prenatal care models and develop new prenatal care models that provide early, accessible, and high-quality prenatal care to a diverse population of maternity patients. Copyright © 2023 Fryer et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY 4.0.

Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Abstract Background American Indians (AI) experience major colorectal cancer (CRC) screening disparities with commensurate inequity in CRC mortality and other outcomes. The purpose of this report is to describe the methods and early results of adapting a previously successful intervention for the AI community. Methods The educational content and delivery strategy of the parent intervention were adapted for AIs guided by an adaptation framework and cultural consultations with the community and clinicians. As part of the environmental scanning, we identified the need to substantively revise our data entry, collection, and tracking system and develop a REDCap database for this purpose. In this study, we staggered the implementation of the intervention in each facility to inform the process from one clinic to the next, and assess both the clinical outcomes of the tailored intervention and the implementation processes across two clinic settings, Facilities A and B. Results The REDCap database is an indispensable asset, and without it we would not have been able to obtain reliable aggregate screening data while improvements to facility electronic health records are in progress. Approximately 8% (n = 678) of screening-eligible patients have been exposed to the navigator intervention. Of those exposed to the navigator intervention, 37% completed screening. Conclusions With the small numbers of patients exposed so far to the intervention, it would be premature to draw any broad conclusions yet about intervention effects. However, early screening completion rates are substantial advances on existing rates, and we have demonstrated that a tailored navigator intervention for facilitating CRC screening was readily adapted with provider and community input for application to AIs. A REDCap database for tracking of CRC screening by navigators using tablets or laptops on- or offline is easy to use and allows for generation of aggregate, anonymized screening data. Trial registration. There was no health intervention meeting the criteria of a clinical trial. The University of Arizona Institutional Review Board granted exemption from obtaining informed consent from patients undergoing CRC screening after administration of the tailored navigation intervention as usual care.

Firefighters are exposed to occupational hazards and have a higher prevalence of health issues. The gut microbiota plays a crucial role in the immune, endocrine, and neural systems, and disruptions in its composition can impact health outcomes. This pilot study aimed to investigate the potential association between occupational factors, changes in gut microbiota, and the development of adverse health outcomes in firefighters. To test this hypothesis, we recruited 15 firefighters and age/sex-matched controls to investigate the relationship between occupational environment and gut microbiota. Firefighters exhibit lower intestinal bacterial alpha diversity and a higher presence of pathogenic bacteria than the control. Moreover, unique gut bacterial taxa were observed in firefighters with high post-traumatic stress disorder (PTSD) scores, which could contribute to immune dysregulation and higher susceptibility to pathogen colonization. These preliminary findings suggest that occupational factors, including exposure to traumatic stressors and chemicals, may influence firefighters’ health by modulating their gut microbiota. The observed changes in gut microbiota composition and the potential link to occupational hazards highlight the need for further research in larger sample-size studies. Understanding the role of gut microbiota in firefighter health may have implications for preventive measures and interventions to mitigate occupational health risks and improve overall well-being.

Objectives A growing body of evidence suggests longer time between symptom onset and start of treatment affects breast cancer prognosis. To explore this association, the International Cancer Benchmarking Partnership Module 4 examined differences in breast cancer diagnostic pathways in 10 jurisdictions across Australia, Canada, Denmark, Norway, Sweden and the UK.Setting Primary care in 10 jurisdictions.Participant Data were collated from 3471 women aged >40 diagnosed for the first time with breast cancer and surveyed between 2013 and 2015. Data were supplemented by feedback from their primary care physicians (PCPs), cancer treatment specialists and available registry data.Primary and secondary outcome measures Patient, primary care, diagnostic and treatment intervals.Results Overall, 56% of women reported symptoms to primary care, with 66% first noticing lumps or breast changes. PCPs reported 77% presented with symptoms, of whom 81% were urgently referred with suspicion of cancer (ranging from 62% to 92%; Norway and Victoria). Ranges for median patient, primary care and diagnostic intervals (days) for symptomatic patients were 3–29 (Denmark and Sweden), 0–20 (seven jurisdictions and Ontario) and 8–29 (Denmark and Wales). Ranges for median treatment and total intervals (days) for all patients were 15–39 (Norway, Victoria and Manitoba) and 4–78 days (Sweden, Victoria and Ontario). The 10% longest waits ranged between 101 and 209 days (Sweden and Ontario).Conclusions Large international differences in breast cancer diagnostic pathways exist, suggesting some jurisdictions develop more effective strategies to optimise pathways and reduce time intervals. Targeted awareness interventions could also facilitate more timely diagnosis of breast cancer.

