Citations

ABSTRACT Rationale Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays. Methods We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug‐resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra‐ and inter‐institution variability and to delineate institutions with the shortest added duration for each variable. Results Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short‐duration evaluations and 414 (25%) were long‐duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups. Conclusions Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commonly employed in epilepsy surgery evaluations. This predictive model can not only estimate evaluation duration but also identify opportunities to improve systemic efficiency. Institution‐level modeling identifies specific program strengths, providing an opportunity to learn from successful processes. Subsequent research will focus on institutional process mapping to better understand systemic practices that lead to improved efficiencies, then sharing these processes across the consortium to shorten evaluation durations.

Limited studies have explored the effects of individual and environmental factors on sleep disturbance in individuals with inflammatory bowel disease (IBD), which is vital for informing future sleep interventions. Thus, the purpose of this study was to explore the possible mediated effects of potential precipitating and/or perpetuating factors on the relationship between sleep disturbance and symptoms in adults with IBD. This is a correlational study of adults with IBD recruited from ResearchMatch. Survey questions asked about demographics, clinical characteristics, sleep hygiene, sleep beliefs and attitudes, sleep environment, sleep control, and symptoms (sleep disturbance, abdominal pain, anxiety, depression, fatigue). Data analysis included descriptive statistics, Pearson correlations, and mediation analysis. We included 250 adults with IBD ( M = 37.9 years old, 64.8% female, 72.4% white). Fifty-four percent of the sample self-reported having a diagnosed sleep disorder. Sleep hygiene and sleep beliefs and attitudes significantly mediated the relationship between sleep disturbance and symptoms (i.e., fatigue, depression, anxiety, and abdominal pain). Whereas the sleep environment and sleep control did not significantly mediate the relationship between sleep disturbance and symptoms. Individuals with IBD experience sleep disturbances, alongside symptoms of anxiety, depression, abdominal pain, and fatigue. Mediation analysis identified sleep hygiene and sleep beliefs, and attitudes as partial mediators. Considering cognitive-behavioral therapy for insomnia is recommended for restructuring these mediating factors. Participants also faced moderate environmental disturbances, suggesting a need for further investigation in this population.

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.

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

ABSTRACT Background Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression‐free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints. Methods Two‐arm, superiority‐design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double‐blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety‐five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic regressions explored associations with trial‐level features. Results After screening, 237 trials were included, enrolling 127,518 patients. A double‐blind design was used in 105 trials (44%, 95% CrI 38%–51%). BICR was used in 111 trials (47%, 95% CrI 41%–53%), including 39 double‐blind trials (16%, 95% CrI 12%–22%). Trials with BICR had higher odds of meeting the primary endpoint (OR 1.84; 95% CI 1.06–3.18; p = 0.03). The PFS assessor identity (central vs. local) or blinding status was not reported in 50 trials (26%, 95% CrI 16%–27%). Trials that met prespecified significance criteria for PFS were more likely to report whether PFS assessors were blinded/unblinded and central/local (OR, 3.05; 95% Cl: 1.60–5.81; p = 0.0007). Conclusions Despite the importance of double blinding in combination with BICR for reducing bias, only a few trials blinded physicians, patients, and primary endpoint assessors. This meta‐epidemiological study illuminates the prevalence of potential assessment biases affecting PFS in Phase III oncology and secondarily emphasizes the need for improved methodology reporting.

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in the treatment of blood cancers, but has been associated with arrhythmias such as atrial fibrillation (AF). The treatment course and cardiovascular outcomes of patients who develop new or recurrent AF after CAR-T has yet to be explored. Methods We extracted a cohort of patients who underwent CAR T-cell therapy between 2016 and 2022. The endpoint of interest was defined as the first episode of new or recurrent AF during or after CAR-T infusion. Patients with persistent or permanent AF were not counted as events. Tocilizumab use was not counted for patients who had an AF event more than 30 days after CAR-T infusion. Chart review was used to delineate patient treatments and outcomes. Survival analyses techniques were used to define risk of new or recurrent AF. Results There were 328 patients who underwent CAR T-cell therapy between 2016 and 2022, of which 41 had prior history of AF. Overall, there were 10 new and 9 recurrent AF events after CAR T-cell infusion, with a composite cumulative incidence risk of 5.8%. The majority of these events occurred within 30 days of receiving CAR-T (N=14, 73.7%). All events that occurred after 30 days were associated with significant hospitalizations unrelated to CAR-T. Rate control was the preferred method of treatment, with beta blockers being the preferred first-line therapy for both patients on and not on baseline beta blockers (Table). 2 patients were given amiodarone prophylactically prior to CAR-T infusion. Only 1 patient received cardioversion, 15 days after the AF event, but had recurrence shortly thereafter. Only 2 patients were on chronic anticoagulation, and both had history of AF prior to CAR-T. Tocilizumab was given to 9 patients (47.4%) before the onset of AF and not significantly associated to decreased risk of developing new or recurrent AF (HR 1.16, CI 0.47-2.83, P=0.75). Tocilizumab was more likely given to patients with higher cytokine release syndrome and neurotoxicity grading (Figure). There were no myocardial infarctions or strokes. Conclusion Atrial fibrillation is a rare complication of CAR T-cell therapy. Rate-control strategies remain the preferred method of treatment. Very few patients were given anticoagulation, but the incidence of subsequent stroke was negligible. More investigation will need to be undertaken to determine methods of preventing AF in the setting of CAR-T therapy.CAR-T AF Patient Case Series

