Citations

PURPOSE Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Early-stage, high-risk patients with TNBC are treated with chemotherapy and pembrolizumab per the KEYNOTE-522 regimen. This report examines real-world clinical effectiveness and toxicity of this regimen. METHODS This 19-site retrospective analysis included all patients who received at least one dose of the KEYNOTE-522 regimen. Safety, efficacy, and health care encounters were collected. RESULTS 675 patients from 19 sites in the United States who received chemotherapy and pembrolizumab for early-stage TNBC were included. 547 (81.0%) patients underwent surgery and 250 (54.7%) patients had a pathologic complete response (pCR). No baseline characteristics were predictive of pCR status. 224 patients (33.2%) had an adverse drug event resulting in ≥1 dose reduction of chemotherapy and were significantly more likely to have residual disease. Immune-related adverse events (irAEs) were observed in 388 (57.5%) patients and grade 3+ irAEs were observed in 176 (26.1%) patients. There was no difference in pCR status between provider's choice chemotherapy schedules. There was no difference of pCR rate between Black and White patients (55.6% v 51.6%, P = .489). White patients were significantly more likely to have any grade and grade 3+ irAEs. Older patients (age ≥65 years) had similar pCR rates compared with younger patients; however, older patients were significantly more likely to have grade 3+ irAEs. CONCLUSIONS In this multi-institutional real-world cohort, we observed a lower pCR rate, higher rates of toxicity, frequent emergency health care utilization, and the reporting of rare irAEs at higher frequency than the KEYNOTE-522 regimen. These findings have important implications for clinical management of patients with early-stage TNBC and warrant further validation with real-world data sets.

ABSTRACT Objective To evaluate intracochlear electrocochleography (ECochG) amplitude parameters during cochlear implantation (CI) using a novel multi‐frequency ECochG algorithm. Methods A multi‐institutional, prospective cohort study was performed at 18 high‐volume CI centers. The inclusion criteria were adults with sensorineural hearing loss and audiometric thresholds of ≤ 90 dB hearing level at 500 Hz undergoing CI with Advanced Bionics (Valencia, CA) Ultra 3D devices between 2024 and 2025. ECochG recordings were performed with simultaneous multi‐frequency stimulation of four frequencies between 125 and 4000 Hz during cochlear implant insertion. Concurrent multi‐frequency recording allowed extraction of amplitude and phase of each frequency individually. Post hoc analysis was performed to determine the difference in the number of drop alarms between single‐ and multi‐frequency ECochG. An ECochG amplitude drop of 6 dB was defined as a drop alarm. Insertion track patterns were compared between single‐ and multi‐frequency ECochG. Results One hundred ninety‐five ears were included. Mean number of drop alarms for the single‐frequency algorithm was 1.72 (95% CI: 1.52, 1.92; median 1) compared to 0.42 (95% CI: 0.31, 0.53; median 0) for multi‐frequency; p < 0.001. The number of Type C patterns (rise in amplitude during insertion followed by a drop) decreased with the multi‐frequency ECochG algorithm compared to the single‐frequency ECochG algorithm. The number of Type D patterns (no‐response) decreased, indicating that multi‐frequency ECochG generated more responses across the cochlea than single‐frequency ECochG. Conclusions A novel multi‐frequency ECochG algorithm during CI is associated with fewer drop alarms and altered insertion track patterns, which may provide a more accurate assessment of the cochlear microenvironment. Level of Evidence 3.

ABSTRACT Bispecific T cell engagers (BTEs) induce MHC‐independent cytotoxicity by bridging T cells to tumor cells via binding a T cell–activating receptor and a tumor‐associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin‐13 receptor alpha 2 (IL13RA2), a tumor‐associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen‐dependent cytokine release and cytotoxicity against IL13RA2‐positive GBM cells. In vivo, hBTE showed robust target‐specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off‐target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2‐expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2‐expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors.

ABSTRACT As interest in the use of cannabinoids for supportive care in pediatric cancers grows, there are emerging concerns about potential interactions with antineoplastic agents. This review provides an overview of potential drug–drug interactions between cannabinoids and 25 antineoplastic agents commonly used in pediatric hematology/oncology. Antineoplastic agents were stratified into low, medium, or high interaction risk based on the potential impact of cannabinoids on metabolic and/or pharmacodynamic pathways. The antineoplastic agents identified as high risk for interactions with cannabinoids included cyclophosphamide, doxorubicin, etoposide, ifosfamide, irinotecan, vinblastine, and vincristine. Key mechanisms of interaction include inhibition of cytochrome P450 enzymes and UDP‐glucuronosyltransferases and modulation of drug transporters such as P‐glycoprotein and breast cancer resistance protein. There is emerging evidence of a synergistic effect between cannabinoids and antineoplastic agents such as temozolomide, vinblastine, vinorelbine, and irinotecan. Pediatric patients exhibit developmental differences in drug metabolism and transporter expression, yet most pharmacokinetic data on cannabinoids are extrapolated from adult studies. There is a lack of pediatric‐specific safety, efficacy, and dosing data that underscores the need for age‐appropriate studies to ensure safe and effective integration of cannabinoids in pediatric cancer care.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351 ) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD] neg ) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg . Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD neg . ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD neg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Abstract Aims Pulsed field ablation for atrial fibrillation offers shorter procedural times and improved safety compared with thermal ablation, but the optimal anaesthesia strategy remains uncertain. Most centres in the USA use general anaesthesia with endotracheal intubation, whereas monitored anaesthesia care without endotracheal intubation may be a safe and efficient alternative. Objectives To compare procedural efficiency and safety between monitored anaesthesia care and general anaesthesia for pulsed field ablation. Methods and results Consecutive adults who underwent pulsed field ablation for atrial fibrillation between 2024 and 2025 at Marshfield Clinic Health System were included. The anaesthesia approach was determined by operator preference. Procedural times, medication use, complications, and patient tolerance were recorded prospectively. Among 200 patients, 100 received monitored anaesthesia care without endotracheal intubation, and 100 received general anaesthesia. The mean age was 67 years, 42% were female, and the mean body mass index was 33 kilograms per square metre. Monitored anaesthesia care shortened case duration (77 vs. 95 min; P &lt; 0.001) and laboratory time (118 vs. 153 min; P = 0.002) and required fewer adjunct medications (P &lt; 0.001). Twenty-five procedures (25%) were challenging due to cough or motion but were all completed safely. Complications occurred in one monitored anaesthesia care case and six general anaesthesia cases (P = 0.054). Pulmonary vein isolation was achieved in all patients. Conclusion Monitored anaesthesia care without endotracheal intubation was safe, efficient, and resource-sparing compared with general anaesthesia for pulsed field atrial fibrillation ablation.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.