Background: Low awareness of BC and its associated risk factors causes delays in diagnosis and impacts survival. It is critical to communicate BC risk to patients in a format that they are easily able to understand. Our study aim was to develop easy-to-follow transmedia prototypes to communicate BC risk and evaluate user preferences, alongside exploring awareness of BC and its risk factors. Methods: Prototypes of transmedia tools for risk communication were developed with multidisciplinary input. A qualitative in-depth online interview study was undertaken using a pre-defined topic guide of BC patients (7), their relatives (6), the general public (6), and health professionals (6). Interviews were analyzed using a thematic approach. Findings: Most participants preferred pictographic representations (frequency format) of lifetime risk and risk factors and storytelling using short animations and comic strips (infographics) for communicating genetic risk and testing: “In a short time, they explained it very well, and I liked it”. Suggestions included minimizing technical terminology, decreasing the delivery speed, “two-way dialogue”, and using local “language for different locations”. There was low awareness of BC, with some understanding of age and hereditary risk factors but limited knowledge of reproductive factors. Interpretation: Our findings support use of multiple context-specific multimedia tools in communicating cancer risk in an easy-to-understand way. The preference for storytelling using animations and infographics is a novel finding and should be more widely explored.

Abstract Background During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model. Methods We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001–2020) using the Cox model (2014), (B) new data (2015–2020) only and (C) all data (2001–2020) using a test that allows for delayed effects. Results Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years. Conclusions The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials. Trial registration ISRCTN22488978 . Registered on 6 April 2000.

Abstract 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

Summary: Background: Screening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM. Methods: Using mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation. Findings: Of 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM. Interpretation: Adiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM. Funding: North West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK.

Clinical trials and cohort studies are required to meet target recruitment of study participants within stipulated timelines, especially when the priority is to include populations traditionally unrepresented in biomedical research. By the third quarter of 2019, the University of Arizona‐Banner Health Provider Organization (UA‐Banner HPO) has enrolled > 30,000 core participants into the All of Us Research Program (AoURP), the research cohort of the Precision Medicine Initiative. The majority of enrolled participants meet the criteria for individuals under‐represented in biomedical research. The enrollment goals were calculated based on a target of 20,000 as set by the National Institutes of Health and our health provider organization achieved enrollment numbers between 17% and 86% above the targeted daily enrollment. We evaluated enrollment methods and challenges to enrollments encountered by the UA‐Banner Health Provider Organization into the AoURP. Challenges to enrollment centered around the need for high‐touch engagement methods, time investment necessary for stakeholder inclusion, and the use of purely digital enrollment methods especially in populations under‐represented in biomedical research. These challenges occurred at the level of the individual, provider, institutions, and community, and cumulatively impacted participant enrollment. Successful strategies for engagement and enrollment leveraged provider partners as advocates for the program. For high‐volume enrollment in clinical research, it is important to engage leaders in the healthcare setting, patient providers, and tailor engagement and enrollment to potential participant needs. We emphasize the need for precision engagement and enrollment methods tailored to individual needs.

Abstract Background Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). The aim of this study was to estimate the association between the Enhanced Liver Fibrosis (ELF) test and liver-related events (LRE) and its performance in predicting LRE in postmenopausal women with risk factors in a nested case-control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). Methods In a cohort of 95,126 we performed a case-control study measuring ELF in blinded samples from 173 participants with self-reported high alcohol use and / or BMI ≥25 kg/m2 comprising all 58 cases who developed LRE and 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8.5 years. Results Using Cox regression at an ELF threshold of 10.51 hazard ratios (HR) for LRE were 4.88 (95% confidence interval (CI) 2.37–10.03) (unadjusted model) and 4.62 (95% CI 2.12–10.08) (adjusted for deprivation and self-reported hypertension, heart disease, hypercholesterolaemia and diabetes). At a threshold of 9.8 HR for LRE were 2.21 (95% CI 1.22–3.97) (unadjusted model) and 2.18 (95% CI 1.19–4.01) (adjusted). ELF was evaluated as a time dependent variable by generating time-dependent Cox models; HRs at an ELF threshold of 10.51 were 1.94 (95% CI 1.10–3.39) (unadjusted) and 2.05 (95% CI 1.16–3.64) (adjusted) and at a threshold of 9.8 HRs were 1.85 (95% CI 1.09–3.15) (unadjusted) and 1.80 (95% CI 1.04–3.13) (adjusted). Area under the receiver operating characteristic curve for recruitment ELF predicting LRE was 0.58 (95% CI 0.49–0.68), and for second subsequent ELF 0.61 (95% CI 0.52–0.71). Conclusion This study demonstrates the association between ELF and CLD in postmenopausal women with risk factors for liver disease, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the potential of ELF as a prognostic tool in health checks in primary care. Trial registration This study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000.

