Citations

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Abstract Objectives Understanding whether the novel long-T ITC complex might assist in interpreting clinical prognostic utility compared to established cardiac biomarkers is needed. We determined long term major adverse cardiac events (MACE) and all-cause mortality (ACM) predicated on novel long-T ITC complex and high sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) assays in the emergency department (ED). Methods cTn assays were measured on the Mindray CL-1200i platform at presentation in consecutive patients enrolled in ‘Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon’ (MERITnI) (NCT05853042) trial with suspected ischemia. Sex specific 99th percentiles upper reference limits (URLs) were: hs-cTnI female 14 ng/L, male 15 ng/L; hs-cTnT female 10 ng/L, male 19 ng/L; long-T ITC complex 0.9 ng/L, same for female and male. Results Of 1,070 patients, 59.4 % were male, 43.4 % White, 45.5 % Black, and 39.5 % ≥65 years. Independent of biomarkers, a continuum of risk over 1 year showed MACE increased to 16.1 % and ACM to 16.5 %. Long-T ITC complex did not show a continuum change, increasing only 0.1 % (HR: 1.001 (1.0–1.001) per ng/L. However, hs-cTnI increased 1.8 % (HR: 1.018 [1.009–1.027] for each ng/L (p<0.0001) and hs-cTnT increased 0.3 % per ng/L (HR: 1.003 [1.001–1.006]) (p=0.0028). Between subjects ≤URLs and >URLs, MACE and ACM all biomarkers showed significant (p<0.0001) differences over 1 year. For MACE in those >URL long-T ITC complex increased 11.2–25.2 %, hs-cTnI 18.0–35.0 % and hs-cTnT 8.9–24.2 %. For ACM in those >URL long-T ITC complex increased 4.5–23.3 %, hs-cTnI 5.0–26.2 %, and hs-cTnT 3.6–24.1 %. Conclusions Novel long-T ITC complex did not provide new prognostic value to either hs-cTnI or hs-cTnT. Patients with increased hs-cTnI and hs-cTnT concentrations had marked increases in MACE and ACM risk at 1-year.

Background The management of osteochondral lesions of the talus (OLT) is challenging, with 2 main options being conservative and surgical management. Orthobiologic therapies come to bridge the gap between these 2 options; however, inconsistencies in indication, composition, and heterogeneous evidence limit clinical decision-making. To address these challenges, 3 International Congress Meetings on Cartilage Repair of the Ankle were convened in Pittsburgh, USA (2017), Dublin, Ireland (2019), and New York, USA (2025) to establish agreement on the role of conservative management and injectable orthobiologic strategies in the treatment of OLT. Methods Seventy-five multidisciplinary experts from over 25 countries and 1 territory participated in a structured Delphi-based consensus process. Blinded surveys, structured questionnaires, and in-person discussions were used to develop and refine statements, supported by literature review and graded evidence (A1–E). Consensus strength was defined as consensus (51%-74%), strong consensus (75%-99%), or unanimous (100%) Results In total, 29 consensus statements were achieved across the 3 meetings. Strong agreement was reached regarding indications and expected outcomes of conservative management, including the role of immobilization and appropriate timing for surgical intervention. Orthobiologic injections, including platelet-rich plasma, concentrated bone marrow aspirate, and hyaluronic acid, were considered appropriate in select patients with persistent symptoms, although no superiority was demonstrated among formulations, preparation methods, or injection strategies. When used as adjuncts to surgical procedures, orthobiologics may improve radiological outcomes, with limited evidence for improvement in clinical outcomes. Technical considerations, including preferred harvest sites and a lack of standardized preparation protocols, were identified, along with key principles for patient counseling Conclusion These international consensus statements establish a standardized framework for the conservative management and use of injectable orthobiologic therapies in OLT. By clarifying indications, technical considerations, and current limitations, this work aims to improve consistency in clinical practice, guide treatment decision-making, and inform future research.

ABSTRACT Angioimmunoblastic T‐cell lymphoma (AITL) is an aggressive peripheral T‐cell lymphoma with poor outcomes, and the role of autologous stem cell transplantation (ASCT) as consolidation after frontline therapy remains controversial. We conducted a retrospective cohort study using the National Cancer Database, including adults diagnosed with AITL between 2004 and 2020 who received frontline systemic therapy. Patients were categorized as chemotherapy alone (Chemo) or chemotherapy followed by ASCT (Chemo + ASCT). To mitigate immortal time bias, prespecified landmark analyses were performed, with a 6‐month landmark analysis as the primary approach and a 9‐month landmark analysis as a sensitivity analysis. Multivariable Cox regression and propensity score weighting using inverse probability of treatment weighting for the average treatment effect were used to address measured confounding. Among 3996 patients receiving systemic therapy, 686 (17.2%) underwent ASCT. In the 6‐month landmark analysis, ASCT was associated with improved overall survival (HR, 0.53; 95% CI, 0.45–0.62; p < 0.001). Findings were consistent in the 9‐month landmark analysis (HR, 0.58; 95% CI, 0.49–0.69; p < 0.001) and IPTW‐adjusted model (HR, 0.51; 95% CI, 0.44–0.60; p < 0.001). In this large real‐world cohort, ASCT consolidation was consistently associated with improved survival in patients with AITL. Although treatment‐response data were unavailable and residual confounding cannot be excluded, these findings provide supportive real‐world evidence and warrant prospective studies with treatment‐timing and response data to better define patient selection.

