BACKGROUND:Immunotherapy based on anti-PD1 inhibitors has significantly improved survival in advanced melanoma. However, a significant proportion of patients do not benefit, and predicting response to immunotherapy remains an area of unmet need. Our group previously defined an immune signature able to predict response to anti-PD1 inhibitors in this scenario. METHODS:In this study, we analyzed two cohorts of patients with advanced melanoma treated with anti-PD1 inhibitors: the GEM cohort, previously used to validate our immune signature, and Campbell's cohort, which contains data about different immunotherapy schemes. Using the 107 genes that compose our immune signature and consensus clustering, samples were classified as immune-low or immune-high. Then, CIBERSORTx and Ecotyper were used to estimate the proportion of each immune cell type and carcinoma ecotypes in both cohorts. RESULTS:We confirmed that the immune-low group includes mostly patients who do not response to anti-PD1 inhibitors. We also studied the distribution of carcinoma ecotypes in the immune-high and immune-low groups defined by our immune classification. Ecotypes CE9 and CE10 clustered in the immune-high group, with good response to treatment. The use of combination immunotherapy improved response rate both in immune-low and immune-high tumors. The immune-high group contained a higher number of CD8 T cells, B memory cells and T follicular helper cells. CONCLUSIONS:Our immune-based classification defines an immune-low group of tumors with poor response to anti-PD1 inhibitors. This immune classification is related to carcinoma ecotypes. Finally, a use of a combo scheme improves the rates of response both in immune-high and low groups but in the case of immune-low tumors, our results suggests that a combo treatment approach could be an adequate strategy and should be further explored in these patients. Altogether, our results support the utility of our immune signature in the prediction of response to anti-PD1 inhibitors in advanced melanoma.
BACKGROUND AND AIMS:The prediction of the first major arrhythmic event (MAE) is still an unmet need in the recently defined scenario of non-dilated left ventricular cardiomyopathy (NDLVC). METHODS:A cohort of 337 patients with NDLVC and no history of MAE was retrospectively identified at two large centres. Patient-tailored diagnostic workup included cardiac magnetic resonance (CMR), endomyocardial biopsy, and genetic testing. The primary endpoint was the occurrence of the first MAE, including sustained ventricular tachycardia (VT), ventricular fibrillation, or appropriate implantable cardioverter-defibrillator therapy, by 60-month follow-up. A pool of 216 NDLVC patients from 11 European centres served as a validation cohort. RESULTS:In the study cohort (mean age 37 ± 15 years, 62% male), the mean left ventricular ejection fraction (LVEF) was 52 ± 8%, and 79% of patients had late gadolinium enhancement (LGE) at baseline CMR. By 60-month follow-up, 51 patients (15%) experienced a MAE. The primary endpoint was predicted by male sex [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.3-4.4, P = .007], baseline non-sustained VT (HR 3.1, 95% CI 1.7-5.6, P < .001), LVEF < 45% (HR 5.5, 95% CI 2.7-11.0, P < .001), septal (HR 2.0, 95% CI 1.0-4.0, P = .046) and ring-like pattern of LGE (HR 1.3, 95% CI .6-2.6, P = .54), pathogenic/likely pathogenic variants in guideline-defined high-risk genes (HR 4.6, 95% CI 2.3-9.1, P < .001), and biopsy/CMR-proven myocardial inflammation (HR 15.7, 95% CI 6.1-40.3, P < .001). The results were confirmed in the validation cohort (Uno's C-index 0.81, 95% CI .75-.88). A novel risk score was subsequently derived. CONCLUSIONS:In NDLVC, male sex, non-sustained VT, LVEF < 45%, septal and ring-like LGE, high-risk genotypes, and myocardial inflammation predicted the first episode of MAE by 60 months.
Rationale: Excessive stress (distending pressure), strain (volume deformation), and drop in inspiratory alveolar pressure are proposed mechanisms for patient self-inflicted lung injury. Objectives: To dissect the influence of inspiratory effort, respiratory mechanics, and ventilation mode on lung stress, strain, and drop in inspiratory alveolar pressure; and explore their impact on oxygenation and lung compliance. Methods: International cohort study analyzing respiratory recordings (esophageal pressure) of patients with acute hypoxemic respiratory failure. Association between muscular pressure (Pmus), surrogates of stress (driving trans-alveolar pressure), strain (tidal volume), and inspiratory alveolar pressure relative to PEEP were explored with mixed-models, including interactions for ventilation mode, respiratory system elastance, and synchrony. Association between these and changes in oxygenation and lung compliance were explored. Measurements and main results: 60 patients from 15 centers represented 528 recordings (339,796 breaths). For each cmH(2)O Pmus increase there was an increase in driving trans-alveolar pressure (median[CI 95%] 0.28[0.27-0.29]cmH(2)O) and tidal volume (0.16[0.16-0.17]ml/kg of predicted body weight) and decrease in alveolar pressure (-0.25[0.24-0.6]cmH(2)O, p<0.001). Volume-control ventilation showed less increase in stress and strain surrogates than pressure-targeted modes, but more drop in alveolar pressure (p<0.001, Pmus:mode interaction). Breath-stacking was infrequent and associated with higher stress. Lower inspiratory alveolar pressure relative to PEEP was associated with subsequent worsening oxygenation (p=0.04) and higher stress with worsening lung compliance (p=0.023). Conclusion: Strong efforts are associated with high surrogates for lung stress, strain, and lower inspiratory alveolar pressure relative to PEEP, differently according to the mode of ventilation, being associated with subsequent worsening oxygenation and lung compliance.
BACKGROUND:Hepatitis C virus (HCV) has significantly impacted people with human immunodeficiency virus (HIV). Harm reduction programs, changing transmission patterns, and direct-acting antivirals (DAAs) have profoundly altered HIV/HCV coinfection trends. This study evaluates HCV prevalence among people with HIV in Spain over 2 decades. METHODS:We conducted 9 cross-sectional studies (2002-2023) in 39-43 centers. Sampled individuals were randomly sampled from people with HIV actively followed up at these centers, with proportional allocation. Main outcomes included the prevalence of anti-HCV antibody and active HCV infection (HCV RNA--positive result). RESULTS:The reference population ranged from 31 800 to 47 006, with sample sizes of 1260-1867. HIV transmission patterns shifted from 2002 to 2023, with injection drug use decreasing from 55% to 21% and the proportion of men who have sex with men increasing from 17% to 46%. HCV seroprevalence fell from 60.8% to 27.4%, and active infection from 46.3% to 0.9%. In the DAA era (2015-2023), active HCV infection dropped by 100% in heterosexuals, 94% in people who inject drugs, and 71% in men who have sex with men. Treatment uptake increased from 23% in 2002 to 99% by 2023 with all-oral DAAs. The prevalence of cirrhosis among active HCV cases peaked at 23.1% in 2015 but fell to 0% by 2021. Among those achieving sustained virologic response, cirrhosis prevalence was 20.4% in 2023. CONCLUSIONS:HIV/HCV coinfection has drastically declined in Spain, with active HCV infection prevalence <1% since 2021. DAAs were pivotal in this achievement. However, cirrhosis remains a concern among those with sustained virologic response. Ongoing surveillance and prevention efforts are essential to sustain these gains and address residual risks.
NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.
