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Abstract Objectives Embedded pragmatic clinical trials (ePCTs) are conducted as part of routine clinical care and therefore use data collected from real-world data sources, such as electronic health record systems and administrative claims. A common approach for using these types of data across all phases of trial conduct is to create a computable phenotype (an explicitly defined data query data, including specified data types, data codes, and logical parameters) to capture patients with a clinical condition, exposure, symptom, characteristic, treatment, or outcome of interest. Materials and Methods The Electronic Health Record (EHR) Core Working Group of the NIH Pragmatic Trials Collaboratory captured the experiences of investigators in developing, adapting, and applying computable phenotype definitions in their studies. Results Four case studies describe different approaches to developing and using computable phenotypes in pragmatic trials. Discussion We recommend: (1) developing computable phenotypes as part of a team with multiple areas of expertise; (2) appropriate validation; (3) dissemination of salient details regarding phenotype creation; and (4) capturing and reporting any modifications made to phenotypes during the conduct of the trial. Conclusion A range of issues and decisions influence how computable phenotypes are developed and used in pragmatic clinical trials. Multidisciplinary teams that understand the context of the data, including the reason the data are collected and potential sources of bias, are best suited for the development and validation of phenotypes for ePCTs.

BACKGROUND: Anthracyclines are a widely used and effective class of chemotherapy. However, a major limitation for their use is cardiotoxicity, manifesting as systolic dysfunction, congestive heart failure, and arrhythmias. The objective of this study was to identify genes and genetic risk variants for doxorubicin-induced arrhythmia. METHODS: We performed genome-wide association studies and meta-analysis across 2 independent nonoverlapping, genetically homogenous data sets from the Molecular Epidemiology Resource (cases N=77, controls N=1184) and Tapestry (cases N=13, controls N=172). Doxorubicin-related arrhythmia was the primary cardiac outcome, followed by investigation of a broader phenotype of cardiac events. Effects of doxorubicin on top-associated genes were assessed by quantitative polymerase chain reaction on RNA extracted from human cardiomyocytes following treatment with doxorubicin and by echocardiography in a zebrafish model of doxorubicin-induced cardiomyopathy. RESULTS: In the meta-analysis, rs12151014 at the KCTD15 locus was associated with doxorubicin-related arrhythmia at the genome-wide significance (minor allele frequency in Molecular Epidemiology Resource cases 0.195 versus 0.069 in controls; Tapestry cases 0.192 versus 0.079 in controls) P =9.01×10 −9 ; odds ratio, 3.61. MMP 16 rs1094199 was associated with the broader phenotype of arrhythmia and heart failure (minor allele frequency in Molecular Epidemiology Resource cases 0.079 versus 0.019 in controls; Tapestry cases 0.038 versus 0.015) P =1.98×10 − 8 ; odds ratio=6.15. In human cardiomyocytes, MMP16 and KCTD15 gene expression was significantly downregulated by doxorubicin, and in a zebrafish MMP16 knockout was protective of doxorubicin-induced decline in left ventricular ejection fraction. CONCLUSIONS: Genetic variants at KCTD15 and MMP16 are associated with doxorubicin-related arrhythmia and cardiac events. MMP16 is a potential cardioprotective therapeutic target.

➢ Periprosthetic joint infection (PJI) remains the most common cause of failure after total joint arthroplasty, with current standard therapies associated with failure rates between 10% and 30%. ➢ The 2025 International Consensus Meeting in Istanbul, Türkiye, highlighted the potential benefits of bacteriophage (phage) therapy in managing PJI. ➢ One of the barriers to integrating phage therapy into standard clinical PJI care is the knowledge gap between preclinical research and clinical practice. ➢ This Expert Review summarizes the key therapeutic advantages of using phages as an adjuvant therapeutic platform for PJI. It also highlights the current challenges that are continuing to limit the integration of phages into standard PJI care.