Background and Aims: Liver transplantation has become an effective therapy for patients with end-stage liver disease. The risk of new-onset diabetes after transplantation (NODAT) and posttransplant metabolic syndrome (PTMS) is high among patients after liver transplantation. These are thought to be associated with increased risks of graft rejection, infection, cardiovascular disease, and death. Our study aimed to document the incidence of NODAT and PTMS and analyze pre and posttransplant predictive factors for their development in patients undergoing a liver transplant. Methods: This was a prospective comparative study on 51 patients who underwent live donor liver transplantation. They were evaluated at baseline, 3 and 6 months after transplantation with fasting glucose, lipids, serum insulin levels, C-peptide, and HbA1C. They were followed up at 5 years to document any cardiovascular events or rejection. Results: The incidence of preoperative diabetes mellitus (DM) in the study group was 25/51 (49%). The incidence of NODAT was 38.5% (10/26 patients) and PTMS 29% (10/35), respectively. Age (47.7 ± 5.4 vs 41.5 ± 12.7 years), HOMA2 -IR (2.3 ± 1.8 vs 2.1 ± 1.6), serum insulin (16.1 ± 12.0 vs 17.9 ± 14.5), and C-peptide (4.6 ± 0.5 vs 4.8 ± 0.7) were similar at baseline in the NODAT group compared to those who did not develop it. Mean tacrolimus levels were higher in PTMS group (6.8 ± 2.9 vs 5.0. ± 2.0 P value = 0.042). By the end of 5 years, 7 patients expired; 6 due to rejection and one due to cardiovascular disease. Moreover, 2 of these patients had preexisting DM and 2 had NODAT. Conclusions: None of the baseline metabolic factors in patients undergoing liver transplant were predictive of the development of NODAT or PTMS. Mean tacrolimus levels were significantly higher in the PTMS group. A 5-year follow-up showed no excess risk of cardiovascular events or rejection in those with preexisting DM or in those who developed NODAT.

Context: Medullary thyroid carcinoma (MTC), being an aggressive disease, requires meticulous follow-up and multidisciplinary management. The clinical presentation, management, outcome of MTC varies among different populations. Aims: An audit was conducted to evaluate the demography, clinical presentation, management, and outcome of MTC in a tertiary care center in South India. Settings and Design: A retrospective analysis was conducted of data from hospital records of patients with MTC treated at our center from 2004 to 2019. Statistical Analysis: All analyses were performed with SPSS software (version 16). Results: Among the 82 patients (M 42, F 40), mean age was 42.07 years (SD 14.5), 46 were operated at our center and 36, outside. Follow-up data were not available for all patients. Median duration of the disease was 36 months and median follow-up was 28 months. Lymphnode dissection was more common (37/46) in patients operated at our center than outside operated patients (17/36) (P < 0.01). At presentation, more than half of the patients had stage IV disease and 8 had distant metastases. Bone, lung, and liver were the common sites of metastases. Persistent hypercalcitoninemia >50 pg/mL was seen in 49.9%. Salvage surgeries of the neck were necessary in 29 patients (38.2%). Mean survival was 66 months and 10-year survival was 35%. Male gender (P = 0.008) and Stage IV disease at presentation (P = 0.038) were associated with poorer survival. Conclusion: MTC, in our population, presented at an advanced stage. Male gender and stage IV at presentation had poor survival. Early diagnosis, aggressive initial neck clearance, close follow-up with tumor markers, appropriate imaging, along with prompt surgical intervention will help to improve outcome.

