Citations

Importance Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration–approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs. Observations This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males. Conclusions and Relevance Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.

Importance Outcomes for patients with unresectable stage III non–small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT) have improved with adjuvant immune checkpoint inhibitors, with a reported 5-year overall survival benefit of approximately 10% for adjuvant durvalumab vs placebo after completion of CRT without progression and with preserved performance status. Starting atezolizumab prior to CRT may allow more patients to benefit from immunotherapy. Objective To evaluate clinical outcomes of patients treated with atezolizumab before and after CRT for unresectable stage III NSCLC. Design, Setting, and Participants This single-cohort, phase II, nonrandomized controlled trial was conducted at 11 US sites. Patients with pathologically confirmed, unresectable stage III NSCLC who were treatment naive and had good performance status were enrolled between January 3, 2018, and July 24, 2019. Data were locked on March 21, 2023. Interventions Patients received four 21-day cycles of atezolizumab, 1200 mg intravenously, with therapy administered on day 1 of each cycle. Patients not experiencing tumor progression continued to CRT (60 Gy to involved fields) concurrent with weekly carboplatin area under the curve of 2 and paclitaxel, 50 mg/m 2 , followed by planned consolidation carboplatin area under the curve of 6 and paclitaxel, 200 mg/m 2 , for two 21-day cycles. Patients not experiencing progression continued atezolizumab, 1200 mg, every 21 days to complete 1 year of therapy. Main Outcomes and Measures The primary end point was the disease control rate at 12 weeks. Secondary end points were progression-free survival, overall survival, overall response rate, safety, and translational science end points. Results A total of 62 patients (median [range] age, 63.9 [38.1-86.5] years; 32 female [51.6%]) were enrolled and received at least 1 dose of atezolizumab. The disease control rate at 12 weeks was 74.2% (80% CI, 65.7%-81.4%). Median progression-free survival was 30.0 months (95% CI, 15.8 to not evaluable), and the median overall survival was not reached. The overall survival rate at 24 months was 73.7% (95% CI, 63.4%-85.7%), and the overall response rate was 66.2%. Seventeen patients (27.4%) experienced grade 3 or higher immune-related adverse events, including 1 with grade 5 pneumonitis and 1 with grade 4 Guillain-Barré syndrome. Thirty patients (48.4%) experienced grade 3 or higher treatment-related adverse events. Conclusions and Relevance These findings suggest that neoadjuvant atezolizumab merits further study based on safety and encouraging outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT03102242

Abstract Context Variants in melanocortin 4 receptor (MC4R) pathway-related genes have been associated with obesity. The association of these variants with cardiometabolic parameters are not fully known. Objective We compared the severity of obesity and cardiometabolic risk markers in children with MC4R pathway-related clinically reported genetic variants relative to children without these variants. Methods A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Results Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the MC4R pathway, and the remaining 65 patients did not have reported MC4R pathway-related variants. Among the MC4R-related variants, PCSK1 risk alleles were most common, reported in 15 children (14%). The maximum body mass index percent of the 95th percentile was not different between groups (P = .116). Low-density lipoprotein cholesterol (LDL-C) was not different between groups (P = .132). However, subgroup analysis demonstrated higher LDL cholesterol in children with the PCSK1 c.661A>G risk allele relative to those with MC4R-related variant of uncertain significance (P = .047), negative genetic testing (P = .012), and those with non-MC4R related variants (P = .048). The blood pressure, fasting glucose, hemoglobin A1C, total cholesterol, alanine transaminase, and high-density lipoprotein cholesterol were not different between groups. Conclusion Variants in the MC4R pathway-related genes were not associated with severity of obesity and cardiometabolic risk markers except for the c.661A>G PCSK1 risk allele, which was associated with higher LDL-C levels.

