Citations

Temozolomide (TMZ) remains the cornerstone of chemotherapeutic agent for glioblastoma (GBM), yet intrinsic and acquired resistance severely limits its clinical benefit. While O6-methylguanine-DNA methyltransferase (MGMT)–mediated repair of TMZ-induced O6-methylguanine (O6-meG) lesions has been extensively studied, the DNA mismatch repair (MMR) pathway is increasingly recognized as a key determinant of TMZ cytotoxicity. Canonical MMR, mediated by MutSα (MSH2–MSH6) and MutLα (MLH1–PMS2) complexes, recognizes O6-meG: thymine mispairs generated during replication and initiates futile repair cycles that culminate in replication stress, replication fork collapse, and apoptotic signaling; intact canonical MMR is, therefore, required for TMZ-induced cell death. Disruption of canonical MMR, frequently via acquired MSH6 mutations, confers TMZ tolerance and drives hypermutated recurrent GBM. Beyond mismatch correction, MMR proteins perform non-canonical functions in DNA damage signaling, replication stress responses, transcriptional regulation, chromatin dynamics, and immune modulation. These activities may shift the outcome from cytotoxic futile repair toward replication stress adaptation, Translesion synthesis (TLS)-mediated lesion tolerance, immune remodeling, and therapeutic resistance. Notably, partial attenuation or functional diversion of MMR may decouple lesion recognition from cytotoxic signaling, enabling TLS-mediated lesion tolerance without complete loss of MMR activity. This review integrates current insights into canonical and non-canonical MMR functions in GBM, defines their distinct contributions to TMZ sensitivity and resistance, and highlights therapeutic opportunities to exploit MMR-associated dependencies, including synthetic lethal strategies and immunotherapeutic vulnerabilities linked to MMR deficiency-driven hypermutation.

Acanthosis nigricans (AN) is a common dermatologic condition characterized by hyperpigmented, velvety plaques that most frequently affect intertriginous areas. Although often associated with insulin resistance and obesity, AN may also serve as a cutaneous marker of underlying endocrinologic disorders, medication effects, genetic syndromes, or internal malignancy. Recognition of AN provides an important opportunity for early identification of systemic disease and implementation of targeted management strategies. This review summarizes the pathogenesis and etiologic subtypes of AN, highlights key clinical features and differential diagnoses, and outlines an evidence-based diagnostic approach. Management strategies are discussed with emphasis on lifestyle modification, pharmacologic therapies, topical treatments, procedural interventions, and the strength of supporting evidence. Practical considerations relevant to physician assistants are emphasized throughout, including interdisciplinary care and patient education. Early recognition and appropriate management of AN can improve both dermatologic outcomes and overall patient health.

Introduction: Limited research explores dermoscopy use among physician associates (PAs), outside of one prior study examining dermoscopy in PA student education. This study sought to investigate dermoscopy use among practicing PAs and its impact on their overall diagnostic confidence, including in darker skin tones, when differentiating between benign and malignant skin lesions. Methods: An anonymous survey was developed in 2023 with input from experts in dermoscopy and survey creation to assess PA confidence in skin lesion evaluation as well as PA dermoscopy knowledge and use, perceptions, barriers to use, and prior education. The dermoscopy survey was included as an optional module in the 2024 American Academy of Physician Associates (AAPA) Salary Survey. Results: Of 3,174 invited PAs, 995 (31.4%) responded. Most had never used dermoscopy in practice (81%) but knew or recognized the term (71%). A majority (53%) believed PAs should be trained in dermoscopy during PA school, and 26% reported no interest in future dermoscopy use. Dermatology PAs reported more frequent dermoscopy use and generally greater confidence in evaluating skin lesions, both overall and in darker skin tones, than PAs in other specialties. PAs in surgical (OR=0.2, 95% CI 0.1-0.6) and medical (OR=0.3, 95% CI 0.2-0.5) subspecialties were less likely to use dermoscopy at least annually compared with PAs in primary care. PAs in rural areas were more likely to feel confident in differentiating skin lesions than those in urban areas (OR 2.9, 95% CI 1.7-5.0). Conclusion: Dermoscopy use is associated with higher overall skin lesion assessment confidence. Wider adoption, especially outside dermatology, requires training, increased advocacy, and expanded education.

