Citations

Abstract In comparative effectiveness research (CER), ensuring internal, construct, and external validity is crucial. Internal validity determines whether observed outcomes are causally linked to an intervention; construct validity assesses whether a study measures what it intends to; and external validity relates to generalizability in routine practice. Double-blind randomized trials optimize internal validity by minimizing bias and confounding, while construct validity is strengthened through pre-specified protocols and standardized data collection. However, controlled conditions limit external validity. Pragmatic RCTs improve generalizability but may compromise internal validity due to open-label designs. Observational CER studies—including observational studies following the target trial emulation framework—offer broader external validity and feasibility in less time and at lower cost. However, due to lack of random assignment, these studies are susceptible to measured and unmeasured confounding. Several techniques help mitigate these concerns, including a detailed pre-specified protocol, tools such as propensity score matching to balance measured confounders, falsification endpoint testing for assessing the presence of unmeasured confounders, and quasi-experimental designs (including instrumental variable analysis), which may be able to address both. Pre-specified sensitivity analyses and triangulation with complementary data sources further enhance robustness. Construct validity in observational CER depends on accurate patient profiling and validated computational phenotypes for identifying patients, exposures, and outcomes. Thoughtful study design and analytic rigor are essential for balancing these validity considerations. This brief review highlights these issues with examples from thrombosis research.

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.

Summary CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy is a pivotal part of the treatment algorithm for large B‐cell lymphoma (LBCL) in the second‐ and third‐line settings based on numerous clinical trials. However, these studies included very few patients with a diagnosis of high‐grade B‐cell lymphoma, not otherwise specified (HGBCL‐NOS) and it is unclear if outcomes are similar to those observed with more common LBCL histologies. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we identified 111 HGBCL‐NOS patients who received CAR‐T therapy. The cytokine release syndrome (CRS) rate was 74% (7.7% grade 3+), median onset was 4 days (1–17) and immune effector cell‐associated neurotoxicity syndrome rate was 45.2% (22.6% grade 3+), median onset was 7 days (1–17). At 2 years post‐CAR‐T infusion, the probability of overall survival and progression‐free survival were 41.6% and 28.7% respectively. The 2‐year non‐relapse mortality and relapse/progression were 3.1% (95% confidence interval [CI]: 0.6–7.6) and 68.1% (95% CI: 57.9–77.6) respectively. Our analysis illustrates that patients with HGBCL‐NOS represent a particularly difficult group to treat, even with CAR‐T therapy. We observed that one third of patients achieved a durable response; however, the overall results were less favourable, with lower overall response rate, overall survival and progression‐free survival as compared to published reports on LBCL.

Abstract Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCPs) represent 8 to 20% of cases. Interim analysis of retrospective data collected from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). Fourteen U.S.-based academic skull base centers between 2011 and 2023. Patients with PCPs. Demographic, imaging, surgical, and outcome variables. Ninety-nine patients with PCPs were included. The mean age was 51.8 ± 14.7, and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were transinfundibular (50.0%), and were treated with an endoscopic endonasal approach (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 67.1% and was associated with pituitary stalk sacrifice (p = 0.003). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p = 0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only one patient was treated with a BRAF inhibitor. A mean follow-up of 12.3 ± 14.6 months was seen for the group. RAPID consortium enabled the largest real-world clinical information dataset for PCPs. Early findings support that GTR and stalk preservation are important to outcomes. Iterative analysis and discussion of data led to the generation of a framework for future studies to fully leverage the capabilities of multicenter registries.

Abstract Background: Understanding of the diagnosis and treatment of adults with community-acquired pneumonia (CAP) has evolved thanks to new evidence, experience, and emerging technologies. This document updates evidence-based clinical practice guidelines on four key questions for the diagnosis and management of adult patients with CAP. Methods: A multidisciplinary panel integrated systematic reviews of comparative evidence with other relevant research and clinical experience, then applied Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology to produce recommendations using the Evidence to Decision Framework. Results: The panel formulated clinical recommendations that address questions related to CAP, including lung ultrasound for diagnosis, empiric antibacterial therapy if a test for a respiratory virus is positive, antibiotic duration, and the use of systemic corticosteroids. Conclusions: The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with CAP.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Abstract Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma, NOS (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin classification, 59% were germinal center B-cell–like (GCB), and 25% were activated B-cell–like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC rearrangement (47% vs 6%); dark zone signature (DZsig) expression (45% vs 7%); and more frequent mutation of ID3, MYC, CCND3, and TP53, all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, and those classified as DLBCL-like were frequently BCL2-rearranged. Among DZsig− GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.