Abstract Across the world, there has been a movement from traditional to modern eating, including a movement of traditional eating patterns from their origin culture to new cultures, and the emergence of new foods and eating behaviors. This trend toward modern eating is of particular significance because traditional eating has been related to positive health outcomes and sustainability. Yet, there is no consensus on what constitutes traditional and modern eating. The present study provides a comprehensive compilation of the various facets that seem to make up traditional and modern eating. Specifically, 106 facets were mentioned in the previous literature and expert discussions, combining international and interdisciplinary perspectives. The present study provides a framework (the TEP10 framework) systematizing these 106 facets into two major dimensions, what and how people eat, and 12 subdimensions. Hence, focusing only on single facets of traditional and modern eating is an oversimplification of this complex phenomenon. Instead, the multidimensionality and interplay between different facets should be considered to gain a comprehensive understanding of the trends, consequences, and underlying factors of traditional and modern eating.

AbstractIntroduction:Although the science of team science is no longer a new field, the measurement of team science and its standardization remain in relatively early stages of development. To describe the current state of team science assessment, we conducted an integrative review of measures of research collaboration quality and outcomes.Methods:Collaboration measures were identified using both a literature review based on specific keywords and an environmental scan. Raters abstracted details about the measures using a standard tool. Measures related to collaborations with clinical care, education, and program delivery were excluded from this review.Results:We identified 44 measures of research collaboration quality, which included 35 measures with reliability and some form of statistical validity reported. Most scales focused on group dynamics. We identified 89 measures of research collaboration outcomes; 16 had reliability and 15 had a validity statistic. Outcome measures often only included simple counts of products; publications rarely defined how counts were delimited, obtained, or assessed for reliability. Most measures were tested in only one venue.Conclusions:Although models of collaboration have been developed, in general, strong, reliable, and valid measurements of such collaborations have not been conducted or accepted into practice. This limitation makes it difficult to compare the characteristics and impacts of research teams across studies or to identify the most important areas for intervention. To advance the science of team science, we provide recommendations regarding the development and psychometric testing of measures of collaboration quality and outcomes that can be replicated and broadly applied across studies.

Abstract An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Abstract Background To address an urgent need to advance the field of community engaged research, faculty at Vanderbilt University Medical Center and Meharry Medical College organized the national meeting "Advancing the Science of Community Engaged Research (CEnR): Innovative & Effective Methods of Stakeholder Engagement in Translational Research, Washington, DC September 14-15, 2017 (See Additional file 1). These meetings brought together a diverse group of stakeholders to share community engaged research evidence and practical knowledge for implementing new and enhancing existing research programs. The conference series’ goals were: 1) to expand the scientific basis for the community engaged research field by convening researchers, community partners, patient advocacy organizations, and others to share innovative methods and strategies; 2) to engage community representatives and patient advocates in the development of new approaches in community engaged research by meaningfully involving them in the planning, as speakers and presenters, and as conference participants; and 3) to catalyze innovative community engaged research using interactive meeting methods that promote learning, support collective problem solving, and encourage new conceptual frameworks. These conferences have advanced community engagement across the translational research spectrum in biomedical research. For the 2017 meeting, described here, the overarching theme was Innovative and Effective Methods of Stakeholder Engagement in Translational Research. Methods The forum was attended by over 210 participants. This conference used novel approaches to fulfill its objectives of participant diversity, meaningful stakeholder engagement, and eliciting varied distinct perspectives to advance the science of community engaged research. Innovative strategies for the conference included: Think Tanks focused on emerging community engaged research topics or topics in need of urgent attention. These dynamic group sessions provided for freely sharing ideas with the purpose of creating change and facilitating new research collaborations. Learning Labs offered unique opportunities to gain practical knowledge regarding innovative methods in community engaged research. Learning Labs also facilitated the wide broadcast of locally successful engagement methods with the goal of speeding the uptake and implementation of community engaged methods. Travel Scholarships were provided for twenty community and patient representatives to participate in the conference. The lack of travel funds was a significant barrier to stakeholder participation in prior community engaged research meetings. The scholarships expanded the role of community and patient representatives in setting research priorities and promoting methods development. Meaningful Engagement meant that community members and patients participated in decision making on all aspects of the conference planning, including the selection of themes, topics, and speakers, and were fully integrated into the conference as speakers, panelists, and moderators. Conclusions Community and stakeholder engagement can directly impact research by enhancing clinical trial design, increasing relevance, and increasing recruitment, accrual and retention (Staley K.: Exploring Impact: Public 53 Involvement in NHS, Public Health and Social Care Research – INVOLVE.; 2009, Johnson et al Clin Transl Sci 8:388-54 390, 2015, Joosten et al Acad Med 90:1646-1650, 2015). The 2017 Advancing the Science of Community Engaged Research meeting, Innovative and Effective Methods of Stakeholder Engagement in Translational Research facilitated meaningful engagement of diverse stakeholder groups including racial and ethnic minorities, community and patient representatives, and junior investigators. Of 210 attendees, 72 completed the evaluation, and, of those, 36% self-affiliated as community members, and 21% as patient/caregiver advocacy, faith-based, or tribal organization members. This conference 1) represented a step toward expanding the scientific basis for the community engaged research (CEnR) field; 2) catalyzed innovative community engaged research; and 3) enhanced the reach and impact of the scientific developments emerging from pioneering work in community engagement.

