Citations

Diffusion MRI (dMRI) enables assessment of white matter microstructural abnormalities in Alzheimer's disease (AD), and multisite datasets enable more robust modeling of non-biological variation that can confound analyses. The Alzheimer's Disease Neuroimaging Initiative (ADNI) includes over 10 dMRI protocols, necessitating robust methods to model protocol-related variability when pooling data. Here, we compared three harmonization approaches: (1) mixed-effects models, (2) ComBat-GAM, and (3) eHarmonize, a reference-based lifespan method. We assessed their ability to reduce protocol-related variability in diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD) while preserving associations with cognitive impairment (CI), and amyloid-beta (Aβ) and tau PET burden in 1,086 ADNI3/4 participants. All approaches yielded more closely aligned FA/MD distributions across protocols. Associations with clinical indicators of CI were highly consistent across approaches, whereas PET associations were less widespread and more variable. Overall, multiple strategies effectively modeled protocol-related variability while preserving AD-related associations.

Abstract Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.

Abstract Background The expanding use of biologic and small-molecule therapies for ulcerative colitis (UC) has raised concerns regarding perioperative safety. We conducted a network meta-analysis to compare short-term postoperative complications associated with preoperative exposure to these agents in patients undergoing colorectal surgery. Methods We systematically searched PubMed, Web of Science, and the Cochrane Library through September 15, 2025, for cohort studies of adults with UC who were exposed to biologic or small-molecule therapy within 12 weeks prior to surgery. Interventions included biologic therapy, small-molecule therapy, and no biologic or small-molecule therapy (control). The primary outcome was overall postoperative complications at 30 and 90 days. Venous thromboembolism (VTE) was assessed as a key secondary outcome. Random-effects network meta-analysis was performed using risk ratios (RRs) with 95% confidence intervals (CIs). Results Sixteen retrospective cohort studies involving 3235 patients were included. At 30 days, ustekinumab and tofacitinib were associated with lower overall postoperative complication rates than control (RR: 0.29; 95% CI: 0.09-0.96; and RR: 0.66; 95% CI: 0.46-0.96, respectively). Anti-tumor necrosis factor (TNF) therapy was associated with higher complication rates compared with vedolizumab, ustekinumab, and tofacitinib at 30 days (RR: 1.27; 95% CI: 1.00-1.63; RR: 3.67; 95% CI: 1.12-12.03; and RR: 1.61; 95% CI: 1.14-2.27, respectively). At 90 days, anti-TNF therapy was associated with higher complication rates than control (RR 1.20, 95% CI 1.03-1.40), although the 90-day analysis was based on limited data. VTE rates were similar across treatments at both time points. Conclusion Preoperative ustekinumab and tofacitinib were associated with fewer 30-day postoperative complications than control or anti-TNF therapy, while vedolizumab was associated with fewer complications than anti-TNF therapy. At 90 days, anti-TNF therapy was associated with higher complication rates compared with control. These findings, particularly at 90 days based on limited data, should be interpreted with caution and require confirmation in well-designed prospective studies with rigorous adjustment for confounding factors.

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Aims Testicular sex cord‐stromal tumours (TSCSTs) are rare neoplasms that arise from (or show differentiation to) elements derived from the sex cords or intertubular stroma. The current classification (World Health Organization, 2022) is based almost entirely on morphology, with many tumour types such as granulosa cell tumours being defined based on their resemblance to ovarian counterparts. Recent studies have uncovered new clinicopathological, molecular and biological nuances within this group of tumours, underscoring differences with ovarian homologues. Methods and results Considering the new data, a group of genitourinary pathology experts (Testicular Sex Cord‐Stromal Tumour [TESST] group) has proposed a revised ‘TESST classification’ that incorporates the best available evidence. This classification is structured and hierarchical, composed of the following tiers: (1) group, (2) category, (3) entity and (4) histological pattern. ‘Group’ refers to the histological compartment a specific tumour belongs to (sex cords, stroma or both), whereas ‘category’ is defined by the phenotype of the tumour, taking non‐neoplastic elements of the ovary and testis as a reference. The third tier, ‘entity’, refers to neoplasms with shared clinicopathological and/or molecular features that justify classifying them as distinct types. Lastly, ‘histological patterns’ are recurrent morphological variations within entities that are not linked to distinct clinicopathological or molecular features. Conclusions We propose a classification that will provide a framework to improve current clinical management and guide future research in the field.

PURPOSE Precision medicine has revolutionized oncology; however, tumor biomarkers are not reflective of the heterogeneous cancer population. We evaluated NRG Oncology prostate cancer (PCa) clinical trials for demographic differences among patients with optional biospecimen collection (BC) consent and biospecimen submission (BSub). METHODS Data from 19 NRG PCa clinical trials closed before 2015 were analyzed. Patients who consented to BC and completed BSub were evaluated by race, ethnicity, median income, area deprivation index (ADI; categorized as highest v lowest three quartiles), age at enrollment, site, and year of enrollment. T/chi-square tests were used for continuous/categorical variables, respectively, followed by logistic regression. RESULTS Of the 15,648 randomized patients eligible for BC, 11,796 (75%) had specimens submitted. In all, 4,598 (82.2%) of 5,597 eligible patients consented for optional BC in nine clinical trials with a separate BC consent process (consent rates by race/ethnicity: 74.1% Black, 72.8% Hispanic/Latino, 83.8% White). A smaller proportion of Black and Hispanic/Latino patients consented to optional BC compared with those who did not (12.1% v 19.5% Black, P < .0001; 3.5% v 5.8% Hispanic, P = .0006). In univariable logistic regression models, high ADI (more socioeconomic disadvantage) was associated with a decreased likelihood for optional BC consent (odds ratio [OR], 0.67 [95% CI, 0.55 to 0.82]; P = .02), but not a decreased likelihood for BSub (OR, 0.74 [95% CI, 0.53 to 1.04]; P = .08). Multivariable models demonstrated that Black/Hispanic/Latino patients were less likely to consent to optional BC, and Black patients were less likely to have BSub ( P < .05 for all). CONCLUSION White/non-Hispanic patients and those with less socioeconomic disadvantage were more likely to consent to optional BC, whereas Black patients were less likely to have BSub. Targeted solutions are needed to improve biorepository representation so that precision medicine approaches better reflect the cancer population.

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O 6 - methylguanine DNA methyltransferase ( MGMT ) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1–mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.