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TL1A inhibitors offer a novel therapeutic strategy in inflammatory bowel disease by combining anti-inflammatory effects with potential antifibrotic activity. Phase 2 studies show clinical efficacy and a favorable safety profile. Ongoing phase 3 trials will further define their role, including the utility of genetic predictors to guide patient-specific therapy.

The manuscript by Fujii et al. describes the first in-human trial testing of the safety and feasibility of intrarectal perfluorodecalin, a potential method of enteral ventilation. The investigators found that a one-time dose of perfluorodecalin was safe and tolerated without significant adverse effects in healthy men. More work is needed to demonstrate whether this compound can effectively improve oxygenation in critically ill patients.

Background: Despite recent chronic lymphocytic leukemia (CLL) treatment advances, resistance and intolerance are challenges. Lisaftoclax is a selective, small-molecule oral BCL-2 inhibitor.

Methods: Lisaftoclax was administered with initial daily dose ramp-up (5-7 days depending on the target dose), followed by daily dosing as monotherapy, plus six 28-day cycles of rituximab or continuous acalabrutinib (ClinicalTrials.gov: NCT04215809). The primary endpoints comprised safety/tolerability (phases 1b and 2) and efficacy (phase 2), while the pharmacokinetic profile was a secondary endpoint.

Findings: Of 176 patients, 154 (87.5%) had relapsed/refractory and 22 (12.5%) treatment-naive CLL. Five patients (2.8%) experienced tumor lysis syndrome (TLS) (2 clinical and 3 laboratory). Any-grade treatment-emergent adverse events (TEAEs) included neutropenia in 67 patients (38.1%), diarrhea or anemia in 51 (29.0%), and COVID-19 in 63 (35.8%). Grade ≥3 cytopenias occurred in 53 patients (30.1%) with neutropenia and 15 (8.5%) with thrombocytopenia. No treatment-related discontinuations or deaths occurred. The overall response rate (ORR) was 67.4% (29/43) with lisaftoclax monotherapy, 84.6% (33/39) with lisaftoclax-rituximab, and 97.7% (85/87) with lisaftoclax-acalabrutinib. In the lisaftoclax-acalabrutinib cohort, this included 22 patients who were treatment naive and 65 relapsed/refractory, among whom 14 patients had prior venetoclax exposure. In these patients, the ORR was 92.9% (13/14); 100% (8/8) of these patients were Bruton tyrosine kinase inhibitor (BTKi) naive, 83.3% (5/6) had prior BTKi exposure, and 64.3% (9/14) were venetoclax refractory. Rituximab or acalabrutinib did not alter the pharmacokinetic profile of lisaftoclax.

Conclusions: Daily ramp-up over 5-7 days (to 400 or 800 mg) with continuous treatment with lisaftoclax alone or plus rituximab or acalabrutinib was well tolerated and led to responses in patients with CLL without clinically significant pharmacokinetic interactions.

Funding: Ascentage Pharma Group Corp Ltd. (Hong Kong).

Background: Enteral ventilation is an emerging approach that provides partial systemic oxygenation independent of pulmonary gas exchange, enabling lung rest. Perfluorodecalin, a clinically approved liquid with high oxygen solubility, is a promising vehicle for enteral oxygen delivery. The primary endpoint of this first-in-human trial was to assess the safety and tolerability of intrarectal perfluorodecalin administration.

Methods: This was a phase 1, single-site, open-label, non-controlled, dose-escalation trial in 27 healthy adult males aged 20-45 years. Participants received a single intrarectal dose of non-oxygenated perfluorodecalin (escalating from 25 to 1,500 mL) retained for 60 min. Safety and tolerability were assessed through monitoring of adverse events, vital signs, clinical laboratory tests, and systemic perfluorodecalin exposure. A pharmacokinetic model using large-animal data was employed to predict potential oxygen transfer.

Findings: No serious adverse events or dose-limiting toxicities occurred. Mild gastrointestinal symptoms, such as abdominal bloating and pain, were transient, dose dependent, and resolved without intervention. All clinical laboratory parameters, including liver and renal function markers, remained within normal limits. Perfluorodecalin concentrations were undetectable in blood (<1.0 μg/mL). The pharmacokinetic model predicted a dose-dependent oxygenation effect, consistent with a modest increase in peripheral oxygen saturation observed in the higher-dose group.

Conclusions: This first-in-human study demonstrates that intrarectal administration of non-oxygenated perfluorodecalin is safe, feasible, and well tolerated. These findings establish a critical safety foundation and support the continued development of enteral ventilation with fully oxygenated perfluorodecalin as an adjunctive strategy to support respiratory failure patients.

Funding: This work was funded by EVA Therapeutics, Inc.

The ATTAIN-1 trial launches a new era in obesity care. Orforglipron, the first oral small-molecule GLP-1 receptor agonist to complete a phase 3 clinical trial, delivers meaningful reductions in body weight and improvements in metabolic health. This advancement moves beyond peptide-based injectables, paving the way for potent obesity therapies that are simpler, more affordable, and accessible to millions worldwide.

Background: Currently, the therapeutic regimens for patients with recurrent adult-type diffuse gliomas are mainly individualized and controversial, and the role of re-resection remains unclear. Here, this study aimed to (1) investigate the optimal re-resection approach within various types of gliomas and (2) develop a prognostic assessment model following re-resection.