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

Abstract Background Appendectomy has been proposed to influence ulcerative colitis (UC) outcomes, but its effect based on timing before or after diagnosis and long-term UC outcomes remains unclear. Materials and Methods Using TriNetX U.S. Collaborative Network, we identified adults with UC (2010-2024) who underwent appendectomy before or after diagnosis. Two 1:1 propensity score-matched comparisons were performed: appendectomy-before-UC and appendectomy-after-UC versus controls. The primary outcome was a 5-year composite of oral/intravenous (IV) corticosteroid use or colectomy. Secondary outcomes included individual composite outcomes and advanced therapy initiation in biologic-naive patients. Subgroup analyses stratified by age and biologic exposure were also performed. Results After matching, appendectomy after UC diagnosis showed no association with the composite outcome (aHR 0.98, 95% CI, 0.83-1.16), oral steroids (aHR 0.90, 95% CI, 0.75-1.09), IV steroids (aHR 1.11, 95% CI, 0.87-1.43), colectomy (aHR 1.24, 95% CI, 0.77-1.99), or advanced therapy initiation (aHR 0.97, 95% CI, 0.63-1.48). Appendectomy before UC diagnosis also showed no difference in the composite outcome (aHR 0.91, 95% CI, 0.76-1.09), oral steroids (aHR 0.88, 95% CI, 0.72-1.08), colectomy (aHR 0.99, 95% CI, 0.60-1.63), or advanced therapy initiation (aHR 0.77, 95% CI, 0.53-1.13). However, IV steroid use was reduced (aHR 0.68, 95% CI, 0.51-0.90, P = .006). In subgroup analyses, advanced therapy initiation was lower in patients aged 18-40 years following appendectomy after UC diagnosis (aHR 0.56, 95% CI, 0.33-0.96, P = .03). Conclusion Appendectomy was not associated with improved long-term UC outcomes of oral/IV steroid use, colectomy or initiation of advanced therapy regardless of timing.

Whole-body cross-sectional imaging has largely replaced skeletal survey as the standard for evaluating hematologic malignancies and bone marrow disorders, but the practical choice between whole-body low-dose CT (WBCT) and whole-body MRI (WBMRI) remains incompletely resolved. This clinical review provides a practical, scenario-based comparison of WBCT and WBMRI across diagnosis, staging, treatment response, and surveillance. We emphasize real-world practical considerations, including scanner access, expertise, patient tolerance, radiation considerations, and cost. In multiple myeloma, with available comparative evidence, we include a focused research synthesis of 3 studies (152 patients) demonstrating high pooled CT-MRI concordance of 0.895 (95% CI: 0.834-0.935) with no detectable heterogeneity ( I 2 =0%), supporting either modality as a reasonable first-line depending on the clinical question. Across all included disease categories, the broader pooled concordance estimate was 0.797 (95% CI: 0.667-0.885) with substantial heterogeneity reflecting variability in clinical context, reference standard, and protocol. WBMRI dominates in non-neoplastic marrow disorders where marrow characterization is essential. In lymphoma, FDG-PET/CT remains the standard for adult disease, with WBMRI most indicated in pediatrics and adolescents. Emerging CT techniques, including dual-energy CT with virtual noncalcium images and photon-counting detector CT, are extending CT into the marrow imaging space and narrowing the historical gap with MRI. Modality selection should be guided by the specific clinical scenario, available resources, and patient factors rather than by global judgments of modality superiority.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

BACKGROUND: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. METHODS: We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50–101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 fluid-attenuated inversion recovery-MRI and diffusion MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). RESULTS: The study population had a mean age of 78 years, 47% were women, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for fluid-attenuated inversion recovery-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Female participants showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas male participants exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. CONCLUSIONS: Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.