Citations

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 Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

Background: Cardiac biomarkers are recognized as potential indicators for brain function, emotion regulation, and psychiatric risk. While research in adults has suggested associations between cardiac variables of autonomic function and neural changes, little is known about these relationships in children and young adults with psychiatric conditions. This systematic review aimed to examine the evidence linking cardiac biomarkers with structural, functional, and connectivity-based brain changes in this population. Methods: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Multiple databases were searched for studies examining associations between any cardiac biomarker and neuroimaging findings in individuals under 21 years old with psychiatric diagnoses. After screening and full-text review, 11 eligible studies were included. Results: The included studies investigating a range of psychiatric conditions and cardiac biomarkers were associated with brain changes across three domains: structure, connectivity, and neural responses. Associations were most consistent between higher vagal tone and structural and functional integrity of emotion-regulating regions such as the prefrontal cortex, amygdala, and insula. However, findings were heterogeneous and potentially moderated by symptom severity or environmental stressors. Conclusions: This review supports the potential of cardiac biomarkers, particularly high-frequency heart rate variability and root mean square of the successive differences, as proxies of brain changes in youth with psychiatric disorders. While promising, current evidence is too limited and variable for clinical applications. Future research should prioritize large-scale, longitudinal studies using harmonized protocols and wearable technologies to validate these indices as translational tools in child and adolescent psychiatry.

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 Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

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.

Abstract Aims We hypothesized that targeting interleukin-6—a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)—may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. Methods ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. Conclusion ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.

Abstract Aims Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular events. However, the effect of Lp(a) on coronary plaque composition and high-risk plaque features has not been fully characterized. This study aimed to investigate the association between Lp(a) and coronary atherosclerotic plaque phenotype at the plaque level. Methods and results This study included 710 patients who underwent coronary computed tomography angiography (CCTA) and had Lp(a) measured between 2008 and 2024. CCTA scans were analysed with a previously validated artificial intelligence-based algorithm (AI-QCT, Cleerly Inc.). The association of Lp(a) with non-calcified and calcified plaque volumes and HRP features was evaluated at the plaque level using generalized estimating equation models adjusted for traditional cardiovascular risk factors. Among the 710 patients, the mean age was 56 ± 10 years and 379 (53%) were male. In total, 3642 plaques were identified. In the adjusted plaque-level analysis, elevated Lp(a) (≥150 nmol/L) was associated with an increase in non-calcified plaque volume per plaque (P = 0.009), but not with an increase in calcified plaque volume (P = 0.81). Furthermore, elevated Lp(a) (≥150 nmol/L) was strongly associated with the presence of high-risk plaque at the plaque level (adjusted odds ratio: 1.78, 95% CI: 1.25–2.54, P = 0.001), whereas low-density lipoprotein-cholesterol and high-sensitivity C-reactive protein were not (P > 0.05). Conclusion In this plaque-level CCTA study of 3642 individual plaques, elevated Lp(a) levels were independently associated with increased non-calcified plaque volume and with the presence of high-risk plaque, but not with calcified plaque volume. These findings elucidate the impact of Lp(a) on unstable plaque phenotypes, even in patients without prior cardiovascular events.

Abstract Pain treatments have modest effects. Health outcomes might be improved if treatments are matched to mechanisms underlying the persistence and biopsychosocial impact of an individual's pain. The International Association for the Study of Pain (IASP) defines 3 mechanistic pain descriptors presumed to involve different mechanisms—nociceptive, neuropathic, and nociplastic. Although treatments to address each descriptor have been proposed, there is no consensus on how to assign descriptors to clinical presentations. A recent consensus identified candidate clinical features to discriminate between descriptors in clinical practice and research. These need refinement to progress towards a tool. This study aimed to determine the rank and relative weight of identified clinical features to aid discrimination between mechanistic pain descriptors. Candidate clinical features (n = 196) were refined by the IASP Terminology Task Force to converge similar and remove redundant features. The Task Force (n = 24) and an expert panel (n = 39) ranked features using 1000minds conjoint analysis software and assigned weights based on discrete pairwise choices. Participants nominated from pairs of scenarios, which most likely indicated that pain aligned predominantly to a descriptor. Highest ranked features for neuropathic and nociplastic pain were aligned with IASP Clinical Criteria. Criteria for nociceptive pain have not been established. A ranked list of features shared by 2 mechanisms (indicating mixed mechanisms) was also identified. This study identified expert consensus on the highest ranked clinical features with potential to discriminate between pain descriptors, reflective of different underlying mechanisms. This study extends current frameworks by identifying and refining key discriminators for future operationalisation and validation.

Abstract Purpose: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. Patients and Methods: Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months. Results: Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; P = 0.28), −33.33 % (IQR, 90; P = 0.04), and −38.6 % (IQR, 88.5; P = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; P = 0.37) and −26.3 % (IQR, 49.5; P = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (P = 0.04) and improved TPB at 12 months (P = 0.05) compared with daily dosing. Conclusions: eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.