Immunotherapy (IO) has improved prognosis of non-small cell lung cancer (NSCLC); however, some patients experience primary IO resistance (PIR). CXCL13 could be a promising PIR biomarker due to its role in antitumor immune responses. 177 patients with stage IV NSCLC receiving IO from the observational, multicenter, real-world study BLI-O were included from 15 centers in Spain. CXCL13 and 39 other cytokines were measured in 158 baseline (BS1) and 98 post-first-cycle of IO (BS2) plasma samples. Additionally, peripheral T and B cell BS2 immunophenotypes were determined. CXCL13 levels were also measured in plasma samples from 38 stage IIIA NSCLC patients treated with neoadjuvant chemoimmunotherapy from the NADIM II trial (NCT03838159). PIR was defined as disease progression within 3 months in non-surgical cases or incomplete pathological response in surgical cases. Metastatic PIR patients had higher CXCL13 plasma levels compared to non-PIR patients, especially in BS2 samples, and exhibited a greater increase of CXCL13 levels after the first cycle of IO. Patients with high BS2 CXCL13 levels showed shorter PFS (p = 0.0002) and OS (p = 0.0007). Females showed a lower percentage of high CXCL13 cases compared to male cases. CXCL13 did not influence the growth of NSCLC cell lines in vitro. Moreover, the expression of the CXCL13/CXCR5 axis was restricted to the immune compartment of tumors. Plasmatic CXCL13 levels were not associated with PD-L1 TPS expression nor TLS density in tumor tissue. However, at systemic level, patients with high CXCL13 levels exhibited impaired B and T cell phenotypes, along with elevated levels of inflammatory cytokines, after first IO cycle. Finally, high BS2 CXCL13 levels in resectable cases were also associated with PIR. Elevated CXCL13 levels after the first cycle of IO are associated with PIR and an altered peripheral immune profile in NSCLC, supporting its potential as a prognostic biomarker in these patients.
Background:Frailty assessment has emerged as a key component of pre-transplant evaluation. We aimed to validate, across international cohorts, the Hematopoietic Cell Transplantation Frailty Scale (HCT-FS) for the assessment of frailty in adult candidates for allogenic hematopoietic cell transplantation (allo-HCT). HCT-FS is designed for integration into routine workflows using existing resources. Methods:In this prospective, observational cohort study, we evaluated the performance of HCT-FS, a frailty scale that categorises patients as fit, pre-frail, or frail based on a cumulative weighted score derived from eight variables. We enrolled participants across 16 allo-HCT programmes (one in Canada, 15 in Spain). Eligible participants were all adult patients evaluated for frailty at the centres during the time frames: from the Hans Messner Allo-HCT Program at Princess Margaret Cancer Center (PMCC) in Toronto, Canada (2018-2024; where HCT-FS was developed) and from 15 Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) centres across Spain (2022-2023). Frailty was systematically assessed in all candidates for a median of 10 min at the first allo-HCT consultation by haematologists or trained nurses using the HCT-FS. The prognostic accuracy of the HCT-FS was assessed by evaluating its ability to discriminate clinical outcomes across frailty categories in the overall cohort and by testing the consistency of these associations within specific patient subgroups. Data were prospectively updated until February 2025. Findings:Overall, 1077 consecutive adult allo-HCT candidates were enrolled and evaluated across the PMCC (n = 734) and GETH-TC (n = 343) cohorts. The median age was 56 years (range 18-76); 411 patients (38.2%) were over 60, and 640 (59.4%) were male. Based on the HCT-FS, 33.4% patients were fit, 53.7% pre-frail, and 12.8% frail. Frailty was associated with longer hospital stays (23, 25, and 28 days for fit, pre-frail, and frail patients, respectively; p = 0.003) and higher ICU admission rates (Day +180: 7.0%, 10.8%, and 20.3% for fit, pre-frail, and frail patients, respectively; p = 0.002). 2-year OS decreased progressively with increasing frailty: 77.2% for fit, 65.7% for pre-frail, and 52.8% for frail (p < 0.001). Corresponding NRM rates were 11.7%, 19.5%, and 32.2%, respectively (p = 0.001). Multivariable analysis confirmed frailty as a predictor of inferior OS and increased NRM, when adjusting for age, comorbidities, performance status, DRI, and donor type. The HCT-FS maintained robust prognostic accuracy across subgroups stratified by age and comorbidity burden. Interpretation:The HCT-FS provided reliable measures of the frailty status of allo-HCT candidates that are informative for transplant outcomes, supporting its potential applicability in clinical practice. Notably, this tool was successfully integrated into clinical practice without additional resources. Future work is needed to further evaluate the applicability of the scale in transplant settings and whether targeted interventions based on can improve transplant outcomes. Funding:None.
