Citations

ABSTRACT Age‐related changes in human hematopoietic stem cells (HSCs) often form the basis for clonal hematopoiesis (CH), which presages the development of overt myeloid neoplasm with variable risk. CH can also arise after exposure to chemotherapy, radiotherapy, or immune interventions. In this study, we performed clinico‐genomic profiling of therapy‐related CH (t‐CH) ( n = 67) versus de novo CH ( n = 123) from a multidisciplinary CHIP Clinic. The most enriched mutations in t‐CH were TET2 (26.2%), DNMT3A (22.4%), and TP53 (8.4%). Median latency period from the time of initial exposure to the diagnosis of t‐CH was 6.96 ± 1.10 years. Patients with t‐CH had inferior event‐free survival compared to de novo CH (median 29.9 months versus 122.1 months, p = 0.0045). Overall survival was also shorter in t‐CH versus de novo CH (median 55.3 months vs. 129.2 months, p = 0.043). Genes that imparted significantly increased risk for progression from t‐CH to overt therapy‐related myeloid neoplasm (t‐MN) included JAK2 (relative risk (RR) 9.42, p = 0.0001), RUNX1 (RR 7.11, p = 0.001), EZH2 (RR 7.11, p = 0.001), and TET2 (RR 13.4, p = 0.01). Clonal dynamic modeling of patients with t‐CH who progressed to overt t‐MN showed an increase in the relative clonal fraction and new clonal outgrowth. In the t‐CH cohort, higher mean variant allele frequency was observed in progressors versus non‐progressors (77.1% vs. 30.6%, p = 0.017). This study sheds light onto outcomes for CH based on differing clinical ontogeny and has implications for previvorship for secondary malignancies.

Abstract Background For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes ( BRCA1, BRCA2, PALB2, ATM, CHEK2 ). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion This flexible, variant-level methodology combines nationally-collected ‘enriched’ datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.

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 on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

OBJECTIVES We aimed to characterize the frequency of major complications of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C) and adolescents present at 6 months after initial presentation. METHODS The Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM) study was a prospective cohort at 20 US pediatric academic medical centers. Individuals aged younger than 21 years meeting any of the following were enrolled: SARS-CoV-2 detection within 7 days, Centers for Disease Control and Prevention (CDC) MIS-C criteria, or CDC MIS-C criteria except having involvement of 1 organ system. The study was designed to assess the proportion of children with major complications (cardiovascular, pulmonary, gastrointestinal/hepatic, renal, and/or neurologic) 6 months after presentation. RESULTS Data were analyzed on 229 hospitalized participants: 59 with COVID-19 (mean age 10.4 years; SD, 5.5) and 170 with MIS-C (mean age 10.1 years; SD, 4.8). Overall, 42.8% were female, making up 55.9% and 38.2% of the COVID-19 and MIS-C groups, respectively. Overall, the frequencies of major complications at 6 months after initial presentation were: 16/195 (8.2%) cardiovascular, 11/154 (7.1%) pulmonary, 11/154 (7.1%) gastrointestinal/hepatic, 3/152 (2.0%) renal, and 3/189 (1.6%) neurologic. Organ system complications did not differ significantly between the COVID-19 and MIS-C groups. Six of 14 (42.9%) COVID-19 and 21/26 (80.7%) MIS-C participants with at least 1 six-month complication had no underlying medical condition that may have been associated with their complication(s). CONCLUSIONS Major complications were infrequent but observed in children without underlying medical conditions, underscoring the importance of prospective follow-up to optimize management and elucidate the complications associated with severe SARS-CoV-2 infection in children.

Abstract Femoroacetabular impingement with cam morphology that fails nonoperative management can be addressed with hip arthroscopy and cam resection. There exists a wide variation of cam morphology due to various etiologies that can make some cam lesions more challenging to address. A thorough preoperative evaluation and the utilization of a variety of intraoperative techniques can allow for adequate arthroscopic resection of these otherwise challenging cam lesions. In this technique video, we describe a systematic approach for the preoperative assessment of femoroacetabular impingement due to a cam lesion and consideration of different approaches for arthroscopic resection based on cam‐specific morphology.

In participants with Crohn disease (CD), an abbreviated MR enterography (MRE) protocol demonstrated similar interreader agreement to contrast-enhanced MRE and high intrareader concordance for detecting active CD and related complications.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Background/Objectives: Primary spinal sarcomas, encompassing both bone and soft tissue histotypes, demand individualized reconstruction due to heterogeneous tumor biology, anatomic complexity, and host environments compromised by radiation, systemic therapy, or prior surgery. This narrative review reframes post-resection spinal reconstruction through a precision-medicine lens. Methods: A structured literature review was performed using PubMed and Scopus, targeting articles published between 2000 and 2026. Searches encompassed spinal sarcoma reconstruction, radiation and fusion, biologic reconstruction, and emerging technologies. Results: Tumor grade, radiation exposure, and systemic therapy timing emerge as multiplicative determinants of reconstructive environment quality, with drug-class-specific perioperative effects warranting stratified management. Vascularized bone grafts achieve reliable fusion in compromised hosts where avascular constructs fail. A precision-oriented reconstructive ladder is proposed as a conceptual, hypothesis-generating framework to guide strategy selection. Hybrid PSI-VBG constructs may further expand reconstructive possibilities. The evidence base remains largely composed of small, retrospective series. Conclusions: Individualized strategies anchored in tumor biology and host environment are the cornerstone of durable spinal sarcoma reconstructions. The proposed framework requires prospective, multi-institutional validation. Standardized outcome definitions, prospective registries, and histotype-stratified analyses are needed to advance the field.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.