Citations

ABSTRACTVenous leg ulcers (VLUs) are traditionally managed with standard‐of‐care dressings, compression and appropriate adjunctive venous interventions for pathologic venous reflux. Due to pathophysiological complexity and underlying patient comorbidities, conducting randomised controlled trials to evaluate the comparative efficacy of advanced treatment modalities is difficult, as many patients would likely be excluded. This retrospective, pragmatic, real‐world evidence (RWE) study compared the healing outcomes of VLUs treated with either ovine forestomach matrix (OFM) (n = 312) or collagen/oxidised regenerated cellulose (ORC) (n = 239) in outpatient wound care centres. Unlike restrictive randomised controlled trials, minimal inclusion and exclusion criteria were applied to create two treatment cohorts that reflected the general VLU population. The incidence (%) of closure was greater in OFM‐treated VLUs at 12, 24 and 36 weeks, and this difference was significant at 24 and 36 weeks compared to collagen/ORC. Median time to wound closure was significantly faster (p = 0.045) in the OFM cohort (11.1 ± 0.6 weeks) compared to the collagen/ORC group (12.3 ± 1.0 weeks). Cox proportional hazards analysis demonstrated that OFM‐treated VLUs had a significantly greater probability of healing (up to ~40%). This RWE comparative efficacy study further substantiates the clinical benefit of OFM in the treatment of chronic wounds, such as VLU, in a real‐world patient cohort.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) can provide curative treatment for hematologic malignancies but is associated with prolonged lymphopenia that may contribute to an increased risk of infection and relapse, resulting in decreased survival. We hypothesized that patients with rapid and robust CD4 T- and B-cell recovery have improved survival and decreased treatment-related mortality (TRM). A total of 2089 patients were included who underwent first allo-HCT for acute myeloid leukemia/acute lymphoblastic leukemia/myelodysplastic syndrome from 2008 to 2019 reported to the Center for International Blood and Marrow Transplant Research with available CD4 counts at days 100 and 180. Patients (median age, 51 years [range, 2-75]) were categorized into 4 groups based on graft-versus-host disease (GVHD) prophylaxis: ex vivo T-cell depletion (TCD/CD34), posttransplant cyclophosphamide, calcineurin inhibitor alone (CNI), or CNI with antithymocyte globulin. Based upon survival, we could identify optimal cutoff points for CD4+ T cells in pediatric (age of <20 years) patients: 248 × 106/L and 420 × 106/L at days 100 and 180, respectively; and in adult (age of >20 years) patients: 104 × 106/L and 115 × 106/L at days 100 and 180, respectively. In adults, day-100 CD4 count was associated with overall survival (OS), progression-free survival (PFS), and TRM but not relapse, incidence of infections, or chronic GVHD. Similarly, CD4 counts above the cutoff point at day 180 in adults were associated with improved OS, PFS, and TRM but no other outcomes. No clinical associations for CD4 counts were identifiable in pediatric patients. These findings underscore the importance of tailoring transplant strategies for adults to optimize immune recovery and improve patient outcomes.

PURPOSE Long-term androgen deprivation therapy (ADT) improves survival in men with high-risk localized prostate cancer (PCa) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration. METHODS A multimodal artificial intelligence (MMAI)–derived predictive biomarker was trained for long-term (LT) versus short-term (ST) ADT using pretreatment digital prostate biopsy images and clinical data (age, prostate-specific antigen, Gleason, and T stage) from six NRG Oncology phase III randomized radiotherapy trials. The novel MMAI-derived biomarker was developed to predict the differential benefit of LT-ADT on the primary end point, distant metastasis (DM). MMAI predictive utility was validated on a seventh randomized trial, RTOG 9202 (N = 1,192), which randomly assigned men to RT + ST-ADT (4 months) versus RT + LT-ADT (28 months). Fine-Gray and cumulative incidence analyses for DM, and secondarily, death with DM, were performed. Deaths without DM were treated as competing risks. RESULTS In the validation cohort (median follow-up, 17.2 years), LT-ADT significantly improved DM from 26% to 17% (subdistribution hazard ratio [sHR], 0.64 [95% CI, 0.50 to 0.82], P < .001). A significant biomarker-treatment predictive interaction was observed ( P = .04) for DM, whereby MMAI biomarker–positive men (n = 785, 66%) had reduced DM with LT-ADT versus ST-ADT (sHR, 0.55 [95% CI, 0.41 to 0.73], P < .001), whereas no treatment benefit was observed for MMAI biomarker–negative men (n = 407; sHR, 1.06 [95% CI, 0.61 to 1.84], P = .84). The estimated 15-year DM risk difference between RT + LT-ADT and RT + ST-ADT was 14% in MMAI biomarker–positive men and 0% in MMAI biomarker–negative men. The MMAI biomarker was also prognostic for DM, irrespective of treatment (sHR, 2.35 [95% CI, 1.72 to 3.19], P < .001). CONCLUSION To our knowledge, the MMAI model is the first validated predictive biomarker to guide ADT duration with RT in localized/locally advanced PCa. Approximately one third of men with high-risk PCa could safely be spared the additional 24 months of ADT and the associated morbidity.