Abstract Background We determined whether circulating cardiac troponin I–cardiac troponin T–troponin C (ITC) complex containing long-form cardiac troponin T (long-T ITC) complex and ratios of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) could differentiate myocardial infarction (MI) from chronic and acute non-MI myocardial injuries in patients with suspected acute coronary syndrome. Methods We measured long-T ITC complex, hs-cTnI, and hs-cTnT (Mindray) at 0- and 2-h in consecutive patients enrolled in the Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon (MERITnI) trial. Results Among the 882 subjects studied (median 3.0 h presentation), 47 had acute MI (5.3%), 116 had acute non-MI myocardial injury, and 90 had chronic myocardial injury. At 0 and 2 h, areas under the curve (AUC) significantly differentiated acute MI from chronic myocardial injury for long-T ITC complex (0.72 and 0.81, respectively; P = 0.0082) but not acute non-MI myocardial injury (AUC, 0.65 and 0.69, respectively; P = 0.23). 0 and 2 h AUCs for long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios also significantly differentiated acute MI from chronic myocardial injury (AUC, 0.79 and 0.86, respectively) and acute non-MI myocardial injury (AUC, 0.68 and 0.71, respectively). There was no biomarker concentration or ratio value discrimination between type 1 and type 2 MIs. Conclusions Long-T ITC concentrations and long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios may clinically assist in differentiating acute MI from non-MI myocardial injuries when evaluating patients with suspected acute coronary syndrome. ClinicalTrials.gov Registration Number: NCT05853042.

ABSTRACT Background Bile acid (BA) malabsorption (BAM) is a common cause of chronic diarrhoea and may occur in some patients due to abnormalities of the gut microbiota. Effects of probiotics on faecal secretory BAs, particularly the primary BA, chenodeoxycholic acid, are unclear. Aim/Methods We conducted a randomized, double‐blind, placebo‐controlled trial of the De Simone formulation 8‐strain probiotic in 24 patients previously diagnosed with BAM. Patients were randomized to 3 weeks of the probiotic (900 billion bacteria) or placebo (maltose), both administered three times daily. Symptoms, serum 7 α C4, faecal primary BAs, intestinal permeability by 13 C‐mannitol‐lactulose test (0.1 and 1 g of the sugars respectively) over 24 h, faecal short chain fatty acids (SCFA), microbiome, and metabolome were assessed at baseline and post‐intervention. Results Data from 22 patients were included. Probiotic supplementation was associated with a significant decrease in % faecal primary BAs (chenodeoxycholic acid and cholic acid) with median change from baseline −5.7 [IQR −10.3, 0.9]% compared to 9.8 [IQR 0.2, 20.6]% on placebo ( p = 0.012). The faecal microbiome was significantly different in the probiotic group after intervention, driven by probiotic‐specific species. There were no significant differences in symptoms, intestinal permeability, or SCFA. However, there was a numerical difference in the changes from baseline in 0‐2 h 13 C‐mannitol excretion −1.9 [−13.9, 4.2] mg for the probiotic and 1.0 (−0.5, 12.7) mg for placebo ( p = 0.084). Conclusions The De Simone formulation probiotic induced significant microbiome and metabolome changes in patients with BAM, ultimately leading to a decrease in % faecal primary BAs and possible reduction in intestinal permeability. Clinical Trials.gov registration NCT #06609148, January 2, 2025.

Abstract Introduction Intracerebral hemorrhage (ICH) carries higher morbidity and mortality than ischemic stroke. Recent studies have demonstrated improved patient outcomes by applying ultra-early bundled interventions including blood pressure management, coagulopathy reversal, and osmotic therapy. Effective strategies to deliver these ultra-early treatment options are currently being explored. On December 19th, 2022, the Mayo Clinic Comprehensive Stroke Center (CSC) launched the “ICH Phases” communication system to accelerate ICH patient care. Objective To evaluate adherence to the AHA/ASA guidelines in acute ICH care following the implementation of our novel-tiered paging system. Methods We retrospectively reviewed patients admitted with spontaneous ICH during 2024 and 2025. We excluded traumatic cases. We extracted clinical data such as time to imaging, documentation of ICH score, blood pressure control, reversal of anticoagulation, venous thrombo-embolism (VTE) prophylaxis and discharge disposition. Results Among 67 patients, 68.7% underwent CT imaging within 25 minutes. We documented the ICH score within 6 hours in 82.9% of patients. Nearly 94.7% of patients with SBP>140 mm Hg received antihypertensive therapy, yet only 18% reached target BP within 60 minutes. We completed the reversal of anticoagulation within 120 minutes in 75% of patients. VTE prophylaxis was initiated within 24 hours in 91% of patients. Discussion Our novel system demonstrated adherence to the AHA/ASA guidelines, and time sensitive benchmarks in neuroimaging, reversal of anticoagulation, and VTE prophylaxis. Early BP control remains a challenge, that highlights the discrepancy between guidelines and real-ground implementation. Conclusion A novel tiered paging system is effective for enhancing early ICH care. Such a holistic system remains critical for sustained improvement in quality of care.