Abstract Introduction: Next generation of Theranostics studies are looking at novel combinations with radiation sensitizers to enhance PRRT’s efficacy. Here, we present safety and efficacy data from a multi-center phase 1 study of a [¹⁷⁷Lu]lutetium-dotatate -triapine combination in patients with GEP-NETs. Methods: The study consisted of two phases (dose escalation and expansion) administering the recommended phase 2 doses (RP2D) for the two agents. All patients received 200 mCi of [¹⁷⁷Lu]lutetium-dotatate on day 1 of four 8-week cycles, in combination with oral triapine administered at assigned dose levels (100 mg, 150 mg or 200mg) from days 1 to 14 of each cycle. Results: A total of 31 (A: 15 ; B: 16 ) patients received treatment. Nine patients experienced dose-limiting toxicities; Grade 3 anemia (n=1), Grade 5 cardiac arrest (n=1), and Grade 4 neutropenia (n=7). Based on the overall safety and pharmacokinetics data, a [¹⁷⁷Lu]lutetium-dotatate (200 mCi) plus triapine (150 mg) dose was selected as the RP2D for the expansion phase. Grade ≥3 treatment related adverse events were observed in 77% patients: anemia (23%), nausea and vomiting (3% ), lymphopenia ( 58%), neutropenia ( 35%) and leukopenia ( 39%). The majority of cytopenias were transient and resolved within two weeks. Among the 28 evaluable patients, the objective response rate (ORR) was 21.4% and the median progression-free survival (mPFS) has not been reached (median follow-up period: 23.7 months). Conclusions: The combination of [¹⁷⁷Lu]lutetium-dotatate (200 mCi) and oral triapine (150 mg D1-14) was well tolerated and demonstrated preliminary activity in patients with well-differentiated GEP-NETs. (NCT04234568).

Introduction: Atherosclerotic lesions preferentially form in arterial regions exposed to disturbed flow (DF), where ECs exhibit mitochondrial (mt) dysfunction, metabolic reprogramming, and senescence. Hippo pathway kinases LATS1/2 maintain EC homeostasis, but how DF–mediated LATS1/2 suppression drives EC metabolic remodeling remains unclear. Hypothesis: We propose that DF activates CD38, leading to mt dysfunction and metabolic reprogramming that promotes EC senescence and aberrant proliferation by LATS1/2 inhibition. Methods: EC-specific Lats1/2 knockout mice were generated using tamoxifen-inducible Cre systems, and DF was induced by partial carotid ligation. Murine and human plaques were analyzed using COMET™ immunofluorescence, and spatial metabolomics. Bioenergetic profiling included Seahorse XF analysis, 13 C-glucose/ 13 C-glutamine tracing, and pharmacologic modulation of CD38, mtROS, and ATP synthase. Results: Complete Lats1/2 deletion caused fatal edema and vascular leakage, while partial loss produced fragile, highly neovascularized plaques. Spatial proteomics revealed a CD38-driven senescence-associated stemness (SAS) phenotype under LATS1/2 deficiency. Metabolomics showed sulfite and taurine accumulation, consistent with SUOX deficiency. Mechanistically, CD38 suppressed SUOX, induced Complex V reverse-mode , increased succinate flux, and accelerated ATP consumption. Despite ATP depletion, glutamate metabolism and TCA cycle flux were enhanced, sustaining EC proliferation under energetic stress. LATS1/2 knockdown reduced mt respiratory capacity (lower OCR peak) without significantly increasing glycolysis, and DF suppressed both OCR and ECAR, indicating impaired energy metabolism under pathological shear stress. CD38 inhibition restored mt respiration and glycolytic capacity by preserving NAD, and rescuing LATS1/2 and DF-mediated defects. Blocking reverse-mode Complex V reduced DF- and LATS1/2-dependent EC senescence and proliferation. Conclusion: Complete LATS1/2 deletion causes fatal vascular leakage, while partial loss drives plaque formation with fragile neovessels through a CD38-dependent SAS phenotype. CD38 suppresses SUOX, induces Complex V reverse-mode , increases succinate flux, and accelerates ATP consumption, enabling EC proliferation despite energy stress. DF and LATS1/2 loss impair mt and glycolytic function, whereas CD38 inhibition restores mt respiration and reduces EC senescence and proliferation to prevent atherothrombosis in DF regions.