BACKGROUND: Differentiating wide complex tachycardias (WCTs) into ventricular tachycardia (VT) and supraventricular wide tachycardia via 12-lead ECG interpretation is a crucial but difficult task. Automated algorithms show promise as alternatives to manual ECG interpretation, but direct comparison of their diagnostic performance has not been undertaken. METHODS: Two electrophysiologists applied 3 manual WCT differentiation approaches (ie, Brugada, Vereckei aVR, and VT score). Simultaneously, computerized data from paired WCT and baseline ECGs were processed by 5 automated WCT differentiation algorithms (WCT Formula, WCT Formula II, VT Prediction Model, Solo Model, and Paired Model). The diagnostic performance of automated algorithms was compared with manual ECG interpretation approaches. RESULTS: A total of 212 WCTs (111 VT and 101 supraventricular wide tachycardia) from 104 patients were analyzed. WCT Formula demonstrated superior accuracy (85.8%) and specificity (87.1%) compared with Brugada (75.2% and 57.4%, respectively) and Vereckei aVR (65.3% and 36.4%, respectively). WCT Formula II achieved higher accuracy (89.6%) and specificity (85.1%) against Brugada and Vereckei aVR. Performance metrics of the WCT Formula (accuracy 85.8%, sensitivity 84.7%, and specificity 87.1%) and WCT Formula II (accuracy 89.8%, sensitivity 89.6%, and specificity 85.1%) were similar to the VT score (accuracy 84.4%, sensitivity 93.8%, and specificity 74.2%). Paired Model was superior to Brugada in accuracy (89.6% versus 75.2%), specificity (97.0% versus 57.4%), and F1 score (0.89 versus 0.80). Paired Model surpassed Vereckei aVR in accuracy (89.6% versus 65.3%), specificity (97.0% versus 75.2%), and F1 score (0.89 versus 0.74). Paired Model demonstrated similar accuracy (89.6% versus 84.4%), inferior sensitivity (79.3% versus 93.8%), but superior specificity (97.0% versus 74.2%) to the VT score. Solo Model and VT Prediction Model accuracy (82.5% and 77.4%, respectively) was superior to the Vereckei aVR (65.3%) but similar to Brugada (75.2%) and the VT score (84.4%). CONCLUSIONS: Automated WCT differentiation algorithms demonstrated favorable diagnostic performance compared with traditional manual ECG interpretation approaches.

BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health–funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18–25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57–1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67–2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02549664.

Within the Department of Medicine (DOM) in a large tertiary academic health care facility in midwestern United States, we have developed an educational offering that incorporates an academic writing program (AWP) blending the approaches of a writing accountability work group, a writing workshop, and didactic writing courses. The purpose of this AWP was to assist healthcare professionals (HCP) with their manuscript writing skills to enhance academic productivity. We report our evolving journey and experiences with this AWP. To date, it has been offered 3 times to 25 HCP over the course of 3 years. Among those responding to a post program follow up survey (N = 11), 8 (73%) indicated that they completed the project that they were working on during the AWP and went on to publish the manuscript (N = 5) or were in the process of submission (N = 2). Some indicated they has also gone on to present posters (N = 2) or were in the process of presenting posters (N = 2) or had received grants (N = 1) or were awaiting grant notice (N = 1). A number of attendees have continued to use and share the tools presented during the AWP. Based on input from attendees and increased requests for this AWP, this educational program has been deemed a success and expansion of this program is currently underway.

INTRODUCTION: The risk of small bowel cancer (SBC) in inflammatory bowel disease (IBD) is unclear. We compared the recent trends of SBC in patients with IBD and stratified them based on disease type. METHODS: We used TriNetX database to access the electronic health records for patients with IBD, ulcerative colitis (UC), and Crohn's disease (CD) from 2005 to 2024. We used propensity score matching to compare the rate of SBC in patients with IBD, UC, and CD compared with the general population. We adjusted for all known confounders. RESULTS: From 2010 to 2024, there was an increasing trend of diagnosed SBC in patients with IBD, with an average annual percentage change of 3.2% ( P < 0.001). Patients with CD (adjusted hazard ratio = 4.83; 95% confidence interval: 3.58–6.53; P < 0.0001) had an increased risk of SBC compared with the general population without IBD, as well as patients with UC (adjusted hazard ratio = 2.28; 95% confidence interval: 1.65–3.14; P < 0.0001). The ileum was the most common location across all subgroups. DISCUSSION: Both patients with CD and, interestingly, UC had an elevated risk of developing SBC compared with the general population.

Abstract Background Prior studies have established an association between a history of abuse and more severe migraine presentation. Objectives This cross‐sectional, observational study of a clinic‐based migraine population used validated measures to elucidate migraine‐specific and migraine‐related burdens among patients with a history of abuse. Methods Patients with migraine ( n = 866) from the American Registry for Migraine Research self‐reported if they had a history of emotional, physical, and/or sexual abuse and completed questionnaires assessing migraine‐related burden: Migraine Disability Assessment, Subjective Cognitive Impairment Scale for Migraine Attacks, Work Productivity and Activity Impairment, Patient‐Reported Outcomes Measurement Information System Pain Interference, Patient Health Questionnaire‐2, and Generalized Anxiety Disorder‐7. Migraine‐related burden in patients with versus without a history of abuse was compared. Subsequently, a mediation analysis evaluated the impact of depression and anxiety symptoms in the relationship between abuse history and migraine burden. Results A history of abuse was reported by 36.5% ( n = 316/866) of participants. After controlling for patient age, sex, years lived with headache, and headache frequency, a history of abuse was significantly associated with more severe migraine‐related disability. The combined burden of depression and anxiety symptoms mediated the relationship. Conclusion A history of abuse is associated with greater migraine‐related disability. Future studies should determine if identification and management of the psychological and physical sequelae of abuse reduce migraine burden.