Citations

Drug-induced QT prolongation (diQTP) can lead to rare, but potentially fatal adverse effects of many medications, yet individual susceptibility varies due to both clinical and genetic factors. SDHAF3 p.F53L (rs62624461) is a genetic variant that plays a role in mitochondrial function and was previously associated with diQTP in one small prior study. Therefore, the objective of this retrospective pharmacogenetic study was to evaluate whether SDHAF3 p.F53L is associated with clinically significant diQTP. Data were obtained from the Michigan Genomics Initiative, which links genotype information with electronic health records at Michigan Medicine. Adult patients with available genotype and electrocardiogram data who received at least one high-risk QT-prolonging drug between 2001 and 2022 were included. The analysis was limited to 5848 patients of European ancestry, of whom 320 (5.5%) were carriers of the SDHAF3 p.F53L variant. QT prolongation was defined as a QTc greater than or equal to 500 ms or an increase greater than 60 ms from baseline during high-risk QT-prolonging drug prescription. Logistic regression under a dominant genetic model assessed associations between variant carrier status and diQTP, with and without propensity score adjustment. Baseline demographics and comorbidities were similar between carriers and noncarriers. No significant association was observed between SDHAF3 p.F53L and diQTP [unadjusted odds ratio (OR) = 1.06, 95% confidence interval (CI) = 0.76–1.48, P = 0.742; adjusted OR = 1.05, 95% CI = 0.74–1.51, P = 0.773]. These results suggest that SDHAF3 p.F53L does not meaningfully influence diQTP risk in a large, real-world clinical cohort. Future studies should examine this variant across diverse populations.

Abstract Background Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored. Methods Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers. Results Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions. Conclusions This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

Background: Posterior medial meniscus root tears (PMMRTs) are frequently observed injuries that alter tibiofemoral biomechanics, yet the long-term outcomes are poorly described. Purpose: To perform a systematic review and meta-analysis of the current literature on long-term clinical and radiographic outcomes of operatively managed PMMRTs. Study Design: Meta-analysis and systematic review; Level of evidence, 4. Methods: A systematic review was performed with the inclusion criteria of English-language studies, diagnosis of PMMRT on magnetic resonance imaging, and minimum 5-year radiographic or patient-reported outcome (PRO) metrics. Data analysis included management strategy, surgical technique, meniscal extrusion, medial joint space, PROs, and radiographic measurements. Failure was defined as conversion to arthroplasty, subsequent partial medial meniscectomy (PMM) and/or proximal tibial osteotomy, or clinical failure on PROs. Continuous outcome variables were analyzed with a random effects meta-analysis of mean differences. Chi-square meta-analysis was also used to analyze categorical variables. Results: Twelve studies were identified with >5-year follow-up after PMMRT (mean ± SD, 84.1 ± 11.0 months). Five studies performed PMM, 6 performed medial meniscus root repair (MMR), and 1 utilized either meniscectomy or repair. There were 797 total patients (female, n = 667; 83.7%), with mean ages ranging from 47.2 to 65. Both interventions showed significant PRO improvements after surgery: PMM (pre- vs postoperative Lysholm, 56.1 vs 68.2; P < .01) and MMR (Lysholm, 52.1 vs 83.1; International Knee Documentation Committee [IKDC], 40.0 vs 72.8; P < .01). MMR had significantly lower Kellgren-Lawrence grades (PMM vs MMR, 2.4 vs 1.8; P < .01) and superior IKDC scores (46.5 vs 72.8; P < .01) as compared with PMM. Additionally, PMM had a significantly higher failure rate (23% vs 5.3%) and conversion to knee arthroplasty (20.5% vs 3.5%) as compared with MMR, with odds ratios of 9.8 and 10.2, respectively. Conclusion: This systematic review and meta-analysis of studies with >5-year minimum follow-up found that PMM was associated with a 10-fold increase in clinical failure and conversion to knee arthroplasty relative to MMR in observational studies. In addition, MMR demonstrated superior Kellgren-Lawrence grades and IKDC scores as compared with PMM. The findings of the current analysis suggest that MMR is associated with superior outcomes as compared with PMM at mid- to long-term follow-up.

