Citations

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.

Abstract Alzheimer’s disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

ABSTRACT Objective To evaluate intracochlear electrocochleography (ECochG) amplitude parameters during cochlear implantation (CI) using a novel multi‐frequency ECochG algorithm. Methods A multi‐institutional, prospective cohort study was performed at 18 high‐volume CI centers. The inclusion criteria were adults with sensorineural hearing loss and audiometric thresholds of ≤ 90 dB hearing level at 500 Hz undergoing CI with Advanced Bionics (Valencia, CA) Ultra 3D devices between 2024 and 2025. ECochG recordings were performed with simultaneous multi‐frequency stimulation of four frequencies between 125 and 4000 Hz during cochlear implant insertion. Concurrent multi‐frequency recording allowed extraction of amplitude and phase of each frequency individually. Post hoc analysis was performed to determine the difference in the number of drop alarms between single‐ and multi‐frequency ECochG. An ECochG amplitude drop of 6 dB was defined as a drop alarm. Insertion track patterns were compared between single‐ and multi‐frequency ECochG. Results One hundred ninety‐five ears were included. Mean number of drop alarms for the single‐frequency algorithm was 1.72 (95% CI: 1.52, 1.92; median 1) compared to 0.42 (95% CI: 0.31, 0.53; median 0) for multi‐frequency; p < 0.001. The number of Type C patterns (rise in amplitude during insertion followed by a drop) decreased with the multi‐frequency ECochG algorithm compared to the single‐frequency ECochG algorithm. The number of Type D patterns (no‐response) decreased, indicating that multi‐frequency ECochG generated more responses across the cochlea than single‐frequency ECochG. Conclusions A novel multi‐frequency ECochG algorithm during CI is associated with fewer drop alarms and altered insertion track patterns, which may provide a more accurate assessment of the cochlear microenvironment. Level of Evidence 3.

Purpose: To evaluate the impact of PSMA PET versus conventional imaging for staging, and the effect of dose escalation (DE) to metastatic lymph nodes in cN1 prostate cancer patients treated with EBRT and ADT. Methods: A retrospective multicenter analysis included 197 propensity score-matched patients (77 staged with PSMA PET, 120 with conventional imaging) treated with EBRT and ADT, with or without DE to lymph node metastases. Matching criteria were T stage, nodal involvement, imaging modality, Gleason score, and ADT duration. Primary endpoint was metastasis-free survival (MFS); secondary endpoints included overall survival (OS), locoregional control (LRC), and toxicity. Results: Median follow-up was 42 months (IQR: 25–59). Median EQD2 (alpha/beta=1.5) to elective nodes was 46 Gy, and to metastatic nodes, 66 Gy (PSMA PET) and 63 Gy (conventional imaging). The 3-year MFS was 80.5% (95% CI: 71.3–90.8%) for PSMA PET and 77.2% (95% CI: 69.5–85.8%) for conventional imaging; 5-year MFS was 59.3% versus 65.8% ( P =0.57). OS at 5 years was 82.2% (PSMA PET) and 77.4% (conventional imaging) ( P =0.72). On multivariable analysis, ISUP grade group 3–5 predicted earlier metastasis (HR: 4.03, 95% CI: 1.61–10.06; P =0.003); higher prostate dose (EQD2 ≥113 Gy) improved MFS (HR: 0.53, 95% CI: 0.30–0.95; P =0.033); long-term ADT (≥24 mo) improved OS (HR: 0.38, 95% CI: 0.19–0.78; P =0.009). No significant difference in toxicity was observed between groups. Conclusions: PSMA PET staging and nodal dose escalation >60 Gy were safe but did not improve MFS, OS, or LRC. ISUP grade group 3–5 and higher prostate dose significantly influenced outcomes.

