Citations

AbstractThe dystrophinopathies encompass the phenotypically variable forms of muscular dystrophy caused by pathogenic variants in the DMD gene. The dystrophinopathies include the most common inherited muscular dystrophy among 46,XY individuals, Duchenne muscular dystrophy, as well as Becker muscular dystrophy and other less common phenotypic variants. With increased access to and utilization of genetic testing in the diagnostic and carrier setting, genetic counselors and clinicians in diverse specialty areas may care for individuals with and carriers of dystrophinopathy. This practice resource was developed as a tool for genetic counselors and other health care professionals to support counseling regarding dystrophinopathies, including diagnosis, health risks and management, psychosocial needs, reproductive options, clinical trials, and treatment. Genetic testing efforts have enabled genotype/phenotype correlation in the dystrophinopathies, but have also revealed unexpected findings, further complicating genetic counseling for this group of conditions. Additionally, the therapeutic landscape for dystrophinopathies has dramatically changed with several FDA‐approved therapeutics, an expansive research pathway, and numerous clinical trials. Genotype–phenotype correlations are especially complex and genetic counselors' unique skill sets are useful in exploring and explaining this to families. Given the recent advances in diagnostic testing and therapeutics related to dystrophinopathies, this practice resource is a timely update for genetic counselors and other healthcare professionals involved in the diagnosis and care of individuals with dystrophinopathies.

AbstractBackgroundMany patients with quiescent inflammatory bowel disease (IBD) suffer from irritable bowel syndrome (IBS)‐like symptoms. Although these symptoms cause significant reductions in quality of life, evidence‐based treatments are lacking as risk factors and pathophysiology of these symptoms are not clearly defined. We aimed to identify risk factors for development of IBS‐like symptoms in IBD patients with quiescent disease.MethodsWe performed a single‐center retrospective cohort study of adults with IBD from 2015 to 2021. Quiescent IBD was defined by a fecal calprotectin level <250 μg/g of stool or endoscopic evidence of quiescent disease. Cox regression was performed to identify variables that were independently associated with the incident development of IBS‐like symptoms in IBD patients.Key ResultsA total of 368 IBD patients were included for analysis, including 278 patients with UC and 88 with Crohn's disease. 15.5% of quiescent IBD patients developed IBS symptoms, with an incidence rate of (95% CI 48.0–82.0) 63.3 per 1000 person‐years. In the multivariate model, mood disorders (including anxiety and depression) and Crohn's disease were associated with increased risk for developing IBS symptoms. Male sex and higher iron levels conferred lower risk for developing IBS symptoms. Results from the multivariable model were similar in sensitivity analysis with quiescent IBD defined by fecal calprotectin level <150 mcg/g.Conclusions & InferencesMood disorder and Crohn's disease were positively associated with IBS‐like symptoms in quiescent IBD, whereas male sex and iron levels were protective. Our results were robust to different fecal calprotectin levels, arguing against inflammation as a mechanism for IBS‐like symptoms. This data suggests noninflammatory mechanisms may be important in the pathogenesis of IBS‐like symptoms in quiescent IBD. Future work may address whether modifying these risk factors may alter disease course.

Introduction: Electro-anatomic mapping (EAM) has been studied as a modality to improve the sensitivity and reduce false negative rates with endomyocardial biopsy (EMB). We systematically reviewed the literature describing EAM guided EMB. Methods: An experienced librarian developed search strategies for Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central, Scopus and Web of Science. There were no restrictions on language or publication date. Animal studies were excluded. Search strategy included MESH headings and keywords including endomyocardial biopsy and electroanatomic mapping. Results: Out of 139 studies initially identified, 16 (9 case series, 7 case reports) were included in this systematic review. EAM guided EMB was performed in 152 patients and results of 241 biopsies were available for analysis. The most common indications for EAM guided EMB were suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), myocarditis and cardiac sarcoidosis (CS). While fluoroscopic visualization of the bioptome close to mapping catheter was the most commonly utilized biopsy technique (n=7 studies), direct visualization of bioptome on CARTO (n=4) and on NavX (n=2) were used as well. Low voltage areas had abnormal myocardial histology more commonly (range 60-100%) than normal voltage areas (range 11-52%). Sensitivity of low voltage areas for abnormal myocardium ranged from 60% to 82%. EAM guided EMB appears safe and adverse events were noted in only one study (remote hemopericardium). Conclusions: EAM guided EMB is a safe and efficacious method to improve the sensitivity and reduce the false negative rate of conventional fluoroscopy guided biopsy.

Abstract Purpose: Aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. Patients and Methods: Postmenopausal women with stage I to III hormone receptor–positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). Results: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. Conclusions: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

AbstractObjectiveDetermine current analytical methods and number of cell‐free (cf) DNA prenatal screening tests performed for common trisomies.MethodsThe College of American Pathologists 2022‐B Noninvasive Prenatal Testing exercise was distributed in December 2022 to 93 participants in 22 countries. Supplemental questions included the number of tests performed in a recent month and the proportion of samples originating outside the United States (US).ResultsEighty‐three participants from three continents returned results; 74 (89%) were suitable for the analyses. Nine manufacturer/platform combinations were identified, most commonly Illumina/Nextseq (55%). The most common methodology was whole genome sequencing (76%). Annualized cfDNA tests were 2.80 million, with Asian, European and North American participants representing 10.6%, 6.5% and 82.9% of tests, respectively. When restricted to US in‐country tests, the annualized rate was 2.18 million, with four of 20 participants testing 79.2%. Among 73 respondents, 63 (86%) were for‐profit, eight (11%) were non‐profit academic or government supported and the remaining two included hospital‐based and private non‐profit. Eighteen (25%) supported relevant academic training.ConclusionIn 2011, screening for common trisomies was based on serum/ultrasound markers with an estimated 2.96 million US pregnancies screened in 131 laboratories. In 2022, cfDNA‐based screening was offered by 20 laboratories testing 2.18 million US pregnancies.

Importance Among women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC. Objective To estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC. Design, Setting, and Participants Participants were enrolled in the Young Women’s Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023. Main Outcomes and Measures The 5- and 10- year cumulative incidence of SPBC. Results In all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70). Conclusions Findings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.

Interstitial lung disease (ILD) is a common and serious complication of systemic autoimmune rheumatic diseases (SARD). The prevalence and prognosis of ILD vary depending on the type and severity of the underlying SARD. Recently, two drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ILD in SARD, and the American College of Rheumatology (ACR) has issued guidelines for the screening and monitoring of these patients. Therefore, it is essential to detect and manage ILD in SARDs as early as possible. High-resolution CT of the chest is the current gold standard test for diagnosis of ILD, yet, it is not uniformly performed as an initial diagnostic test. This review discusses the latest advances in imaging techniques for the diagnosis, assessment, and follow-up of SARD-ILDs.