Background: Klinefelter syndrome (KFS) is the commonest chromosomal abnormality, yet remains largely underdiagnosed due to its varied clinical presentation. This study was done to understand the clinical spectrum in our population. Aim: We intended to study the clinical characteristics of children and adults with KFS in our population. We also desired to identify any special features of Klinefelter variants. Methods: Forty-four patients with karyotype diagnosis of KFS during the time period 2007-2015 were included in this retrospective study. Clinical details and hormonal profile were obtained from hospital information system. Results: Our study population consisted of 17 (38.6%) participants in pediatric age group (age

Background: Prediction of outcome in diabetic foot infection (DFI) remains difficult due to lack of active signs of infection, and apparently normal white blood cell (WBC) count. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have been studied previously in this regard and were not useful. Hence, we evaluated procalcitonin (PCT) as a prognostic marker in this study. Objectives: We aimed to study the role of PCT, CRP, and ESR levels in predicting clinical outcome of acute DFI. Materials and Methods: A total of 250 subjects (197 men, 53 women) with acute DFI were enrolled. WBC count, ESR, CRP, and PCT were done for all subjects at admission after obtaining informed consent. Subjects were managed according to hospital protocol and followed up for 1 month. Clinical outcome was assessed based on mobility and morbidity status of the subject. Results: Old age, anemia, hyponatremia, hypoalbuminemia, and elevated serum creatinine were risk factors for poor outcome. Presence of cardiac failure, diabetic retinopathy, peripheral vascular disease, previous amputations, and positive bone culture had negative influence on clinical outcome. Elevated WBC count, ESR, CRP, and serum PCT were significantly associated with bad outcome. Elevated PCT (>2 ng/ml) [odds ratio (OR) (95% confidence interval (CI)), 2.03 (1.13–5.19), P < 0.001], gangrene [OR (95% CI), 2.2 (1.02–4.73), P = 0.04], and sepsis [OR (95% CI), 10.101 (4.34–23.25), P < 0.001] were good predictors of clinical outcome in acute DFI. Conclusion: PCT proved to be a reliable marker of acute DFI and good predictor of clinical outcome than existing markers WBC count, ESR, and CRP. Hence it should be useful for clinicians while managing acute DFI.

Unselected population-based personalised ovarian cancer (OC) risk assessments combining genetic, epidemiological and hormonal data have not previously been undertaken. We aimed to understand the attitudes, experiences and impact on the emotional well-being of women from the general population who underwent unselected population genetic testing (PGT) for personalised OC risk prediction and who received low-risk (

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual‐participant data meta‐analysis of 5 UK‐based cohorts and 1 matched case‐control study. Fatty acids (ie, omega‐3 docosahexaenoic acid, omega‐6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high‐throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76–0.95 per standard unit of docosahexaenoic acid), there was evidence of high between‐study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75–0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03–1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82–1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.