Background: Artificial intelligence (AI) platforms can potentially enhance clinical decision-making (CDM) in primary care settings. OpenEvidence (OE), an AI tool, draws from trusted sources to generate evidence-based medicine (EBM) recommendations to address clinical questions. However, its effectiveness in real-world primary care cases remains unknown. Objective: To evaluate the performance of OE in providing EBM recommendations for five common chronic conditions in primary care: hypertension, hyperlipidemia, diabetes mellitus type 2, depression, and obesity. Methods: Five patient cases were retrospectively analyzed. Physicians posed specific clinical questions, and OE responses were evaluated on clarity, relevance, evidence support, impact on CDM, and overall satisfaction. Four independent physicians provided ratings using a 0 to 4 scale. Results: OE provided accurate, evidence-based recommendations in all cases, aligning with physician plans. OE was scored on a scale of zero to four, where zero was very unclear, and four was very clear. Mean scores across cases were clarity (3.55 ± 0.60), relevance (3.75 ± 0.44), support (3.35 ± 0.49), and satisfaction (3.60 ± 0.60). However, the impact on CDM was limited (1.95 ± 1.05), as OE primarily reinforced rather than modified plans. Conclusion: OE was rated high in clarity, relevance, and evidence-based support, reinforcing physician decisions in common chronic conditions. While the impact on CDM was minimal due to the study’s retrospective nature, OE shows promise in augmenting the primary care physician. Prospective trials are needed to evaluate its utility in complex cases and multidisciplinary settings.

Abstract Increased innate immune activity promotes neurodegeneration and contributes to progression in multiple sclerosis. This prospective case-control study aims to investigate thalamic microglia density on 18kDa translocator protein PET in patients with multiple sclerosis using a third-generation radioligand, 11C-ER176, and investigate the associations of 11C-ER176 PET uptake with imaging and clinical measures of progression in multiple sclerosis. Patients with multiple sclerosis (n = 50) and controls (n = 55) were prospectively enrolled and they underwent 11C-ER176 PET and MRI including diffusion MRI with neurite orientation dispersion and density imaging. Disease characteristics, expanded disability status scale and multiple sclerosis functional composite scores were obtained in patients with multiple sclerosis. Age at imaging (mean ± standard deviation: patients = 49.6 ± 12.9 years, controls = 48.2 ± 15.4 years, P = 0.63) and sex (female ratio; patients = 72%, controls = 65%, P = 0.47) were not different between the groups. Thalamus 11C-ER176 PET uptake was highest in patients with progressive multiple sclerosis (1.272 ± 0.072 standardized uptake value ratio), followed by patients with relapsing multiple sclerosis (1.209 ± 0.074 standardized uptake value ratio) and lowest in controls (1.162 ± 0.067 standardized uptake value ratio, P &lt; 0.001). Patients with thalamic lesions had higher thalamus 11C-ER176 PET uptake than those without thalamic lesions in both relapsing multiple sclerosis and progressive multiple sclerosis (P &lt; 0.001). In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with lower thalamic volume (r = −0.45, P = 0.001), higher mean diffusivity (r = 0.56, P &lt; 0.001), lower neurite density index (r = −0.43, P = 0.002), lower orientation dispersion index (r = −0.40, P = 0.005) and higher free water fraction (r = 0.42, P = 0.003) in the thalamus. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake also correlated with higher mean diffusivity (r = 0.47, P &lt; 0.001) and lower neurite density index (r = −0.36, P = 0.012) in the corpus callosum. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with worse expanded disability status scale scores (r = 0.33, P = 0.02), paced auditory serial addition test scores (r = −0.43, P = 0.003) and multiple sclerosis functional composite z-scores (r = −0.46, P = 0.001). Microglia density in the thalamus is highest in patients with progressive multiple sclerosis and is associated with imaging biomarkers of neurodegeneration and clinical disease severity. As a signature imaging biomarker of progression in multiple sclerosis, effectively reflecting the global disease burden, 11C-ER176 PET may aid development and efficacy evaluation of therapeutics targeting microglia.

This Viewpoint discusses clinicians as legal petitioners of extreme risk protection orders to promote the safety and well-being of patients and communities.

Abstract This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets. See related commentary by Lee, p. 875

Abstract Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well characterized, given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) &lt;40 mL/min. CrCl &lt;30 mL/min or dialysis dependence was defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age, 71 vs 67 years; P = .002) and have a higher median number of previous lines of therapy (7 vs 6; P = .04). Rates and severity of cytokine release syndrome (51% vs 59%; grade ≥3: 1.2% vs 1%) and immune effector cell–associated neurotoxicity syndrome (16% vs 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day 30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in most patients with RI outside of the context of disease progression. Overall response rate (52% vs 56%; P = .61) and survival outcomes (median progression-free survival, 4.6 vs 6.5 months; P = .62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI, including those on dialysis, with a similar safety and efficacy profile to patients without RI.