Although structured reporting of adverse events related to medical therapies is a critical aspect of clinical trials, the current practice fails to capture postoperative complications accurately or systematically, which precludes our ability to fully assess the impact of the risks of surgical interventions on oncologic outcomes. The incorporation of standardized, procedure‐specific definitions and severity classifications for postoperative complications into adverse event reporting in trials conducted through the National Clinical Trials Network is proposed.

Background High‐risk non‐muscle‐invasive bladder cancer (HRNMIBC) has a variable prognosis, managed predominantly by local surgical resection and intravesical Bacillus Calmette–Guérin (BCG), or radical cystectomy (RC). Current treatments are poorly tolerated, have supply limitations and often fail to control the disease. Treatments overcoming these limitations are needed to improve HRNMIBC outcomes. Many novel agents have been approved in recent years (including systemic pembrolizumab, nogapendekin alfa inbakicept‐pmln, N‐803), but long‐term efficacy is unknown. Given advanced bladder cancer findings, we believe direct intravesical administration of atezolizumab may aid with managing HRNMIBC or muscle‐invasive bladder cancer in patients who are ineligible for cisplatin‐based neoadjuvant chemotherapy. Study design The INtraVESical immunoTherapy (INVEST) trial is a UK‐based, open‐label, non‐randomised, single‐centre, Phase Ib dose escalation, window of opportunity study exploring atezolizumab administration via intravesical routes (passive instillation and direct injection [sub‐urothelial]) in patients with bladder cancer with all stages undergoing RC. For both routes, an initial dose confirmation stage will determine toxicity and recommended atezolizumab dosage, followed by a dose expansion stage to further evaluate safety and toxicity at the recommended dose. Endpoints We aim to investigate safety (primary) and preliminary activity (secondary) of intravesical atezolizumab delivered by passive instillation and direct injection into the tumour/bladder wall in patients with bladder urothelial cell carcinoma prior to RC. Primary endpoints include dose limiting toxicities and adverse events. Secondary endpoints include progression‐free survival, pathological complete response rate and treatment compliance. Exploratory endpoints include pharmacokinetic profile (assessed by serum and urine concentrations at prespecified timepoints), spatial analysis of atezolizumab distribution within RC tissue by imaging mass spectrometry and overall survival. Patients and Methods Atezolizumab will be administered intravesically by either passive instillation or direct injection into the tumour/bladder wall. Cohorts will receive either 600 mg or 1200 mg doses administered as a single dose or as multiple doses (weekly for 3–6 weeks). Trial Registration International Standard Randomised Controlled Trial Number: ISRCTN15842444 , registered 2 December 2022.

Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions. Methods This international multi-center observational retrospective study included patients with advanced NSCLC with or without pericardial effusions receiving ICIs. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Cox proportional hazards multivariable models assessed the association between survival outcomes and clinicopathologic variables, and an inverse probability of treatment weighting (IPTW) model compared outcomes between the two groups. Results A total of 1248 patients with advanced NSCLC treated with ICIs across 13 institutions were included. Of these, 85 patients (6.8%) had pre-existing pericardial effusions. Compared to controls, patients with pericardial effusions were younger (median age 63 vs 67 years, P = .007), diagnosed more frequently with PD-L1 positive tumors (96% vs 76%, P < .001), and had a higher median number of baseline metastatic sites (3 vs 1, P < .001). IrAEs were similar between both groups (42% vs 38%), and no cardiac irAEs occurred in patients with pericardial effusions. PFS (median 5.6 vs 4.6 months, P = .3) and OS (median 10.2 vs 14.7 months, P = .50) were not statistically different between patients with pericardial effusions and the controls, respectively. In both multivariable and IPTW models, pericardial effusions were not associated with PFS or OS. Conclusions Among patients with NSCLC and pre-existing pericardial effusions, ICIs demonstrate meaningful clinical benefit similar to those without effusions, with no new cardiac or severe toxicities.

ABSTRACT The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST‐Mol) differentiate low, intermediate, and high‐risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients ( n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST‐Mol risk categories. At a median follow‐up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non‐ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non‐ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high‐risk (median 50 vs. 14 months; p < 0.01), intermediate‐risk (81 vs. 28 months; p < 0.01), and low‐risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST‐Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time‐dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST‐Mol high‐ and intermediate‐risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST‐Mol high‐ and intermediate‐risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.

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.