Citations

TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43–dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN , RAP1GAP , SYT7 , and KCNQ2 . Using human stem cell–derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

Abstract Isolated cardiac sarcoidosis (iCS), defined by granulomatous inflammation limited to the myocardium, represents the most diagnostically challenging and prognostically adverse form of sarcoidosis. As it is fundamentally a diagnosis of exclusion, iCS diagnosis relies on the absence of extracardiac sarcoid and the integration of multimodality imaging, endomyocardial biopsy, and molecular testing, each with inherent limitations. Cardiac magnetic resonance and positron emission tomography provide complementary assessment of inflammation, fibrosis, and ventricular function, enhancing diagnostic confidence. Electroanatomic mapping-guided biopsy may improve histologic yield, whereas genetic testing helps exclude phenocopies such as arrhythmogenic, hypertrophic, or dilated cardiomyopathies. Circulating biomarkers remain non-specific but may complement imaging-based algorithms. Future research should focus on harmonized imaging protocols, non-FDG radiotracers, and molecular tissue profiling to refine activity assessment and guide therapy. Multimodal, probability-based frameworks represent the most promising approach for earlier, more accurate diagnosis and risk stratification in iCS.

Abstract Darier disease (DD) is a rare autosomal dominant genodermatosis. This comprehensive review, developed by the Darier Disease International Task Force (DDITF), consolidates current knowledge on the genetic basis, molecular pathophysiology, clinical presentation, diagnosis and management of DD, offering a global perspective that unites shared expertise. The disease arises from pathogenic variants in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca 2+ ‐ATPase isoform 2 (SERCA2), leading to disrupted calcium homeostasis and impaired desmosomal integrity. Clinically, DD is classified based on lesion type (classic vs. non‐classic) and is often accompanied by significant extracutaneous manifestations. Management remains challenging and requires a multifaceted approach, including topical therapies, systemic retinoids and lifestyle modifications. Emerging treatments that target the underlying molecular mechanisms offer promise for improved outcomes. This review aims to provide an updated reference and practical guidance for clinicians involved in the care and study of DD.

ABSTRACT Introduction/Aims Patients with cervical spinal cord injury (SCI) prioritize recovery of upper extremity function. Upper extremity reconstruction can restore function in carefully selected individuals. Infralesional cord damage, observed below the neurological level of injury (NLI), may affect postoperative outcomes. We characterized the extent of infralesional lower motor neuron (LMN) injury in patients with traumatic cervical SCI. Methods Each patient underwent electromyography (EMG) of potential donor and recipient muscles based on preoperative clinical evaluation and specific candidacy for nerve and/or tendon transfers. The presence of infralesional pathologic insertional activity (IA), reduced motor unit potential (MUP) recruitment and/or neurogenic MUPs was assessed. The caudal‐most segment with infralesional LMN injury was determined. Inclusion criteria were patients with (1) traumatic cervical SCI; (2) injury ≥ 3 months duration; (3) preoperative planning EMG for nerve and/or tendon transfers. Results Forty‐eight upper extremity EMGs in 25 patients (68% male; mean age 39.5 years at injury) with traumatic cervical SCI were included. The NLI was at C7 or above in each patient, and 64% of SCIs were motor complete. Infralesional EMG abnormalities (median time from injury to EMG 466 days) were found a median of 3.0 (IQR 3.0–4.0) segments below the NLI. Three patients with an NLI as rostral as C1–C2 exhibited LMN injury seven segments below the NLI. Discussion In persons with traumatic cervical SCI, evidence of LMN injury may be observed several segments below the NLI. Defining the true extent of LMN involvement directly informs timing and selection of reconstructive procedures to maximize functional recovery.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

TPS7100 Background: Bruton tyrosine kinase covalent inhibitors (cBTKi) have been transformative in CLL treatment. Despite achieving extended remissions, in most patients disease still relapses despite cBTKi therapy, often associated with BTK C481 mutations. Non-covalent BTKi (ncBTKi), including pirtobrutinib, can overcome this resistance (Sharman et al. ASCO . 2025). Pirtobrutinib received FDA approval in Dec 2025, for R/R CLL/CLL patients pretreated with cBTKi. Rocbrutinib (LP-168) is a highly selective next-generation BTKi that can covalently bind wild-type and gatekeeper mutations (T474X, commonly seen in patients relapsed after pirtobrutinib) and non-covalently target C481-mutated BTK , with preclinical efficacy in treatment-naïve and BTKi-resistant CLL (Gordon et al. IWCLL . 2025). In the rocbrutinib phase 1 trial (NCT04775745), encouraging safety and efficacy have been observed in CLL patients with prior exposure to BTKi and/or BCL2 inhibitor (BCL2i) (Woyach et al. Blood. 2025). Presented here is the design of a phase 3 trial aiming to compare the efficacy of rocbrutinib versus pirtobrutinib in cBTKi-pretreated R/R CLL/SLL patients. Methods: ROCKET-CLL (NCT07342478) is a randomized, open-label, multicenter, phase 3 study comparing rocbrutinib (Arm 1) to pirtobrutinib (Arm 2) in R/R CLL/SLL subjects who previously received treatments including covalent BTKi. Eligible subjects must require treatment per 2018 iwCLL criteria, have measurable lesions by CT, an ECOG performance score of 0-2, and adequate hematologic and other organ functions. About 306 subjects will be randomized 1:1 based on stratification factors such as 17p deletion/ TP53 mutation presence, reasons for discontinuing prior cBTKi, prior BCL2i treatment, and geographic region. Participants assigned to each arm will receive rocbrutinib (200 mg QD) or pirtobrutinib (200 mg QD) tablets continuously until disease progression, unacceptable toxicity, withdrawal, or other study discontinuation criteria are met. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee (IRC) per iwCLL 2018 criteria with CLL (Hallek et al. 2018) and Lugano 2014 criteria with SLL (Cheson et al. 2014). Important secondary endpoints include overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), overall response rate (ORR), duration of response (DOR), PFS assessed by investigator (INV), concordance between IRC and INV PFS, safety and tolerability, and population PK. Exploratory endpoints include health-related quality of life and biomarker assessment. Recruitment is ongoing. Clinical trial information: NCT07342478 .

