Citations

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Introduction: Mortality in patients with unruptured intracranial aneurysm (UIA) is significantly higher than the general population. However a minority of the deaths are due to subarachnoid hemorrhage. Hypothesis: There are differential characteristics of patients that might predict specific causes of death that would be informative in counseling patients about aneurysm risk. Methods: 4059 patients with UIA who were enrolled prospectively between 1991 and 1998 were followed by 61 medical centers in North America, Canada, and Europe. Patients have at least one UIA, which may or may not be symptomatic. Patients were Rankin grade 1 or 2 at enrollment. Patients were followed annually from enrollment to 2007. For patients who died a death certificate search was done and information was requested from local physicians and other contacts. A National Death Index search in 2008 determined cases who died and cause of death. Foreign centers also did a national search where possible. Patients who died before 30 days post treatment or lost to follow up before 30 days post enrollment were excluded. Results: Twenty-five percent of patients died during follow-up. The life expectancy was significantly less than age-, sex-, and country-matched expected estimates. Among the total of 4004 patients with UIA who survived 30 days after enrollment, 2331 were treated and 1673 were not. There were 965 deaths after 30 days after treatment, of which 320 died from vascular disease (252 died from non-SAH vascular disease), 114 died from respiratory tract disease, 255 died from cancer, and the rest died of other or unknown reasons. Predictors of SAH death were aneurysm size, site, age and convulsive disorders at enrollment. Factors related to vascular death were UIA treatment, age, gender, race, hypertension, Rankin at discharge and diminishing influence of aneurysm characteristics over time. Respiratory deaths were related to treatment, race, smoking, age, initial Rankin and presentation with convulsive disorder. Cancer deaths were related to gender, race, smoking and age. Conclusions: In patients with UIA, an assessment of risk for death underscores the importance of age, race and gender and several modifiable risk factors. Patient management should include not only aneurysm rupture prevention but also modification of smoking and hypertension.

Background and Purpose: The CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) consists of 2 parallel randomized stroke prevention trials in patients with asymptomatic high-grade stenosis of the cervical carotid artery. The purpose of this report is to detail the outcomes of a health screening effort to increase trial enrollment of women and minorities. Methods: Life Line screening (LLS) conducts nationwide screening for vascular disease. Screenings within a 50-mile radius of each CREST-2 center were identified for participation in a joint CREST-LLS program over the course of one year (November 2018 to October 2019) whereby patients with an abnormal carotid ultrasound were referred to the local CREST-2 center for further workup, management, and potential consideration for trial enrollment. Results: LLS completed the screening of 588 198 individuals in 29 732 zip codes across the United States. Of those, 230 021 individuals were screened at events occurring near a CREST-2 clinical center and 646 (0.3%) were found to have abnormal carotid ultrasound findings. Each of the 646 individuals was contacted by CREST-LLS program staff for permission to be referred to their local CREST-2 center; 200 (31%) consented to be contacted by CREST-2. Of those, 39 (19.5%) agreed to be, and were, evaluated at their local CREST-2 center. High-grade stenosis was confirmed in 27 patients. A total of 3 patients were eligible for the trial and were enrolled, one woman but no racial/ethnic minorities. Conclusions: The LLS program appears to identify community-living individuals with high-grade carotid stenosis through ultrasonography. However, the prevalence of abnormal carotid findings was low. In addition, screening and offering participation into the CREST-2 trial had no substantial impact on the proportion of women and minorities enrolled in the trial. Additional innovative strategies are needed to promote enrollment of diverse patients with carotid stenosis into stroke prevention trials.

Abstract ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis‐associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour‐infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients ( p = 0.012) and was associated with MMRd ( p < 0.001) and the presence of CD8 + TILs ( p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss‐of‐function mutation as a result of small indels ( p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss‐of‐function mutations in endometriosis‐associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