Abstract Glioblastoma (GBM), isocitrate dehydrogenase wild-type (IDHwt) and central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) are aggressive brain tumors with overlapping MRI features, yet distinct treatment approaches. Noninvasive tools are needed to aid in differential diagnosis. Deep learning on T1 postcontrast and T2-weighted MRI sequences were used to differentiate GBM and CNS-DLBCL. A three-stage temporal study design was utilized. Model development was performed on 146 patients with CNS-DLBCL and 146 age-matched, sex-matched, and MRI year–matched patients with GBM diagnosed at Mayo Clinic between 1998 and 2019. Models were tested on independent temporal test cohorts. Initial testing included 240 independent GBM diagnosed at Mayo Clinic between 1998 and 2019. The prospective test cohort included 37 patients with CNS-DLBCL and 256 patients with GBM diagnosed at Mayo Clinic after January 1, 2020, and 36 patients with CNS-DLBCL diagnosed at an external institution. Of the patients diagnosed at Mayo Clinic, 47% had MRIs generated from non-Mayo institutions. Two different model approaches were compared: (i) ensemble approach using area under the receiver operating characteristic curve (AUC) and cross-validation for model selection and (ii) loss approach minimizing cross-entropy loss and cross-validation to evaluate prediction performance. The AUCs on the prospective test cohort were 0.84 [95% confidence interval (CI), 0.78–0.90] and 0.83 (95% CI, 0.77–0.88) for the ensemble and loss approaches, respectively. Stability of ensemble prediction improved with the increasing number of models. Stratified AUC analysis demonstrated consistent performance across sex and age. We utilized a robust temporal study design and applied 2 different analytic approaches to develop a classification model. The findings confirm the feasibility of using MRI-based deep learning models to differentiate GBM from CNS-DLBCL. Significance: GBM, IDHwt and CNS-DLBCL are aggressive brain tumors with overlapping MRI features, yet distinct treatment approaches. Noninvasive tools are needed to aid in differential diagnosis. We developed MRI-based deep learning models to differentiate GBM, IDHwt from CNS-DLBCL using a rigorous three-stage temporal design that included prospective validation. The model AUC on a prospective cohort was 0.84.

Abstract INTRODUCTION : Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early‐onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well‐characterized sample with sporadic EOAD. METHODS : Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early‐onset non‐AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS : After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p‐tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non‐amnestic cognitive impairment across the sample. DISCUSSION : These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD‐specific and non‐specific plasma markers may play across the course of AD care.

Background Strengthening emergency care systems could reduce death and disability in low- and middle-income countries (LMICs), yet many struggle to provide timely, high-quality care. LMICs also face growing risks from climate-related shocks and mass casualty events. This study identifies unmet emergency care needs in Nepal—one of the world’s most climate-vulnerable countries—using high-resolution geospatial data to estimate socioeconomic and climate-related inequalities. Methods We conducted a cross-sectional geospatial analysis using data from the 2022 Nepal Demographic and Health Survey (DHS), the 2021 DHS Service Provision Assessment and publicly available climate vulnerability data. Government hospitals were classified into three emergency care levels using World Health Organzation criteria: A (basic 24-hour services), B (A plus resuscitative capabilities) and C (B plus ≥50 beds and a surgeon). Household location and injury data were obtained from the DHS. Accessibility was defined as the proportion of the population within 1-hour and 2-hour travel times, estimated using AccessMod 5.8, incorporating road networks, rivers, land cover and elevation. Findings Most public hospitals (77.7%) met Level A criteria but only 49.3% met Level B and 10.8% met Level C. Nationally, 78.7% of households had 1-hour access to Level A care, 71.8% to Level B and 44.6% to Level C. Adjusted logistic regression showed rural, poorer and climate-vulnerable households had significantly lower 1-hour access compared with urban households, rural households had lower odds of access: Level A OR: 0.33 (95%CI 0.30 to 0.37), Level B OR: 0.33 (95%CI 0.30 to 0.36), Level C OR: 0.56 (95%CI 0.51 to 0.61). Households in high climate vulnerability areas had reduced access across all levels. Conclusions Substantial gaps and inequities in timely access to high-quality emergency care exist in Nepal. Rural, poorer and climate-vulnerable populations experience markedly lower access. Targeted, decentralised strengthening of emergency care capacity is essential both in Nepal and in other LMICs facing similar constraints.