Abstract Background In the absence of routine ovarian cancer screening, promoting help-seeking in response to ovarian symptoms is a potential route to early diagnosis. The factors influencing women’s anticipated time to presentation with potential ovarian cancer symptoms were examined. Methods Cross-sectional questionnaires were completed by a sample of women at increased familial risk (n = 283) and population risk (n = 1043) for ovarian cancer. Measures included demographic characteristics, symptom knowledge, anticipated time to symptom presentation, and health beliefs (perceived susceptibility, worry, perceived threat, confidence in symptom detection, benefits and barriers to presentation). Structural equation modelling was used to identify determinants of anticipated time to symptomatic presentation in both groups. Results Associations between health beliefs and anticipated symptom presentation differed according to risk group. In increased risk women, high perceived susceptibility (r = .35***), ovarian cancer worry (r = .98**), perceived threat (r = −.18**), confidence (r = .16**) and perceiving more benefits than barriers to presentation (r = −.34**), were statistically significant in determining earlier anticipated presentation. The pattern was the same for population risk women, except ovarian cancer worry (r = .36) and perceived threat (r = −.03) were not statistically significant determinants. Conclusions Associations between underlying health beliefs and anticipated presentation differed according to risk group. Women at population risk had higher symptom knowledge and anticipated presenting in shorter time frames than the increased risk sample. The cancer worry component of perceived threat was a unique predictor in the increased risk group. In increased risk women, the worry component of perceived threat may be more influential than susceptibility aspects in influencing early presentation behaviour, highlighting the need for ovarian symptom awareness interventions with tailored content to minimise cancer-related worry in this population.

Abstract Background Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. Methods We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. Results A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC. Conclusions Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent.

Abstract Background Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence. Methods We analyzed 699 cancerous and non-cancerous tissues using a methylation array or reduced representation bisulfite sequencing to discover the most specific OC methylation patterns. A three-DNA-methylation-serum-marker panel was developed using targeted ultra-high coverage bisulfite sequencing in 151 women and validated in 250 women with various conditions, particularly in those associated with high CA125 levels (endometriosis and other benign pelvic masses), serial samples from 25 patients undergoing neoadjuvant chemotherapy, and a nested case control study of 172 UKCTOCS control arm participants which included serum samples up to two years before OC diagnosis. Results The cell-free DNA amount and average fragment size in the serum samples was up to ten times higher than average published values (based on samples that were immediately processed) due to leakage of DNA from white blood cells owing to delayed time to serum separation. Despite this, the marker panel discriminated high grade serous OC patients from healthy women or patients with a benign pelvic mass with specificity/sensitivity of 90.7% (95% confidence interval [CI] = 84.3–94.8%) and 41.4% (95% CI = 24.1–60.9%), respectively. Levels of all three markers plummeted after exposure to chemotherapy and correctly identified 78% and 86% responders and non-responders (Fisher’s exact test, p = 0.04), respectively, which was superior to a CA125 cut-off of 35 IU/mL (20% and 75%). 57.9% (95% CI 34.0–78.9%) of women who developed OC within two years of sample collection were identified with a specificity of 88.1% (95% CI = 77.3–94.3%). Sensitivity and specificity improved further when specifically analyzing CA125 negative samples only (63.6% and 87.5%, respectively). Conclusions Our data suggest that DNA methylation patterns in cell-free DNA have the potential to detect a proportion of OCs up to two years in advance of diagnosis and may potentially guide personalized treatment. The prospective use of novel collection vials, which stabilize blood cells and reduce background DNA contamination in serum/plasma samples, will facilitate clinical implementation of liquid biopsy analyses.

Abstract Background We investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to the UKCTOCS trial. Methods 95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none,

BackgroundVarious risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours.Methods and findingsGenetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk.ConclusionsOur comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95% CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95% CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95% CI: 60.8–75.5), 99.7% (95% CI: 99.7–99.7), and 11.8% (95% CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95% CI: 52.6–69.9); 99.7% (95% CI: 99.7–99.7) and 8.3% (95% CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Women with germline variants in BRCA genes are predisposed to ovarian cancer. In this study, the authors demonstrate that fimbrial tissue from the ovary, the site of ovarian cancer, in BRCAmutant carriers contains marked DNA methylation changes compared with the proximal region of the ovary.