BACKGROUND:Larotrectinib is a first-in-class, selective tropomyosin receptor kinase (TRK) inhibitor with proven activity across solid tumors. This study aimed to describe larotrectinib's effectiveness in patients with solid tumors in Spain. METHODS:SPAINTRK (NCT06837090) was a retrospective study including adult and pediatric patients with solid neoplasms treated with larotrectinib through compassionate use, between European Medicines Agency (EMA) approval and commercialization in Spain. TRK fusions were determined as part of standard care using next-generation sequencing (NGS), fluorescence in situ hybridization, or immunohistochemistry plus a confirmatory molecular test. The primary endpoint was duration of response (DoR). No formal sample size was calculated. RESULTS:From February to June 2025, 20 patients aged ten months to 81 years were included. Eight solid tumor types with TRK fusions were included involving NTRK1 gene in 8 patients (40 %), NTRK2 in 5 (25 %), and NTRK3 in 7 (35 %). NGS was used in 65 %. Median DoR was 24.5 months (95 % CI: 11.1- not reached) and objective response rate was 60 % (95 % CI: 36.1-80.9). At one year, 75 % of responses (9 out of 12) were ongoing, and 12 patients (60 %) remained progression-free. At data cutoff (median follow-up of 24.4 months (95 % CI: 13.2-35)), 41.7 % of the patients with a response were disease-free and/or remained on treatment. Treatment-related neutropenia and transaminitis were reported in 15 % of patients each. CONCLUSIONS:Larotrectinib evoked broad and durable antitumor activity in a plethora of solid tumors with NTRK fusions. Safety profile was consistent with that of clinical trials, even after long-term administration. While NGS use is increasing, broader access is needed.
Background/Objectives: Atrial fibrillation (AF) is the most common sustained arrhythmia in adults, with a prevalence that increases with age. In older patients, its clinical impact is particularly relevant due to higher mortality and greater comorbidity burden. This study aimed to compare patients aged ≥80 years with younger patients in a large AF cohort. Methods: The REGUEIFA registry is an observational, prospective, multicentre study including consecutive patients with AF managed by cardiologists. Baseline clinical characteristics, comorbidities, complementary test findings, AF type, therapeutic strategies, anticoagulation patterns, and patient-reported outcomes were compared. Results: A total of 1007 patients were included, of whom 18.2% were aged ≥80 years. Older patients showed a higher prevalence of hypertension, renal dysfunction, conduction disorders, chronic obstructive pulmonary disease, and neoplastic disease, along with higher thromboembolic (CHA2DS2-VASc 3.7 ± 1.04 vs. 2.1 ± 1.49; p < 0.001) and haemorrhagic risk (HAS-BLED 1.3 ± 0.8 vs. 0.6 ± 0.7; p < 0.001). Permanent AF was more frequent, whereas rhythm control strategies and antiarrhythmic drug use were less common, and quality of life was poorer. Anticoagulation rates were high in both groups (≈90%), with greater use of vitamin K antagonists (VKAs) in older patients, although anticoagulation control was similar. Patients treated with direct-acting oral anticoagulants reported a lower treatment burden and greater perceived benefit than those receiving VKAs. Conclusions: Patients aged ≥80 years with AF exhibit greater comorbidity, poorer perceived health status, and higher thromboembolic and haemorrhagic risk. Their management is more often oriented towards rate control strategies and VKA use, while rhythm control approaches are more common in younger patients.