SummaryBackgroundRumination syndrome is a functional gastroduodenal disorder characterised by effortless regurgitation of recently ingested food. Emerging evidence reports duodenal eosinophilic inflammation in a subset, suggesting a shared pathophysiology with functional dyspepsia (FD).AimTo assess the clinical features of rumination syndrome and FD in a community‐based study.MethodsWe mailed a survey assessing gastrointestinal symptoms, diet and psychological symptoms to 9835 residents of Olmsted County, MN, USA in 2017‐2018; diagnostic codes were obtained from linked clinical records. The two disorders were assessed as mutually exclusive in ‘pure’ forms with a separate overlap group, all compared to a control group not meeting criteria for either. Prevalence of associations, and univariate and independent associations with predictors were assessed by logistic regression.ResultsPrevalence of rumination syndrome and FD were 5.8% and 7.1%, respectively; the overlap was 3.83‐times more likely than expected by chance. Independent predictors for rumination (odds ratio (OR), 95% confidence interval (CI)) were female gender (1.79, 1.21‐2.63), smoking (1.89, 1.28‐2.78), gluten‐free diet (1.58, 1.14‐2.19), allergic rhinitis (1.45, 1.01‐2.08) and depression (1.10, 1.05‐1.16). FD was independently associated with female gender, depression, non‐coeliac wheat sensitivity, migraine, irritable bowel syndrome and somatic symptoms. A similar reported efficacy (≥54%) of low fat or dairy‐free diets was found with both disorders (P = 0.53 andP = 1.00, respectively). The strongest independent associations with overlapping FD and rumination syndrome were a history of rheumatoid arthritis (3.93, 1.28‐12.06) and asthma (3.02, 1.44‐6.34).ConclusionRumination syndrome overlaps with FD with a shared risk factor profile, suggesting a common pathophysiology.

Background and Purpose: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. Methods: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. Results: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles ( P <0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile ( P =0.015). Lower performance was attributed largely to Word List Recall ( P <0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected, P ≤0.01). The scores for left versus right carotid disease were similar. Conclusions: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02089217.

Introduction: Inclusion of asymptomatic patients in randomized trials comparing revascularization to medical therapy has been questioned if they have been previously symptomatic. Hypothesis: Duration of asymptomatic status is not associated with better outcomes following endarterectomy (CEA) or stenting (CAS). Methods: Patients in CREST were classified as asymptomatic if they had not had a TIA or stroke ipsilateral to the study artery within 6 months prior to randomization. We compared those patients who had always been asymptomatic (AA) to those who had been previously symptomatic (PS) ≥ 6 months prior to randomization. Proportional hazards models adjusting for age and treatment were used to assess risk of 30-day stroke or death (S+D), and risk of any 30-day S+D plus ipsilateral stroke at 4 years by asymptomatic status Results: Among the 1056 asymptomatic patients who received the assigned procedure within 30 days of randomization, 977 (93%) were AA and 79 (7%) were PS. There was no difference in the 30-day and 4 year outcomes (Table). Conclusion: In CREST, 93% of the asymptomatic patients were always asymptomatic. Similar outcomes for the previously symptomatic patients (7%) supports the inclusion of such patients in randomized trials comparing CEA and CAS to medical treatment.

Background: Carotid endarterectomy (CEA) is the leading procedure for carotid stenosis, yet national data on trends in rates and outcomes are limited. We determined CEA rates among Medicare beneficiaries and evaluated mortality and readmission over 8 years. Methods: We used Medicare fee-for-service data to identify beneficiaries aged ≥65y who had their first CEA (ICD-9 38.12) from 2003-2010 and calculated annual rates per 100,000 person-years (PY). We fit mixed models to assess trends in patient-level outcomes, adjusting for demographics, comorbidities, and symptomatic status. We also evaluated hospital-level trends by calculating risk-standardized mortality (RSMR) and readmission (RSRR) rates. A spatial mixed model adjusted for age, sex, and race was fit to calculate county-specific risk-standardized CEA rates in 2003-2004. Results: There were 505,966 unique CEA hospitalizations. The annual number of CEA discharges decreased from 81,604 in 2003 to 47,597 in 2010 (42% decrease), though the patient characteristics remained largely similar. The national CEA rate was 283 per 100,000 PY in 2003, and there was considerable geographic variability (Figure A). This rate decreased each year to a low of 172 per 100,000 PY in 2010. The rate of stroke or death within 30 days decreased from 3.2 to 2.7%, with a significant adjusted annual reduction of 3% (Figure B). Annual reductions in other short- and long-term outcomes were similar, ranging from 2-3%. The median hospital-level 30-day RSMR decreased over time from 0.99 to 0.57%, while the variation between hospitals increased (interquartile range of 0.7-1.67 percentage points). The 30-day RSRR decreased from 11.0 to 10.1%, but there was more homogeneity across hospitals and years. Conclusions: CEA use among Medicare patients decreased dramatically from 2003-2010, while mortality and readmission outcomes improved. The relative importance of biological and sociological mechanisms for these trends merits further study.

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.