Context: Most of the information on remission related factors in Grave's disease are derived from Western literature. It is likely that there may be additional prognostic factors and differences in the postdrug treatment course of Grave's disease in India. Aim: To study factors which predict remission/relapse in Grave's disease patients from South India. Also to establish if technetium (Tc) uptake has a role in predicting remission. Subjects and Methods: Records of 174 patients with clinical, biochemical, and scintigraphic criteria consistent with Grave's disease, seen in our Institution between January 2006 and 2014 were analyzed. Patient factors, drug-related factors, Tc-99m uptake and other clinical factors were compared between the remission and nonremission groups. Statistical Analysis Used: Mann–Whitney U-test and Chi-square tests were used when appropriate to compare the groups. Results: Fifty-seven (32.7%) patients attained remission after at least 1 year of thionamide therapy. Of these, 11 (19.2%) patients relapsed within 1 year. Age, gender, goiter, and presence of extrathyroidal manifestations were not associated with remission. Higher values of Tc uptake were positively associated with remission (P- 0.02). Time to achievement of normal thyroid function and composite dose: Time scores were significantly associated with remission (P - 0.05 and P - 0.01, respectively). Patients with lower FT4 at presentation had a higher chance of remission (P - 0.01). The relapse rates were lower than previously reported in the literature. A higher Tc uptake was found to be significantly associated with relapse also (P - 0.009). Conclusion: The prognostic factors associated with remission in Graves's disease in this South Indian study are not the same as that reported in Western literature. Tc scintigraphy may have an additional role in identifying people who are likely to undergo remission and thus predict the outcome of Grave's disease.

Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on RANKL/osteoprotegerin (OPG) signalling. We analysed serum levels of RANKL, OPG, RANKL/OPG complex, oestradiol (E2), and progesterone (P) during menstrual cycle progression in 391 BRCA1/2-mutation carriers and 782 noncarriers. These studies were complemented by analyses of RANKL and OPG in the serum and mammary tissues of female cynomolgus macaques (n = 88) and serum RANKL and OPG in postmenopausal women (n = 150). BRCA-mutation carriers had lower mean values of free serum OPG in particular in BRCA1-mutation carriers (p = 0.018) compared with controls. Among BRCA1/2 mutation carriers, lower OPG levels were associated with germline mutation locations known to confer an increased breast cancer risk (p = 0.003). P is associated with low OPG levels in serum and tissue, particularly in BRCA-mutation carriers (rho = −0.216; p = 0.002). Serum OPG levels were inversely correlated (rho = −0.545, p

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2–5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871–0.952) and 90.5% (82.5–98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women.

Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were recruited through London primary care networks. Inclusion criteria: women ≥18 years. Exclusion criteria: prior ovarian/tubal/peritoneal cancer, previous genetic testing for OC genes. Participants accessed an online/web-based decision aid along with optional telephone helpline use. Consenting individuals completed risk assessment and underwent genetic testing (BRCA1/BRCA2/RAD51C/RAD51D/BRIP1, OC susceptibility single-nucleotide polymorphisms). A validated OC risk prediction algorithm provided a personalised OC risk estimate using genetic/lifestyle/hormonal OC risk factors. Population genetic testing (PGT)/OC risk stratification uptake/acceptability, satisfaction, decision aid/telephone helpline use, psychological health and quality of life were assessed using validated/customised questionnaires over six months. Linear-mixed models/contrast tests analysed impact on study outcomes. Main outcomes: feasibility/acceptability, uptake, decision aid/telephone helpline use, satisfaction/regret, and impact on psychological health/quality of life. In total, 123 volunteers (mean age = 48.5 (SD = 15.4) years) used the decision aid, 105 (85%) consented. None fulfilled NHS genetic testing clinical criteria. OC risk stratification revealed 1/103 at ≥10% (high), 0/103 at ≥5%–p = 0.30), anxiety (p = 0.10), quality-of-life (p = 0.99), and distress (p = 0.25) levels did not jointly change, while OC worry (p = 0.021) and general cancer risk perception (p = 0.015) decreased over six months. In total, 85.5–98.7% were satisfied with their decision. Findings suggest population-based personalised OC risk stratification is feasible and acceptable, has high satisfaction, reduces cancer worry/risk perception, and does not negatively impact psychological health/quality of life.

