Citations

PURPOSE Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780 ). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score–matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Rationale Extracorporeal membrane oxygenation (ECMO) is an increasingly utilized form of life support for patients with cardiac and/or respiratory failure. Fungal infections remain a serious challenge in patients supported by ECMO, with an estimated prevalence of up to 10% and high morbidity and mortality. While routine antifungal prophylaxis is uncommon in ECMO centers and widely debated, its impact on incidence, pathogenic organisms, resistance patterns, and outcomes has not been described. Methods This was a ten-year experience study of fungemia in patients receiving ECMO where most patients received antifungal prophylaxis. Institutional protocol was to prescribe prophylactic fluconazole based on risk stratification, substituted with echinocandins if indicated. Adults (18 years and older) with ECMO runs between 2014-2024 were screened for fungal organism growth on culture, then narrowed to those with positive blood cultures drawn in the window from 24 hours after cannulation through 72 hours after decannulation. Clinical, microbiological, and outcomes data were descriptively summarized. Institutional review board approved with a waiver of informed consent. Results Among 1,039 adult ECMO runs (979 patients), thirteen patients with fungemia were identified for a calculated incidence rate of 1.29 per 1000 ECMO days (95% CI 0.75 to 2.23). Twelve patients (92%) received antifungal prophylaxis; 85% had echinocandin and 38% azole exposure, with some overlap. Median duration of antifungal exposure was 14 days prior to positive culture. Seven patients (54%) had an open sternum at the time of ECMO cannulation, while 11 (85%) had femoral ECMO access. Four patients (31%) had Candida species isolated from other sources prior to fungemia (mediastinum and respiratory system). Candida parapsilosis (31%), C. albicans (23%), and C. guilliermondii (15%) were the most common isolates. The most likely sources were vascular access catheters (38%) and mediastinum (31%). Seven patients (54%) had suspected or confirmed seeding of ECMO hardware after positive blood cultures, though only two circuit exchanges were performed. Four patients (31%) showed evidence of non-susceptibility to their prophylactic antifungal class (Table 1), with a median 35-day exposure prior to positivity among those patients. Only 62% of patients demonstrated blood culture clearance (median 3 [IQR 2.5-7.75] days). Nearly all patients (92%) died within the hospital stay, including all patients with resistant organisms. Conclusions In an ECMO center with routine antifungal prophylaxis practices, the rate of fungemia identified during ECMO support was low. When fungemia developed, there was a high proportion of drug resistance and mortality. This abstract is funded by: None

Abstract A population of pathologic fibroblasts has been identified in several human fibrotic lung diseases, including IPF. These cells, marked by high expression of collagen triple-helix repeat containing 1 (CTHRC1), display an invasive phenotype and aggressively deposit extracellular matrix. The goal of this study was to identify transcriptional regulators of the CTHRC1+ pathologic fibroblast state. We analyzed published single-cell RNA sequencing data of IPF and control lungs to predict transcription factor activity in CTHRC1+ fibroblasts, which led us to hypothesize that transcription factors in the nuclear factor of activated T-cells (NFAT) family may contribute to the pathologic fibroblast state. To test whether NFAT family members promote and/or maintain pathologic fibroblasts, we silenced each cytosol-localized NFAT (NFATc1-4) in lung fibroblasts from IPF donors (passage 3-6, N = 5 donors) and measured expression of key NFAT target genes related to fibrosis using qPCR. NFATC1 silencing significantly reduced expression of CTHRC1, SERPINE1, FN1, HAS2, and TNC, whereas other computationally predicted regulators showed little effect. Our computational analysis also predicted high activator protein 1 (AP-1) activity in pathologic fibroblasts, which interestingly has been found to act in concert with NFATs to promote an effector response in T-cells. Thus, we hypothesized that NFAT:AP-1 signaling may be involved in lung fibroblast activation. To test this hypothesis, we employed a small molecule inhibitor of NFAT:AP-1 complex formation on DNA (“Compound 10”, 25-50 µM). NFAT:AP-1 inhibition significantly reduced expression of fibrillar collagens COL1A1 and COL3A1, as well as CTHRC1 in primary IPF lung fibroblasts. Additionally, NFAT:AP-1 inhibition prevented TGF-β-mediated increase of several fibrosis-related NFATc1 targets. Aside from CTHRC1, NFAT:AP-1 inhibition led to decrease in a different set of NFATc1 targets than NFATc1 silencing, suggesting a potentially complex relationship between NFATc1 and AP-1 in fibroblast gene regulation. Finally, in mouse precision cut lung slices (PCLS) stimulated with a fibrosis-inducing cocktail ex vivo, NFAT:AP-1 inhibition prevented increased expression of Col1a1 and Cthrc1. Taken together, these studies suggest that NFATc1, together with AP-1, is involved in fibrogenic activation of pathological fibroblasts. Ongoing and future experiments will determine the roles of these signaling mechanisms in matrix deposition and contraction, as well as fibroblast invasion using human fibroblasts and PCLS models. Furthermore, we aim to determine how mechanical forces and soluble factors encountered in IPF lungs promote NFAT signaling in fibroblasts. This abstract is funded by: NHLBI, Pulmonary Fibrosis Foundation

Background: Complex repairs of radial meniscal tears have shown increased fixation strength compared to conventional sutures. A simplified 2-suture hybrid and a novel dual tie-grip repair with interconnected vertical mattress sutures spanning the tear were tested and compared to all-inside double-horizontal and tie-grip repairs. Hypothesis: The dual tie-grip repair would increase the initial compression load across the tear and show the least cyclic displacement and highest failure strength. Study Design: Controlled laboratory study. Methods: A total of 40 porcine medial menisci were assigned to 4 repair groups: double-horizontal, hybrid, tie-grip, and dual tie-grip (10 per group). Results from tie-grip repairs were used to assess the effect of vertical mattress suture interconnection. After suture placement according to the described technique and fixation, the initial compressive load, stiffness, and relief displacement were measured. The repaired specimens underwent cyclic loading between 5 and 30 N over 1000 cycles (0.75 Hz), while cyclic stiffness and displacement were measured. Ultimate stiffness and load-to-failure were analyzed at 3.15 mm/s. Results: Analysis of variance revealed that dual tie-grip and hybrid repairs showed higher initial compressive load and relief displacement than the other techniques, with dual tie-grip repair reaching the highest values for both metrics (load: 19.3 ± 2.3 N [ P < .001]; displacement: 0.75 ± 0.19 mm [ P < .001]). The double-horizontal repair had the lowest initial stiffness ( P < .001). Cyclic displacement was lowest for the dual tie-grip repair and highest for the double-horizontal repair (both P < .001). All repaired specimens stiffened during cycling without intergroup differences. Analysis of covariance for stiffness over displacement revealed higher stabilization ( P < .040) with dual tie-grip repair and reduced stabilization ( P < .001) with double-horizontal repair. Despite comparable ultimate stiffness across groups, the dual tie-grip repair failed predominantly by suture rupture at the highest ultimate load (275.5 ± 26.2 N; P < .001), whereas the double-horizontal repair failed by tissue rupture the earliest (127.2 ± 15.9 N; P < .001). Conclusion: The dual tie-grip repair provided the highest initial compression across the radial meniscal tear, the lowest cyclic displacement, and the greatest load-to-failure among all techniques in a porcine cadaveric model. The simplified 2-suture hybrid repair showed higher initial compression than other repairs and comparable cyclic stability to the tie-grip repair. Clinical Relevance: The dual tie-grip repair provided high compression across the radial tear and strong resistance to cyclic displacement. Future clinical series assessing differences in healing rates among different repair groups are warranted.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.