Citations

ABSTRACT Introduction/Aims Ultrasound (US) guidance may ensure proper needle placement during electromyography (EMG) when assessing for suitable donor muscles for upper limb reconstruction. A distinct intermuscular fascial border aids in delineating the separation between the brachioradialis (BR) and extensor carpi radialis longus (ECRL) muscles. However, this border may be absent, making correct needle placement complex and assessment more difficult. The purpose of this study was to describe the presence and absence of this fascial border in healthy individuals to help with accurate EMG needle placement. Methods Twenty healthy patients underwent sonographic examination by a single sonographer physician of the ECRL and BR to identify the presence or absence of the intermuscular fascial border. Results The fascial border that routinely separates the ECRL and BR was absent in at least one arm in 20% of subjects (12.5% of upper limbs). One subject had an absent fascial border in both upper limbs. Discussion US can assess for the presence or absence of intermuscular fascial borders. This assessment is important for accurate EMG needle placement and localization. While the clinical significance of an absent ECRL‐BR fascial border is currently unknown, future studies should examine the effect of absent ECRL‐BR fascial borders on wrist extension.

ABSTRACT The American Board of Dermatology (ABD) Continuing Certification Program (CCP) for board‐certified dermatologists helps advance its vision, which includes quarterly web‐based knowledge assessments. In 2022, the ABD began a review of gaps in knowledge assessment, practice improvement reporting, and areas of educational interest. The American Board of Medical Specialties directed member boards to share frequently occurring deficits with specialty societies to identify and prioritize gaps. This report summarizes pediatric dermatology findings from this review.

Abstract Uterine leiomyosarcoma (ULMS) is an orphan disease that frequently recurs and metastasizes, with patients undergoing multiple lines of chemotherapy due to lack of effective therapeutic targets. To address this gap, we used single-cell RNA sequencing and spatial transcriptomic analysis to comprehensively profile ULMS. We uncovered multiple states of tumor cells, including tumor cells with mesenchyme-like features, ischemic tumor cells defined by a MYC program, inflammatory tumor cells with active interferon signaling, and stem cell-like hormone receptor-positive cells. The inferred spatial correlates of these tumor cell states demonstrated unique localization patterns. By correlating these signatures to bulk RNA sequencing data, we demonstrate the relevance of these findings to clinical outcomes. Finally, using the single-cell integration and drug response prediction algorithm (scIDUC), we propose drug predictions that may target specific tumor states. Our findings suggest new avenues for further exploration of individualized and multifaceted therapeutic strategies to treat ULMS.

Abstract Two recent studies suggested that the APOE ε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in the SNCA region have strong association with Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and idiopathic REM sleep behaviour disorder (iRBD), while APOE is a genetic risk determinant for only DLB. To determine if genetic-level interactions between SNCA and APOE exists that can explain the protein-level association, we investigated the genotypic interaction of APOE and SNCA in cohorts of PD, DLB and iRBD. We analysed genome-wide association study (GWAS) data from 5229 PD patients and 5480 controls, 2610 DLB patients and 1920 controls, and 1055 iRBD patients and 3667 controls. We used logistic regression interaction models across all three cohorts independently between the (i) top GWAS signals of SNCA single nucleotide polymorphisms (SNPs) and APOE haplotypes and (ii) SNP×SNP and three-way SNP interaction across the entire coding region plus 200 kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions between APOE and SNCA across PD, DLB and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them do not affect the risk of PD, DLB and iRBD.

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

ABSTRACT Background We recently published the first real‐world multicenter and multi‐institutional study of cisplatin, gemcitabine, and durvalumab in patients with advanced biliary tract cancer (BTC). Here we present an expanded patient cohort with an increased sample size and longer median follow‐up. Methods The study population included patients with advanced BTC, who received cisplatin/gemcitabine plus durvalumab at 55 centers across 12 countries in Europe, the United States, and Asia. The primary endpoints of the study were progression‐free survival (PFS) and overall survival (OS). Secondary endpoints were overall response rate (ORR) and safety. Results Overall, 1358 patients were enrolled. Median PFS was 7.6 months (95% CI: 7.2–8.1), and median OS was 15.6 months (95% CI: 14.8–16.5). ORR was 35.6%, and DCR was 82.7%. Any grade AEs occurred in 1213 patients (89.3%). Grade 3–4 AEs occurred in 597 patients (43.2%). The rate of immune‐related AEs (irAE) was 20.3%. Grade 3–4 irAE occurred in 3.0% of patients. At the multivariate analysis for OS, normal albumin level (HR 0.68, 95% CI 0.57–0.81, p < 0.0001), CEA levels within normal ranges (HR 0.68, 95% CI 0.57–0.82, p < 0.0001), NLR < 3 (HR 0.62, 95% CI 0.52–0.74, p < 0.0001), ECOG PS 0 (HR 0.51, 95% CI 0.42–0.61, p < 0.0001), and prior surgery (HR 0.80, 95% CI 0.65–0.99, p = 0.036) were positive prognostic factors. Conclusion The updated findings, derived from an expanded cohort, further support the adoption of durvalumab in combination with gemcitabine and cisplatin in routine clinical practice, reinforcing the efficacy and safety outcomes demonstrated in the phase III TOPAZ‐1 trial.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR‐CM compared with heart failure. Methods In this multicenter, observational study, patients with ATTR‐CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all‐cause death alone or combined with heart failure hospitalization. Results Patients with ATTR‐CM (median age, 76 [interquartile range, 72–83] years, 98% men, left ventricular (LV) ejection fraction 30% [26–33]) showed greater QRS shortening after CRT implantation ( P =0.012), but not after a median of around 1 year ( P =0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P =0.124), or to the last echo ( P =0.796), which was performed after 1.3 years in patients with ATTR‐CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR‐CM had a shorter survival than controls ( P <0.001 for both end points). Patients with ATTR‐CM experiencing an early improvement in LV ejection fraction had a longer survival (log‐rank, 4.3; P =0.038). Conclusions Following CRT implantation, patients with ATTR‐CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all‐cause death.

