Citations

The indications for immune checkpoint inhibitor (ICI) use in cancer treatment continue to expand. This is attributable to their proven anticancer activity in addition to their tolerability and favorable toxicity profile as compared to conventional chemotherapeutic agents. ICIs work by blocking the inhibitory signals between tumor cells and T-cells, thereby enhancing the T-cell cytotoxic activity to inhibit tumor growth. Because of their immune-stimulating effect, ICIs are linked to adverse renal outcomes in both native and transplanted kidneys. The risk of kidney allograft rejection in the setting of ICI use has been reported to be around 40%, leading to an increased risk of graft loss. In this report, we review the literature examining outcomes in kidney transplant recipients receiving ICIs for various oncologic indications.

Coronary artery disease (CAD) is the leading cause of death globally. Apolipoprotein A-1 (apoA-1), the primary protein component of high-density lipoprotein (HDL), facilitates reverse cholesterol transport and has emerged as a potential therapeutic target. While pharmacologic efforts to raise HDL-C levels have failed to reduce cardiovascular events, focus has shifted to HDL functionality, particularly cholesterol efflux capacity (CEC). ApoA-1 infusions have demonstrated antiatherogenic effects in preclinical models and early human trials by enhancing CEC and promoting cholesterol clearance. This review summarizes the rationale and evolving clinical trial landscape investigating apoA-1 infusions as a novel therapy for CAD prevention and treatment.

ABSTRACTBackgroundBlau syndrome is a rare, autosomal dominant granulomatous disease caused by mutations in the NOD2/CARD15 gene. While the classic triad of arthritis, dermatitis, and uveitis is well known, the full range of cutaneous manifestations remains underexplored.ObjectiveTo expand the understanding of cutaneous findings in Blau syndrome, correlate these findings with NOD2 variants, and evaluate treatment outcomes across organ systems.MethodsA retrospective review of medical records from January 1999 to January 2024 identified 14 patients with Blau syndrome supported by the presence of NOD2 variants. Clinical data on dermatological features, genetics, and treatment responses were analyzed and categorized into specific and non‐specific cutaneous findings.ResultsOf the 14 patients with Blau syndrome, 85% (12/14) demonstrated skin involvement. Specific findings included lichenoid or granulomatous papules and nodules (50%, 6/12), while non‐specific findings (83%, 10/12) were more diverse, including dermatitis (6/10), chronic urticaria (5/10), ichthyosiform eruptions (4/10), vasospastic disorders (5/10), and oral/genital ulcers (2/10). Skin biopsies in three patients with specific findings revealed non‐caseating granulomas. Genetic analysis identified multiple NOD2 variants, though no clear genotype–phenotype correlation was observed. TNF‐alpha inhibitors demonstrated efficacy in controlling ocular and joint disease.ConclusionBlau syndrome presents with a broader spectrum of cutaneous findings than previously recognized. These findings highlight the importance of dermatological evaluation and a multidisciplinary approach to optimize diagnosis and management.

Abstract Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Purpose: Atrial fibrillation (AF), the most common arrhythmia in older adults, is often treated with cryoballoon ablation (CBA) or laser balloon ablation (LBA) when refractory to medication. We used real-world patient data to investigate differences in arrhythmia-free survival, procedure and fluoroscopy times, and complications between these techniques. Methods: In this single-center, retrospective study of 178 patients with symptomatic paroxysmal AF referred for first-time pulmonary vein isolation (PVI), 103 underwent CBA, and 75 underwent LBA. Recurrence was defined as any atrial arrhythmia of > 30 seconds’ duration after a three-month blanking period. Complications at 30 days were recorded. Kaplan-Meier analysis was used to estimate arrhythmia-free survival at one year for both groups. Categorical variables were expressed as n (%) and continuous variables as mean ± standard deviation or median (Q1, Q3). Results: Baseline characteristics were similar between groups, with exception to left atrial volume index (CBA 32.2 ± 10.9 ml/m2; LBA 36.0 ± 11.0 ml/m2, p = 0.047). History of stroke was higher in CBA (13.6% vs 2.7%; p = 0.012), as was coronary artery disease (35.0% vs 14.7%, p = 0.002). Median fluoroscopy and procedure times (min) were significantly shorter in LBA (24.2 vs 31.6, p = 0.004; 141.0 vs 210.0, p < 0.0001, respectively). One-year arrhythmia-free survival rates were similar (CBA 79.1% vs LBA 78.7%, p = 0.934), as were total complication rates (21.4% vs 16.0%, p = 0.289), including rates of transient ischemic attack/stroke and vascular complications. Conclusions: In patients with paroxysmal AF undergoing PVI, CBA and LBA were equally efficacious at one year and demonstrated acceptably low complication rates. LBA was associated with reduced procedure time and fluoroscopy exposure.