Introduction: Abnormal sleep has been linked to increased dementia risk, but the pathophysiological processes driving this connection are unclear. To provide insight into the biological pathways underlying the relationship between sleep and brain health, we tested the hypothesis that increased obstructive sleep apnea (OSA) severity and shorter habitual sleep duration are associated with a higher burden of Alzheimer’s disease (AD) pathology, neurodegeneration, and neuroinflammation measured through plasma biomarkers. Methods: ARIC participants who took part in the Sleep Heart Health Study at Visit 4 (1996-98) with stored plasma samples at Visit 3 (1993-95) and Visit 5 (2011-13) were examined (n=261; mean age 61.3 years; 43.3% male). OSA severity, categorized based on the number of apneas and hypopneas per hour of sleep (<5 events/hour [Normal], 5 to <15 events/hour [Mild OSA], or ≥15 events/hour [Moderate/Severe OSA]) was assessed via in-home polysomnography, and average habitual sleep duration (<7 hours, 7 to <8 hours, or ≥8 hours) was self-reported. Plasma biomarkers of amyloid beta (Aβ) 42 and 40, phosphorylated Tau 181 (p-Tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa immunoassays. Covariate-adjusted linear regression models estimated associations of sleep indices in 1996-98 with standardized plasma biomarker measurements in 1993-95 (3 years earlier) and in 2011-13 (15 years later). Covariate-adjusted linear mixed effects models quantified associations of sleep measures with the 5-year rates of change in standardized biomarker levels (1993-2013). Results: Compared to a habitual sleep duration of 8 hours or more, sleeping less than 7 hours per night was associated with higher NfL, a biomarker of neurodegeneration, 15 years later (β = 0.252; 95% confidence interval [CI]: 0.003, 0.501). Sleep indices were not associated with biomarker levels 3 years earlier. Counter to our hypothesis, Moderate/Severe OSA was associated with slower increases in p-Tau181 (β = -0.102; 95% CI: -0.198, -0.006), a biomarker of AD pathology, over a median of 17.9 years. Conclusions: Short habitual sleep duration may impact dementia outcomes through neurodegenerative and other processes rather than through pathways specific to AD pathology or neuroinflammation. Longitudinal studies with sleep measurements in larger, more diverse samples are needed to further distinguish the pathways linking sleep to dementia.

Abstract Cerebellopontine angle (CPA) tumors, including vestibular schwannomas (VS), often require microsurgical resection. These are typically surgical procedures performed by co-surgeons, and some controversy and confusion exist regarding use of common procedural terminology (CPT) codes for billing, given the American Medical Association (AMA) describes two distinct coding sets for such cases. This investigation endeavored to: (1) Comprehensively review all surgical coding options; (2) instruct on application; and (3) explore contemporary coding trends among surgeons. A multi-disciplinary task force (otologist/neurotologists and neurosurgeons) performed direct correspondence with various surgical societies, private consultancies, and the AMA. Survey instruments were distributed to active surgeons. Investigational period: 2022 to 2025. Survey instruments distributed at the 2023 American Neurotology Society (ANS) Fall Meeting. ANS, American Academy of Otolaryngology (AAO-HNSF), and the North American Skull Base Society (NASBS) representatives. Usage rate for CPT code sets (percentage of responders). Two CPT coding systems are currently accepted for surgical management of CPA tumors. The traditional/legacy codes (Indicator-2) allow use of co-surgery modifiers (-62). The newer approach/resection codes (skull base codes; Indicator-1) restrict modifier use. The history, application, and controversies surrounding the codes are detailed herein. About 40% of surgeons reported use of the traditional codes, while 45 to 49% use the skull base codes. Response rate was 31% of the active ANS membership in 2023. The AMA recognizes two CPT code sets for surgical management of CPA tumors. Both are appropriate, if properly applied. Contemporary surgeons likely utilize the sets in equal proportions.