ABSTRACT Background and Purpose Radiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance. Methods A total of 601 individuals were included (342 people with MS [PwMS] from two cohorts and 259 healthy controls [HC]). Radiomic features (RF) and volumes were extracted from the whole thalamus, five thalamic nuclei, and the putamen segmented on three‐dimensional T1‐weighted images. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in PwMS and the Digit Symbol Substitution Test (DSST) in HC. In the first MS cohort, multivariate linear regression in a discovery set ( N = 103) identified thalamus‐derived RF associated with SDMT, which were retested in a replication set ( N = 63). Their associations with PASAT in a second MS cohort ( N = 176) and DSST in HC were also evaluated. We then tested whether the same RFs, when extracted from the putamen, was associated with SDMT. Least Absolute Shrinkage and Selection Operator (LASSO) models assessed the combined predictive value of RF and volumes. Results Twenty‐eight RF–region of interest (ROI) pairs were associated with SDMT in the replication set (false discovery rate [FDR] < 0.05). Of these, 24 were also associated with PASAT (FDR ≤ 0.03), and 2 with DSST. Only ventral nuclei volume showed replicated associations among volumetrics. Only four putamen‐derived pairs were associated with SDMT (FDR = 0.04). LASSO results confirmed RF outperformed volumes. Conclusion RF extracted from the thalamus is strongly associated with cognitive performance in PwMS, outperforming volumetric measures and supporting their potential as sensitive imaging biomarkers.

Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) and hypofractionated therapy for liver malignancies, with the goal of providing a technical assessment to promote broader adoption and support future clinical trials. Methods and Materials: An extensive survey was conducted by NRG Oncology across North American proton treatment centers to assess the current practices of proton liver SBRT and hypofractionated therapy. The survey focused on key aspects, including patient selection, prescription and normal tissue constraints, simulation and motion management, treatment planning, quality assurance (QA), treatment delivery, and the use of image-guided radiation therapy (IGRT). Results: This survey captures the current practice patterns and status of proton SBRT and hypofractionated therapy in liver cancer treatment. Proton therapy is increasingly preferred for treating inoperable liver malignancies due to its ability to minimize healthy tissue exposure. However, the precision required for proton therapy presents challenges, particularly in managing uncertainties and target motion during high-dose fractions and short treatment courses. Survey findings revealed significant variability in clinical practices across centers, highlighting differences in motion management, dose fractionation schedules, and QA protocols. Conclusion: Proton SBRT and hypofractionated therapy offer significant potential for treating liver malignancies. A comprehensive approach involving precise patient selection, treatment planning, and QA is essential for ensuring safety and effectiveness. This survey provides valuable insights into current practices and challenges, offering a foundation for technical recommendations to optimize the use of proton therapy and guide future clinical trials.

Objective Mechanical thrombectomy (MT) is well-established for the treatment of acute ischemic stroke (AIS) from large vessel occlusion (LVO), with growing data supporting the expansion to distal and medium vessel occlusions (DMVO). Despite successful recanalization in DMVO, certain patients still experience poor long-term clinical outcomes, prompting our study to comprehensively explore pre-MT factors influencing outcome despite excellent recanalization (final modified Thrombolysis in Cerebral Infarction [mTICI] score ≥2c). Methods We retrospectively examined data from patients who consecutively underwent MT for a primary middle cerebral artery (MCA) DMVO across 37 centers in North America, Asia, and Europe. We identified baseline clinical and imaging factors associated with poor clinical outcome (defined as a modified Rankin Scale [mRS] score of 3–6) at 3 months, despite excellent recanalization using a multivariable model. Results Between September 2017 and July 2021, 623 patients achieved mTICI > 2b and they were included in our study. Among them, 198 (32%) experienced a poor clinical outcome (mRS 3–6). Predictors of poor clinical outcome included higher age (OR 1.05 [1.03–1.07], p < 0.001), higher NIHSS at admission (OR 1.12 [1.08–1.15], p < 0.001), higher baseline mRS (OR 1.77 [0.96–3.26], p = 0.067), and diabetes (OR 1.59 [1.01–2.48], p = 0.044). Higher ASPECTS was associated with a decreased risk of poor clinical outcome (OR 0.82 [0.71–0.94], p = 0.006). Conclusion Older age, diabetes, higher baseline mRS, and NIHSS were associated with poor clinical outcome in MCA DMVO despite excellent recanalization. Conversely, a higher ASPECTS decreased the probability of such an outcome.