TPS3686 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA–) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA– (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Accrual is 1,123/1,912 (as of 1/20/2026). *Drs. Dasari and Lieu contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

TPS3675 Background: Multi-agent chemotherapy regimens (eg, mFOLFOX6) ± anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor regimens are currently the standard of care for patients (pts) with mCRC without targetable mutations. However, the 5-year survival rate remains low at approximately 16% (SEER, 2025). The addition of biological therapies (eg, bevacizumab [bev], an anti-VEGF monoclonal antibody) to immune checkpoint inhibitors (ICIs) has demonstrated a synergistic antitumor effect in solid tumors. However, ICI monotherapy has limited activity in mismatch repair proficient (pMMR)/microsatellite stable (MSS) mCRC. Simultaneous bispecific targeting of programmed death 1 (PD-1) and VEGF in conjunction with cytotoxic chemotherapy has the potential to enhance antitumor activity. PF-08634404 is a fully human immunoglobulin G4 (IgG4) bispecific antibody targeting PD-1 and VEGF. A phase 2 study of PF-08634404 with XELOX or mFOLFOX6 demonstrated promising antitumor activity with a manageable safety profile in first-line (1L) mCRC (Xu X, ESMO 2025; Abstract 796P). Methods: Symbiotic-GI-03 (NCT07222800) is an ongoing, double-blind, randomized, phase 3 study evaluating the efficacy and safety of 1L PF-08634404 + mFOLFOX6 vs bev + mFOLFOX6. Inclusion criteria are age ≥18 y; mCRC with measurable disease per RECIST 1.1; no prior systemic therapy for metastatic disease; ECOG PS 0 or 1; and adequate hematologic, hepatic, and renal function. Pts with BRAF V600E-mutant or mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) CRC, active central nervous system metastases, or clinically significant risk of hemorrhage/fistula will be excluded. Approximately 800 pts will be randomized 1:1 to receive PF-08634404 + mFOLFOX6 or bev + mFOLFOX6 until disease progression, unacceptable toxicity, withdrawal of consent, or death. Randomization will be stratified by region (North America, Europe, or rest of world), RAS status (mutant or wildtype), and presence of liver metastasis (yes or no). The dual primary endpoints are progression-free survival (PFS) by blinded independent central review and overall survival; for each, a stratified log-rank test will be used to compare arms. Hazard ratios with corresponding 2-sided 95% CIs will be estimated using a stratified Cox proportional hazards model, and medians will be estimated using the Kaplan-Meier method with corresponding 2-sided 95% CIs calculated using the log(-log) method. Secondary endpoints include PFS by investigator, objective response rate, duration of response, PFS after next-line therapy, safety/tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes. Enrollment began in December 2025. Clinical trial information: NCT07222800 .

TPS10628 Background: Despite advances in cancer treatment, a lack of established population-level cancer screening strategies for early detection across cancer types contributes to cancer-related mortality. Emerging MCED liquid biopsy tests represent a screening approach with potential to enable detection of multiple malignancies at earlier stages in the disease process. We previously showed that an initial classifier based on a genome-wide methylome enrichment platform detected 12 cancer types, including early-stage, low-shedding tumors (Park et al. AACR 2023. Abs 1030). However, clinical performance of the platform has not been evaluated prospectively. Thus, the CAMPERR study (NCT05366881) was designed to train and validate a cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMeDIP-seq)-based test for detection and differentiation of 20 pre-selected cancer types, representing 93% of annual cancer incidence and 88% of annual cancer deaths. Longitudinal follow-up for a subset of participants with lung cancer will enable training and validation for MRD-based recurrence prognostication. Methods: This case-control study is enrolling participants with 20 different pre-specified cancer types (n=2400) and those without known cancer (n=3900). Eligible participants are ≥40 years of age and not receiving treatment for cancer at the time of enrollment or taking any demethylating/hypomethylating agents. Cases include individuals with newly diagnosed (≤120 days), untreated cancer or recurrence of a cancer originally diagnosed >5 years ago. Cancers of interest are stage I-IV bladder, brain, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatobiliary, leukemia, lung, lymphoma, multiple myeloma, ovarian, pancreatic, prostate, renal, sarcoma, and thyroid. Participants with stage I-III lung cancer will have clinical follow-up and blood draws after completion of first-line treatment, every 3 mo for the first year thereafter, and every 6 mo for an additional 2 years. Eligible control participants have not been diagnosed with invasive cancer in the last 5 years and will have clinical follow-up ≥12 mo from enrollment to evaluate cancer status. Liquid biopsy results will not be returned to clinicians or participants. The primary objective is cancer detection. Secondary objectives include detection of specific cancer types, identification of the tissue of origin, and prognostication of clinical outcomes (eg, recurrence-free survival, overall survival). CAMPERR is currently enrolling at 15 sites. As of December 3, 2025, 2108 of 2400 cancer cases have been enrolled, including prostate (n=225), lung (n=216), colorectal (n=211), breast (n=193), and pancreatic (n=192); controls are fully enrolled. Clinical trial information: NCT05366881 .