Abstract Context Benign thyroid nodules (BTNs) are highly prevalent, and current treatment options are primarily invasive. There is a need for effective, noninvasive alternatives. Objective To systematically evaluate the efficacy of repurposed pharmacologic agents in reducing the size of BTNs. Data Sources MEDLINE, EMBASE, Cochrane databases, and Scopus were searched from inception to December 18, 2024. Study Selection We included preclinical and clinical studies evaluating repurposed drugs for BTNs in adults. Of 1499 records screened, 20 studies met inclusion criteria: 6 randomized controlled trials (RCTs), 6 prospective cohorts, 3 retrospective observational studies, 3 case reports, 1 cross-sectional study, and 1 preclinical study. Data Extraction Data were extracted independently in duplicate using a standardized form. Data Synthesis Narrative synthesis was conducted due to heterogeneity. Metformin was the most frequently evaluated agent (7 studies), with 5 studies (including 2 RCTs) reporting statistically significant reductions in dominant nodule volume. One prospective study demonstrated a reduction in the maximum nodule diameter, which was not statistically significant, and 1 RCT showed no changes in nodule size after intervention. Statins (4 studies) and somatostatin analogues (4 studies) showed mixed results. Myo-inositol with selenium, herbal formulations, and immune checkpoint inhibitors showed promise in single studies or case reports. Conclusion Metformin shows the most consistent potential for noninvasive reduction of BTN size, particularly in patients with metabolic comorbidities. However, current evidence is limited and heterogeneous. Further large-scale studies are needed to confirm efficacy and guide clinical use.

Abstract Diffuse midline glioma (DMG) is a universally fatal pediatric brainstem cancer. Outside of clinical trials, palliative radiotherapy (RT) remains the only approved treatment, with a median overall survival (OS) of &lt;12 months. The brain-penetrant oral therapy dordaviprone (ONC201) has demonstrated early clinical efficacy by activating the overexpressed mitochondrial protease ClpP, inducing mitochondrial dysfunction. Our previous studies identified that dordaviprone triggers compensatory energy production via the PI3K/mTOR pathway to avoid cell death. To overcome this adaptation, we combined dordaviprone with the brain-penetrant pan-PI3K/mTOR inhibitor paxalisib, showing synergistic anti-tumor effects across multiple immunocompromised patient-derived xenograft models. These results led to the international Phase II clinical trial (PNOC022/NCT05009992), where &gt;20% of patients enrolled pre-radiation achieved survival beyond 2 years. However, approximately 20% of patients experienced immune-related toxicities-mucositis, colitis, and skin reactions, likely driven by paxalisib’s pan-PI3K inhibition, as PIK3CG (p110γ) and PIK3CD (p110δ) are enriched in hematopoietic cells. In contrast, PIK3CA (p110α) is a known genetic dependency in DMG. We hypothesized that the brain-penetrant, p110α-selective inhibitor GCT-007 could maintain therapeutic efficacy while reducing immune toxicity. DMG patient-derived cell lines showed comparable sensitivity to paxalisib and GCT-007 (mean IC50: 0.659 μM vs. 0.775 μM, respectively). Unbiased proteomic profiling in two DMG lines treated with GCT-007 identified robust downregulation of PI3K/AKT/mTOR signaling, confirmed via immunoblotting. Pathway enrichment further showed upregulation of oxidative phosphorylation, reinforcing the rationale for synergistic combination with dordaviprone. In aggressive immunocompetent syngeneic models, GCT-007 significantly extended overall survival (median 53 vs. 40 days, p=0.0001). When combined with dordaviprone, enzastaurin, or immune checkpoint inhibitors (ICI), GCT-007 increased survival in immune-competent DMG models by an average of 53% to 77% compared to vehicle (p=0.001), with 25% of mice in the GCT-007 + ICI cohort achieving long-term survival. Ongoing spatial profiling of the tumor immune microenvironment and organ-toxicity screening is underway to support translation.