Methods: A retrospective cohort composed of patients with adult-type diffuse gliomas who had re-resection after recurrence was established, sourced from the Chinese Glioma Genome Atlas (CGGA) database. Inverse probability weighting was used to mitigate the interference of confounding variables and to examine the correlation between re-resection and outcomes under different residual tumor volume thresholds. A prognostic decision tree model was created and validated.

Findings: We investigated 335 patients who underwent a first re-resection after the recurrence from 2006 to 2021, including 129 patients with astrocytoma, 73 patients with oligodendroglioma, and 133 patients with glioblastoma. It was revealed that different types of gliomas corresponded to disparate optimal resection strategies. The type of glioma, World Health Organization (WHO) grade at recurrence, whether radiotherapy was received before re-resection, and the residual tumor volume after re-resection had a significant impact on the survival and progression after re-resection.

Conclusion: Our study supports the view that re-resection may potentially prolong the survival period of patients with recurrent adult-type diffuse gliomas, although distinct surgical strategies ought to be implemented for patients with different pathological types.

Funding: This work was funded by the Beijing Municipal Health Commission Research Ward Excellence Clinical Research Program (BRWEP2024W032040202).

Background: Neoadjuvant therapies for high-risk PCa have shown promise but remain confined to clinical trials. Translating neoadjuvant approaches into routine care thus underscores the critical need for innovative early-phase neoadjuvant trials to evaluate safety and efficacy in localized disease, where tumors are more responsive to intervention.

Methods: In this open-label phase 1 trial (NCT03262103), 12 patients with clinically localized intermediate- to high-risk PCa scheduled for radical prostatectomy (RP) received sequential intratumoral and intramuscular injections of poly-ICLC (Hiltonol®), with the primary endpoint to define a safe dose and schedule and one of the secondary endpoints to characterize associated adverse events.

Findings: All patients tolerated poly-ICLC without dose-limiting toxicity or treatment withdrawal. Median follow-up was 4.5 years. Seventy percent of the evaluable patients had PSA₀ (measured as PSA <0.1 ng/mL) 1 year post-RP. Gleason score at final pathology was downgraded in 66.7% of all patients and 70% of the high-risk subgroup. Tissue transcriptomic analysis revealed decreased metastasis signature post-treatment, with upregulation of immune cell-related and favorable-prognosis genes. Intratumoral and intramuscular poly-ICLC also enhanced immune activation signatures in the blood and increased NK cells in both blood and tissues. Treatment increased post-treatment infiltration of CD4⁺, CD8⁺, and PD-1⁺ T cells; CD56⁺ NK cells; CD20⁺ B cells; and tertiary lymphoid structure-like aggregates.

Conclusions: Intratumoral poly-ICLC immunotherapy for PCa is safe and may modulate the tumor microenvironment, enhancing antitumor responses. These findings support larger, controlled trials to assess effects on long-term clinical outcomes.

Funding: This work was funded by the Arthur M. Blank Family Foundation.

Duchenne muscular dystrophy (DMD) is severe and the most common form of muscular dystrophy in childhood. There is no cure for this condition, but several approved therapeutic approaches aim to delay disease progression. Multiple ongoing clinical trials attempt to address the root cause of the condition: exon skipping antisense oligonucleotides (ASOs-targeting specific mutations) and AAV-mediated gene replacement therapy.

Lisaftoclax, a next-generation BCL2 inhibitor, demonstrated promising efficacy and safety in the phase 1b/2 APG2575CU101 trial by Davids et al. in chronic lymphocytic leukemia (CLL).¹ With rapid dose ramp-up and high response rates across monotherapy and combination cohorts, including high-risk and previously treated populations, lisaftoclax shows potential as an effective therapeutic option for CLL, pending validation in larger trials.

Background: Objective metrics to assess systemic metabolic health and early disease-related changes are lacking. Whole-body 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) can quantify organ-specific glucose metabolism but is underutilized for inter-organ metabolic analysis.

Methods: We analyzed 658 whole-body FDG-PET scans to construct partial correlation networks (PCNs) reflecting direct metabolic connectivity between organs. We introduced two network metrics, density and disorder, and used them to test PCN robustness to technical and biological factors and to evaluate PCNs as markers for allostatic load (e.g., inflammation or cancer burden).

Findings: PCNs were highly reproducible and insensitive to FDG dose, scanner type, normalization method, or repeated scans. A lower body mass index (BMI; <25.3 kg/m²) was associated with higher PCN density (33% vs. 14%, p = 0.02) and lower disorder (p = 0.04). Patients with cancer had markedly reduced density (7% vs. 30%, p < 0.001) and higher disorder (p = 0.01) compared to healthy individuals. High C-reactive protein (CRP) and leukocytes were similarly linked to reduced density (6% vs. 12%, p = 0.018, and 6% vs. 10%, p = 0.012, respectively). Elevated norepinephrine was associated with lower density (4% vs. 14%, p = 0.04) and higher disorder (p = 0.12). Networks with low density showed hub formation in skeletal muscle and subcutaneous adipose tissue. PCNs derived from FDG-PET were structurally similar to those based on hexokinase 2 expression (p = 0.01), supporting biological validity.

Conclusions: Whole-body FDG-PET-derived PCNs are a robust, systems-level biomarker of metabolic homeostasis. This method detects early deviations from health and may inform preventive interventions, risk stratification, and therapeutic monitoring.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.