Background: Tubo-ovarian cancer (OC) continues to be the most lethal of all gynaecological cancers. Over half of women are diagnosed with late stage (III/IV) disease, which has a five-year survival rate of 11%. Socioeconomic status (SES) has been shown to have an impact on outcomes of several cancer types, including OC. This study aims to investigate any potential association between SES and stage at diagnosis of OC. Methods: Women from the non-screening arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) with a confirmed diagnosis of OC prior to 01 January 2015 and an English index of multiple deprivation (IMD) score were eligible for the study. The association between IMD and OC stage (FIGO) was analysed using an ordinal logistic regression model adjusted for age at diagnosis and BMI. Results: Four-hundred and fifty seven women were eligible for inclusion in the primary analysis. The odds of being diagnosed with the higher dichotomization of stage (I vs. II/III/IV; I/II vs. III/IV; I/II/III vs. IV) was 1.29 (p = 0.017; 95% CI: 1.048−1.592) per unit SD (standard deviation) increase in IMD. This translates to a 29% increase in odds of being diagnosed at the higher stage per each unit SD increase in IMD. Conclusion: Increased deprivation is consistently associated with a higher probability of being diagnosed with later stage OC.

Background: We report on a unique audit of seven sonographers self-reporting high visualization rates of normal postmenopausal ovaries in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This audit was ordered by the trial’s Ultrasound Management Subcommittee after an initiative taken in 2008 to improve the quality of scanning and the subsequent increase in the number of sonographers claiming very high ovary visualisation rates. Methods: Seven sonographers reporting high rates (>89%) of visualizing normal postmenopausal ovaries in examinations performed between 1st January and 31st December 2008 were identified. Eight experts in gynaecological scanning reviewed a random selection of exams performed by these sonographers and assessed whether visualization of both ovaries could be confirmed (cVR-Both) in the examinations. A random effects bivariate probit model was fitted to analyse the results. Results: The eight experts reviewed images from 357 examinations performed on 349 postmenopausal women (mean age 60.0 years, range 50.2-73.3) by the seven sonographers. The mean cVR-Both obtained from the model for these sonographers was 67.2% with a range of 47.6-86.5% (95%CI 63.9-70.5%). The range of cVR-Both between the experts was 47.3-88.3% and the intra-class correlation coefficient (ICC) for left and right ovary confirmation was 0.39. Conclusions: The audit suggests that self-reported visualization of postmenopausal ovaries is unreliable, as visualisation of both ovaries could not be confirmed in almost a third of examinations. The agreement for visualization of both ovaries based on review of a static image between experts and sonographers and between expert reviewers alone was only moderate. Further research is needed to develop reliable Quality Control metrics for transvaginal ultrasound.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Introduction People with diabetes are at risk of developing chronic kidney disease. However, limited data are available to quantify their risk of kidney function decline in South Asia. This study evaluates the rate and predictors of kidney function decline among people with type 2 diabetes in South Asia.Research design and methods We analyzed data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) Trial to quantify the rate of decline in estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (n=1146) over 2.5 years of follow-up. The CARRS Trial evaluated a multicomponent intervention of decision-supported electronic health records and non-physician care coordinator to improve diabetes management at 10 diabetes clinics in India and Pakistan. We used linear mixed models to estimate eGFR slope among all participants and tested the association of eGFR slope with demographic, disease-related, and self-care parameters, accounting for randomization and site.Results The mean age of participants was 54.2 years, with a median duration of diabetes of 7.0 years (IQR: 3.0 - 12.0) and median CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) eGFR of 83.6 (IQR: 67.7 to 97.9) mL/min/1.73 m2. The overall mean eGFR slope was −1.33/mL/min/1.73 m2/year. There were no differences in the eGFR slope by treatment assignment to intervention versus usual care. In the adjusted regression model, pre-existing diabetic retinopathy (slope difference: −2.11; 95% CI: −3.45 to –0.77), previous cardiovascular disease (−1.93; 95% CI: −3.45 to –0.40), and statins use (−0.87; 95% CI: −1.65 to –0.10) were associated with faster eGFR decline.Conclusions People with diabetes receiving care at urban diabetes clinics in South Asia experienced annual eGFR decline at two times higher rate than that reported from other contemporary international diabetes cohorts. Risk factors for faster decline were similar to those previously established, and thus care delivery models must put an additional emphasis on kidney protective therapies among subgroups with microvascular and macrovascular diabetes complications.Trial registration number NCT01212328.