Citations

Background: Childhood obesity is associated with dyslipidemia, fatty liver disease, and type 2 diabetes. Expert guidelines recommend screening for these conditions in children with obesity. Aims and objectives: The objective of the study was to compare rates of laboratory screening for dyslipidemia, fatty liver disease, and type 2 diabetes in children with obesity prior to and following implementation of a point-of-care decision support tool. Methods: We performed a retrospective record review of children with body mass index (BMI) ≥95th percentile for age and gender (age 7–18 years) undergoing well-child/sports examination visits. Multivariable logistic regression models were used to adjust for patient and provider confounders. Results: There was no increase in the rates of screening following implementation of the point-of-care decision support tool. Tests were more likely to be recommended in children with severe obesity and in females. Conclusions: The implementation of a point-of-care decision support tool was not associated with improvement in screening rates for dyslipidemia, fatty liver disease, and type 2 diabetes for children with obesity. Further strategies are needed to improve rates of screening for obesity-related comorbid conditions in children with obesity.

Background Cardioversion is common among patients with atrial fibrillation (AF). We hypothesised that novel oral anticoagulants (NOAC) used in clinical practice resulted in similar rates of stroke compared with vitamin K antagonists (VKA) for cardioversion. Methods Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, patients with AF who had a cardioversion, follow-up data and an AF diagnosis within 6 months of enrolment were identified retrospectively. Clinical outcomes were compared for patients receiving a NOAC or VKA for 1 year following cardioversion. Results Among 13 004 patients with AF, 2260 (17%) underwent cardioversion. 1613 met the inclusion criteria for this analysis. At the time of cardioversion, 283 (17.5%) were receiving a VKA and 1330 (82.5%) a NOAC. A transoesophageal echocardiogram (TOE) was performed in 403 (25%) cardioversions. The incidence of stroke/transient ischaemic attack (TIA) at 30 days was the same for patients having (3.04 per 100 patient-years) or not having (3.04 per 100 patient-years) a TOE (p=0.99). There were no differences in the incidence of death (HR 1.19, 95% CI 0.62 to 2.28, p=0.61), cardiovascular hospitalisation (HR 1.02, 95% CI 0.76 to 1.35, p=0.91), stroke/TIA (HR 1.18, 95% CI 0.30 to 4.74, p=0.81) or bleeding-related hospitalisation (HR 1.29, 95% CI 0.66 to 2.52, p=0.45) at 1 year for patients treated with either a NOAC or VKA. Conclusions Cardioversion was a low-risk procedure for patients treated with NOAC, and there were statistically similar rates of stroke/TIA 30 days after cardioversion as for patients treated with VKA. There were no statically significant differences in death, stroke/TIA or major bleeding at 1 year among patients treated with NOAC compared with VKA after cardioversion.

Repair of ventral hernias constitutes one of the most common surgical procedures. Although an abundance of data exists on objective outcome measures, very little information exists on subjective measures of surgeon preference and patient satisfaction in surgical management of ventral hernias. Moreover, there are minimal data on indications for elective repair of ventral hernias. Two questionnaires were sent to a population of general and plastic surgeons active in hernia surgery. The first of these aimed at gathering information from surgeons about their indications and contraindications for repair of ventral hernias. The second survey was aimed at determining surgeons’ perception of patient satisfaction with repair of large ventral hernias (greater than 15 cm width). Five hundred sixty-eight surgeons responded to the first survey and 336 responded to the second survey. The most common indications for elective repair of abdominal wall hernias were generalized pain (68.7%) and cosmesis (54.6%), whereas the most common contraindications were morbid obesity (43.3%), American Society of Anesthesiologists Class III or IV (35.4%), and enterocutaneous fistula (33.1%). The majority of surgeons do not routinely repair large abdominal wall hernias in asymptomatic patients, but 31.6 per cent do repair asymptomatic large hernias. Most surgeons reported that the majority of patients had resolution of pain and subjective impression of improved cosmesis after surgery. This study demonstrates uniform indications and contraindications for surgical repair of ventral hernias among surgeons as well as surgeons’ perception of improvements in satisfaction of most patients after surgery. Future studies will focus on comparing surgeon and patient satisfaction.

Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Abstract Background: Accurate circulating biomarkers for detecting residual disease can help guide therapy decisions, particularly in early-stage cancer patients. However, currently available methods lack the sensitivity required to confidently assess the presence of residual disease in patients with low tumor burden. To address this need, we have developed TARDIS (Targeted Digital Sequencing), a personalized, multiplexed amplicon sequencing method capable of tracking as many as 100 or more mutations simultaneously. Methods: We obtained tumor biopsies and longitudinal plasma samples from patients with early-stage breast cancer, glioblastoma, and pancreatic cancer. Each tumor biopsy was analyzed whole-exome sequencing. Founder mutations were selected, accounting for copy number alterations (analyzed using sequenza) and a consensus allele fraction approach that combined pyclone and custom in-house methods. Patient-specific TARDIS primers were designed to detect these mutations in plasma cfDNA. Error suppression in TARDIS was achieved using a combination of unique molecular identifiers and fragment sizes to group sequencing reads into read families. Results: In 33 patients with early-stage breast cancer treated with neoadjuvant therapy, we targeted between 3 and 116 (mean 30) mutations per patient and analyzed between 1 and 4 longitudinal plasma samples using TARDIS. Prior to treatment, we detected ctDNA in 100% patients with Stage I-III breast cancer (n=32, 95% CI= 89%-100%). We detected tumor-specific mutations in 100% of baseline breast cancer plasma samples. After completion of neoadjuvant therapy and before surgery, ctDNA levels were significantly lower in patients with pathologic complete response (pathCR, no evidence of disease at surgery) compared to patients with residual disease (median tumor fractions 0.003% and 0.017%, respectively, p=0.0058, AUC=0.83). Conclusions: TARDIS enables highly sensitive detection of ctDNA in patients with nonmetastatic cancers. Analysis of longitudinal plasma samples using TARDIS holds promise for personalizing the extent of treatment in patients with curable disease. Multiple clinical validation studies across cancer types are ongoing to define quantitative thresholds for changes in ctDNA levels that could improve clinical decision making. Citation Format: Bradon R. McDonald, Tania Contente-Cuomo, Stephen-John Sammut, Michelle D. Stephens, Ahuva Odenheimer-Bergman, Brenda Ernst, Nieves Perdigones, Suet-Feung Chin, Maria Farooq, Rosa Mejia, Patricia A. Cronin, Karen S. Anderson, Heidi E. Kosiorek, Donald W. Northfelt, Ann E. McCullough, Bhavika K. Patel, Jeffrey N. Weitzel, Thomas P. Slavin, Carlos Caldas, Barbara A. Pockaj, Muhammed Murtaza. Personalized monitoring of treatment response using Targeted Digital Sequencing of circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A51.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.