Purpose To evaluate retear rates, clinical outcomes, and complications of a consecutive series of full‐thickness rotator cuff repair cases augmented with an autograft biceps patch. Methods A retrospective review was performed of patients undergoing rotator cuff repair with autograft biceps patch augmentation. Patients underwent either magnetic resonance imaging or ultrasound to evaluate rotator cuff repair integrity at a minimum of 6 months postoperatively. Patient‐reported outcomes including the American Shoulder and Elbow Surgeons Score and Single Assessment Numeric Evaluation score were also collected and evaluated for clinical significance at a minimum of 12 months postoperatively. Analysis of retear rates was performed by comparing observed retear rates to expected retear rates using the modified Rotator Cuff Healing Index score. Results The final cohort included 25 rotator cuff repair cases. Postoperative imaging was obtained by magnetic resonance imaging in 22 patients at a mean of 9 months postoperatively (range, 6.0‐15.3 months) and ultrasound in 3 patients at a mean of 30.4 months (range, 28.8‐32.2 months). The expected retear rate using the modified Rotator Cuff Healing Index score was 21.5% for the entire cohort. There was 1 retear, resulting in an actual retear rate of 4% at an average of 23.5‐month follow‐up ( P = .0196). The average Single Assessment Numeric Evaluation score was 93 (standard deviation 9), and the average American Shoulder and Elbow Surgeons Score was 96 (standard deviation 6.3) at an average of 23.5‐month follow‐up (range 14‐32). Patient acceptable symptomatic state was achieved by 96% of the cohort for the American Shoulder and Elbow Surgeons Score and 88% of the cohort for the Single Assessment Numeric Evaluation score. There were no cases of reoperation or complications. Conclusions In this consecutive series, the biceps autograft “smash” patch for rotator cuff augmentation resulted in a low rate of retears, favorable patient‐reported outcomes, and no complications. This augmentation option has the potential to be safe and effective for improving rotator cuff repair healing rates. Level of Evidence Level IV, retrospective case series.

This case series describes multicenter experience with interleukin 6 (IL-6) receptor blockers used during attacks in aquaporin 4–immunoglobulin G–positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD).

ABSTRACT Aging reshapes the architecture of human skeletal muscle, yet objective tissue‐level markers that capture this process remain limited. We combined large‐scale histology with deep learning to identify reproducible features of muscle aging and to test their biological relevance. We analyzed 974 hematoxylin–eosin whole‐slide images from a population resource using a dual‐attention convolutional neural network and an independent Mask R‐CNN model to quantify nuclear size and density, verified by manual review. The classifier distinguished young from aged muscle with high accuracy (AUC 0.91; accuracy 86.2%), and attention maps consistently highlighted nuclear enlargement and spatial disorganization as salient features. Nuclear diameter increased with age (Spearman's ρ = 0.71, p < 0.0001) across automated and manual measurements. Transcriptomes matched to the same donors showed that samples with larger nuclei were enriched for pathways related to chromatin remodeling, proteostasis, cellular senescence, mitochondrial activity, and telomere regulation, whereas smaller nuclei aligned with anti‐inflammatory and DNA repair programs. External pediatric inflammatory myopathies exhibited nuclear enlargement comparable to aged muscle, suggesting inflammation‐related premature histologic aging. These findings identify nuclear enlargement as a robust, quantifiable feature that integrates structural and molecular signatures of muscle aging. The proposed deep learning–based nuclear morphometry provides a scalable framework for tissue‐level aging biomarkers and suggests a potential “muscle aging clock” applicable to both physiological aging and disease states.

The NCCN Guidelines for Melanoma: Cutaneous provide strategies for the diagnosis, treatment, and follow-up of patients with cutaneous melanoma, which is among the most common cancers in the United States. The outcome of cutaneous melanoma is significantly influenced by stage at initial presentation. Generally, localized disease and smaller primary tumors have been associated with more favorable prognosis. Thus, the select content featured in this issue focuses on risk factors associated with cutaneous melanoma development and which should be considered during an initial assessment. These include (1) phenotypic predispositions, (2) personal medical history or comorbidities, (3) genetic predispositions, and (4) environmental factors.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. 1 The NCCN Guidelines Panel for AML convenes annually to update recommendations for the diagnosis and treatment of AML in adults. These recommendations are based on a review of recently published clinical trials that have led to significant improvements in treatment or have yielded new information regarding biologic factors that may have prognostic importance. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding the monitoring and management of measurable (minimal) residual disease.