Citations

ABSTRACT Background ASP‐1929 photoimmunotherapy—cetuximab conjugated to IRDye 700DX and red light (690 nm) for localized drug activation—results in rapid, selective cell killing. Methods This phase Ib/II open‐label study evaluated ASP‐1929 photoimmunotherapy plus pembrolizumab in patients with recurrent/metastatic HNSCC (≥ 1 accessible lesion, PD‐L1 combined positive score ≥ 1, ineligible for standard locoregional therapy). Primary objectives were safety/tolerability and objective response rate (ORR). Secondary objectives included overall survival (OS) and progression‐free survival (PFS). Results Eighteen patients (median age 63 years, 74% male) comprised the photoimmunotherapy‐evaluable population. The confirmed ORR was 27.8% (95% CI 9.7–53.5); four of five responders had complete responses (95% CI, 6.4–47.6). Median OS was 25.6 months (95% CI, 14.6–not evaluable); median PFS was 2.9 months (95% CI, 1.4–14.6). The most common serious adverse reactions were dysphagia and tongue edema (each n = 2; 10.5%). Conclusions ASP‐1929 photoimmunotherapy plus pembrolizumab was generally tolerable, with promising efficacy in patients with recurrent/metastatic HNSCC.

Abstract The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P< .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T–related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Abstract Rumination syndrome (RS) is a common pediatric disorder of gut–brain interaction. However, a dearth of research on efficacious treatment to help guide clinical decision‐making remains. Thus, relying on well‐established treatment recommendations for other conditions with similar mechanisms or symptom profiles may be helpful; for example, conceptualizing RS treatment targets to address it as a “tic disorder of the gut” could be beneficial. To demonstrate the clinical utility of this conceptualization, we presented two cases that provide broad implications for treating pediatric RS. In both cases, akin to pediatric tic and related disorders, cognitive distress and physical discomfort were alleviated temporarily by rumination episodes. Thus, we recommend a targeted diagnostic assessment, including a functional analysis incorporating a transdiagnostic evaluation of symptoms. Close comanagement with specialty physicians and psychologists is also highly recommended. The patients represent complex yet standard cases seen in pediatric psychology outpatient clinics, suggesting the clinical utility of implications for psychologists and allied health professionals.

The NCCN Clinical Practice Guidelines (NCCN Guidelines) for Wilms Tumor (WT; nephroblastoma) cover strategies for the screening, diagnosis, and treatment of WT, which is the most frequent primary kidney tumor in children. WT can generally be separated into 2 histology types: favorable histology WT and anaplastic WT. Five-year survival is high for children with favorable histology WT who receive appropriate treatment; however, survival rates are much lower for patients who present with higher stage diffuse anaplastic WT. Treatment of WT can range from surgery alone to surgery plus intensive chemotherapy and radiation depending on whether the tumor is unilateral or bilateral, histology, and local stage. The goal of therapy is to maximize cure while minimizing long-term toxicities. The content featured in this issue covers the NCCN panel’s recommendations for overall management of both favorable histology WT and anaplastic WT.

Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5′ RNA ligase-mediated rapid amplification of cDNA ends (5′ Repeat-RLM-RACE), we identified C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, intronic template transcripts–even those with short (32 nucleotide) leaders–exhibited robust expression compared to exon–intron and repeat-containing lariat reporters. To assess endogenous repeat-containing lariat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intron-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development.

INTRODUCTION: Treatment of celiac disease (CeD) requires a strict gluten-free diet (GFD). Adherence is difficult to assess and influenced by many factors. Identification of potential gluten exposures is essential, but no validated screening measures exist in pediatrics. The aim of this study was to develop and validate a measure screening for gluten exposure risk in pediatric patients with CeD. METHODS: The Gluten Exposure Risk Assessment (GERA) was developed in 3 phases. First, items were generated and refined by a modified Delphi process. Next, psychometrics, factor structure, and validity were examined in a sample of caregivers of pediatric patients younger than 18 years with CeD at 12 pediatric celiac centers. Finally, the final measure was tested on an independent sample population using confirmatory factor analysis and test-retest data. RESULTS: A total of 134 items were generated representing up to 6 domains, with 36 items selected for initial testing. Based on psychometrics and confirmatory factor analysis data from 484 caregivers, the final measure included a total of a single screening question and 9 validated items representing 2 domains (Home, Outside). Repeat testing on a separate sample (N = 369) confirmed factor structure and validity of the final measure (Comparative Fit Index = 0.96, Tucker–Lewis index = 0.95, root mean square error of approximation = 0.06). DISCUSSION: The GERA is a valid screening measure, completed by caregivers, for assessment of gluten exposure in children and adolescents with CeD following a GFD. GERA is a useful tool for evaluating the potential of risk of gluten exposure and potential need for intervention.