Reducing and controlling metabolic active tumor volume prior to CAR T-cell infusion can improve survival outcomes in patients with large B-cell lymphoma.

Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline (n = 74) and pre-LD (n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV (< 190 cc) had a better time to progression (TTP) and overall survival (OS) compared to high MATV patients (p < 0.001). High MATV patients who remained stable or reduced upon bridging therapy showed a significant improvement in TTP (p = 0.041) and OS (p = 0.015), compared to patients with a high pre-LD MATV (> 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens.

Psychosocial Determinants of Sleep Behavior and Healthy Sleep Among Adolescents: A Two-Wave Panel Study.

To date, it remains unknown which psychosocial determinants identified by several leading behavior change theories are associated with different sleep parameters among adolescents. Therefore, this study investigates whether changes in knowledge about healthy sleep, attitude toward healthy sleep and going to bed on time, self-efficacy to engage in healthy sleep behavior, perceived parental and peer norms, perceived barriers (e.g., worrying, fear of missing out), and perceived support (e.g., bedtime rules, encouragement) related to healthy sleep are associated with changes in adolescents' sleep duration on school days and free days and sleep quality over a period of 1 year. Two-wave data of 1648 Flemish adolescents (mean age = 15.01, SD = 0.65, 46.3% female) were analyzed using linear models. Increased levels of parental social support, positive attitude towards and perceived advantages of healthy sleep, norm-knowledge, and perceived peer behavior were associated with sleep duration, with parental social support having the strongest association. Increased levels of perceived barriers were associated with decreased levels of sleep quality parameters, and increased levels of self-efficacy, positive attitude, and parental modeling were associated with improved sleep quality parameters, with perceived barriers having the strongest association. The current results indicate that behavior change theories are useful in the context of adolescent sleep behavior and suggest that perceived parental support (i.e., bedtime rules) and perceived barriers are most strongly associated with adolescents' sleep duration and/or quality.

Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61-0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment.

The Dutch CAR-T Tumorboard Experience: Population-Based Real-World Data on Patients with Relapsed or Refractory Large B-Cell Lymphoma Referred for CD19-Directed CAR T-Cell Therapy in The Netherlands.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020-May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

Establishing a Health CASCADE-Curated Open-Access Database to Consolidate Knowledge About Co-Creation: Novel Artificial Intelligence-Assisted Methodology Based on Systematic Reviews.

BACKGROUND: Co-creation is an approach that aims to democratize research and bridge the gap between research and practice, but the potential fragmentation of knowledge about co-creation has hindered progress. A comprehensive database of published literature from multidisciplinary sources can address this fragmentation through the integration of diverse perspectives, identification and dissemination of best practices, and increase clarity about co-creation. However, two considerable challenges exist. First, there is uncertainty about co-creation terminology, making it difficult to identify relevant literature. Second, the exponential growth of scientific publications has led to an overwhelming amount of literature that surpasses the human capacity for a comprehensive review. These challenges hinder progress in co-creation research and underscore the need for a novel methodology to consolidate and investigate the literature. OBJECTIVE: This study aimed to synthesize knowledge about co-creation across various fields through the development and application of an artificial intelligence (AI)-assisted selection process. The ultimate goal of this database was to provide stakeholders interested in co-creation with relevant literature. METHODS: We created a novel methodology for establishing a curated database. To accommodate the variation in terminology, we used a broad definition of co-creation that encompassed the essence of existing definitions. To filter out irrelevant information, an AI-assisted selection process was used. In addition, we conducted bibliometric analyses and quality control procedures to assess content and accuracy. Overall, this approach allowed us to develop a robust and reliable database that serves as a valuable resource for stakeholders interested in co-creation. RESULTS: The final version of the database included 13,501 papers, which are indexed in Zenodo and accessible in an open-access downloadable format. The quality assessment revealed that 20.3% (140/688) of the database likely contained irrelevant material, whereas the methodology captured 91% (58/64) of the relevant literature. Participatory and variations of the term co-creation were the most frequent terms in the title and abstracts of included literature. The predominant source journals included health sciences, sustainability, environmental sciences, medical research, and health services research. CONCLUSIONS: This study produced a high-quality, open-access database about co-creation. The study demonstrates that it is possible to perform a systematic review selection process on a fragmented concept using human-AI collaboration. Our unified concept of co-creation includes the co-approaches (co-creation, co-design, and co-production), forms of participatory research, and user involvement. Our analysis of authorship, citations, and source landscape highlights the potential lack of collaboration among co-creation researchers and underscores the need for future investigation into the different research methodologies. The database provides a resource for relevant literature and can support rapid literature reviews about co-creation. It also offers clarity about the current co-creation landscape and helps to address barriers that researchers may face when seeking evidence about co-creation.

Semi-automated 18F-FDG PET segmentation methods for tumor volume determination in Non-Hodgkin lymphoma patients: a literature review, implementation and multi-threshold evaluation.

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool. A software tool, MUltiple SUV Threshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures. High variability and significant differences between the MATVs based on different segmentation methods (p < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc. No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter.

CD47 Expression Defines Efficacy of Rituximab with CHOP in Non-Germinal Center B-cell (Non-GCB) Diffuse Large B-cell Lymphoma Patients (DLBCL), but Not in GCB DLBCL.

Addition of rituximab (R) to "CHOP" (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients who receive R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 "don't eat me" immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B-cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) CD47 mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy (P = 0.001), but not CHOP therapy (P = 0.645). Accordingly, patients with low CD47 expression benefited most from the addition of rituximab to CHOP [HR, 0.32; confidence interval (CI), 0.21-0.50; P < 0.001]. This negative impact of high CD47 expression on OS after R-CHOP treatment was only evident in cancers of non-GCB origin (HR, 2.09; CI, 1.26-3.47; P = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68-1.99; P = 0.58). This differential impact of CD47 in non-GCB and GCB was confirmed in vitro, as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of CD47 mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients, and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.