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Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients.

Background: Liver diseases drive the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB4) index is a non-invasive scoring method for detecting liver fibrosis, but the prognostic impact of using it for AF patients is still unknown. Herein, we evaluated using the FIB4 index as a risk assessment tool for cardiovascular events and mortality in patients with AF. Methods: We performed a post-hoc analysis of a prospective, observational multicenter study. A total of 3067 patients enrolled in a multicenter Japanese registry were grouped as first tertile (FIB4 index &lt, 1.75, n = 1022), second tertile (1.75 &le, FIB4 index &lt, 2.51, n = 1022), and third tertile (FIB4 index &ge, 2.51, n = 1023). Results: The third tertile had statistically significant results: older age, lower body mass index, increased heart failure prevalence, and lower clearances of hemoglobin and creatinine (all p &lt, 0.05). During the follow-up period, incidences of major bleeding, cardiovascular events, and all-cause mortality were significantly higher for the third tertile (all p &lt, 0.05). After multivariate adjustment, the third tertile associated independently with cardiovascular events (HR 1.72, 95% CI 1.31&ndash, 2.25) and all-cause mortality (HR 1.43, 95% CI 1.06&ndash, 1.95). Adding the FIB4 index to a baseline model with CHA2DS2-VASc score improved the prediction of cardiovascular events and all-cause mortality, as shown by the significant increase in the C-statistic (all p &lt, 0.05), net reclassification improvement (all p &lt, 0.001), and integrated discrimination improvement (all p &lt, 0.001). A FIB4 index &ge, 2.51 most strongly associated with cardiovascular events and all-cause mortality in AF patients with high CHADS2 scores (all p &lt, 0.001). Conclusions: The FIB4 index is independently associated with risks of cardiovascular events and all-cause mortality in AF patients.

Background: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist, but the real-world data after approval of direct oral anticoagulants (DOACs) are still lacking in Japan. We investigated the association of the baseline renal function and adverse clinical events and risk of adverse clinical events with DOACs compared to warfarin for each renal functional level in Japanese AF patients. Methods: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter observational registry (median follow-up period: 39 months). The creatinine clearance (CrCl) values were estimated by the Cockcroft–Gault formula, and divided into normal renal function, and mild and moderate-severe CKD (CrCl ≥ 80, 50–79, &lt, 50 mL/min). Results: In the SAKURA AF Registry, the baseline CrCl data were available for 3242 patients (52% for DOAC and 48% for warfarin user). The relative risk of adverse clinical events was significantly higher in the patients with a CrCl &lt, 50 mL/min as compared to those with a CrCl ≥ 80 mL/min (adjusted HRs: 2.53 for death, 2.53 for cardiovascular [CV] events, 2.13 for strokes, and 1.83 for major bleeding). Risks of all adverse clinical events were statistically even between DOAC and warfarin users for each renal function level. Conclusion: Moderate–severe CKD was associated with a higher mortality, CV events, strokes, and major bleeding than normal renal function. The safety and effectiveness of DOACs over warfarin were similar for each renal function level. By a worsening renal function, the incidence of adverse clinical events increased, especially deaths and CV events as compared to strokes and major bleeding.