PURPOSE Systematic integration of tobacco cessation treatment within cancer centers is needed to improve smoking cessation outcomes among cancer patients and survivors. The current study characterizes baseline rates of tobacco use, use of cessation support, and changes in tobacco use over time among 756 participants diagnosed with cancer and enrolled in 9 ECOG-ACRIN Cancer Research Group trials. MATERIALS AND METHODS Participants completed surveys at trial enrollment and at 3- and 6-month follow-ups. Descriptive statistics were used to characterize patient characteristics and selected items from the Cancer Patient Tobacco Use Questionnaire (C-TUQ). Generalized estimating equations were used to examine the time point effect on tobacco product use. RESULTS At baseline, 11% of participants (n = 740) currently smoked cigarettes. Among participants with data available at all time points (n = 443), prevalence of current smoking was stable over time, with 7.2% of participants (n = 32) reporting current smoking at baseline, 7.0% (n = 31) at the 3-month follow-up assessment, and 6.8% (n = 30) at the 6-month follow-up assessment. Most participants (n = 77/104) who smoked cigarettes within the year prior to their cancer diagnosis continued smoking after their diagnosis, and during (n = 44/72) and following completion (n = 30/46) of their treatment. Sixty-two percent of participants (n = 81) who were currently smoking at baseline reported using smoking cessation medication and 32.1% reported use of nonpharmacologic smoking cessation support since their cancer diagnosis. In longitudinal analyses, the odds of using cigarettes since their cancer diagnosis, 3-month follow-up, and 6-month follow-up was higher than the odds of using cigarettes for the past 30 days at baseline (odds ratio [OR] = 1.97, OR = 1.62, and OR = 1.50, respectively; all p s < .01). CONCLUSION Smoking persists over time among patients with cancer enrolled in therapeutic cancer trials. Findings highlight the importance of increasing access to integrated and longitudinal smoking cessation support.

Abstract Introduction and Purpose: Immune checkpoint signaling represents a major barrier to effective antitumor immunity by suppressing cytotoxic T-cell activity. Cytokine-inducible SH2-containing protein (CISH) is a genetically validated intracellular immune checkpoint that constrains cytotoxic T-cell and natural killer cell signaling. Emerging evidence supports a critical, T cell-intrinsic role for CISH in lymphoma. Despite strong biological validation, CISH targeting has thus far been limited to genetic manipulation in adoptive cell therapies. We sought to establish CISH as a drug-tractable target by discovering a first-in-class, cell-permeable small-molecule CISH inhibitor/degrader suitable for scalable immunotherapy development. Methods: CISH biology was characterized using datasets of patients with B-cell lymphoma and isogenic cellular models to define target-dependence benchmarks. Structure-guided small-molecule discovery was enabled through homology modeling and AlphaFold-based predictions of CISH structure. A focused library of covalent CISH binders was synthesized using systematic variation of SH2-engaging motifs and electrophilic warheads. Compounds were evaluated using biophysical binding assays, mass spectrometry–based covalent engagement, cellular degradation, and signaling readouts. Results: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis identified CISH as one of the most highly expressed genes in intratumoral T cells associated with a poor prognosis in patients with non-Hodgkin lymphoma, supporting disease relevance and target enrichment. Genetic ablation or knockdown of CISH in a T cell model (KARPAS299) induced reproducible, target-dependent phenotypes, including enhanced S-phase entry and augmented STAT5 phosphorylation following IL-2 stimulation, establishing rigorous cellular benchmarks for pharmacologic modulation. We designed and synthesized over 50 candidate CISH binders incorporating covalent SH2-domain engagement. Multiple compounds showed direct binding to CISH by thermal shift analysis and selective covalent modification at Cys144 by mass spectrometry. Introduction of a masked phosphate motif significantly improved intracellular exposure, confirmed using a BODIPY-labeled analog. Lead compounds demonstrated target engagement by cellular thermal shift assay and induced rapid, concentration-dependent degradation of endogenous CISH within 4 hours in cells, while maintaining high selectivity over related SOCS family members, demonstrating both target engagement and specificity. Conclusions: This work establishes CISH as a chemically tractable intracellular immune checkpoint and reports the discovery of the first selective, cell-permeable small-molecule CISH degrader. These data provide a strong foundation for further structure activity relationship optimization and position CISH degradation as a promising drug discovery strategy to modulate T cell function and enhance antitumor immunity. Citation Format: Hao Xie, Xinyi Tang, Sujeewa Ranatunga, Stephen M. Ansell. Discovery of a small-molecule degrader targeting the intracellular immune checkpoint CISH [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B049.