ABSTRACTIntroductionIntramyocardial needle ablation is a novel technique for treating refractory ventricular tachycardia (VT) and premature ventricular complexes (PVC). However, studies defining the effectiveness and safety of this procedure are limited. This meta‐analysis aims to evaluate the safety and effectiveness of needle ablation for VT and PVC refractory to standard ablation.MethodsEmbase, Ovid (includes Medline), and ClinicalTrials.gov were searched from inception to December 31, 2024. Human studies on needle ablation for recurrent VT and PVC were included. Primary outcome was immediate effectiveness (no immediate post‐procedural inducible VT or PVC). Secondary outcomes were long‐term effectiveness (no clinical VT or PVC at 6 months) and safety (composite measure of peri‐ and post‐procedural complications).ResultsA total of five studies including 180 patients (140 VT; 40 PVC) were analyzed. Mean ages ranged from 54 to 66 years. Among 129 patients with VT, immediate effectiveness was 75% (95% CI, 54–92; I2 80%), and cumulative freedom from clinical VT dropped to 43% at 6 months (95% CI, 35–52; I2 0%). Among 40 patients with PVC, immediate effectiveness was 82% (95% CI, 67–94; I2 0%), and long‐term effectiveness was 76% (95% CI, 61–90; I2 0%). Safety outcomes were reported in 19% of patients (95% CI, 13–27; I2 0%) and 10% of patients (95% CI 1, 23; I2 0%) in the VT and PVC arm, respectively. Death related to ablation was report in 7 patients (5.0%) only in the VT studies.ConclusionIntramyocardial needle ablation is an emerging alternative approach for refractory VT and PVC ablation, showing cautious but promising results and safety profiles. Prospective studies and an international registry could provide valuable insights needed for optimal patient selection and protocol refinement.

Objectives: The delirium course of critically ill adults can be classified into trajectories based on the severity and duration of delirium as shown by a recent study. It is unknown whether these trajectories and associated outcomes are reproducible. We aimed to define delirium severity trajectories using the Intensive Care Delirium Screening Checklist (ICDSC) and delirium duration and evaluate the association of trajectory membership with clinical characteristics and 30-day post-discharge mortality. Design: Population-based retrospective cohort. Setting: Fourteen medical-surgical ICUs in Alberta, Canada from January 1, 2014, to December 21, 2019. Patients: We included adult patients (≥ 18 yr old) with an ICU length of stay of greater than or equal to 24 hours, an ICDSC score indicating delirium (≥ 4), and 30-day follow-up data were included. Group-based trajectory modeling identified trajectories over a 7-day period with SAS v9.4 (SAS Institute, Cary, NC). Interventions: None. Measurements and Main Results: Demographic (age, sex) and clinical data (2 × d ICDSC score, comorbidities, illness severity, admission reason, procedures, length of stay, in-hospital, and 30-d post-discharge mortality) were captured from electronic medical records. In total, 21,071 patients were included, with a median age of 59 years (interquartile range, 46–70 yr), 59% male (n = 12,547), and 3% died at 30 days (n = 541). The five-trajectory model was selected. These trajectories followed previously defined patterns: 1) Mild-Brief (19.4%); 2); Severe-Rapid Recovers (18.5%); 3) Severe-Slow Recovers (31%); 4) Mild-Accelerating (14.1%); and 5) Severe-Nonrecovers (16.9%). Trajectory membership was not significantly associated with 30-day post-discharge mortality; however, clinically relevant trends were observed. Conclusions: The current study substantiates the proof-of-concept model of five delirium severity trajectories. Trajectory membership did not predict 30-day post-discharge mortality. Further research is needed to understand the associations between trajectory membership, biological-based biomarkers, and patient-relevant outcomes.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.