👤 Jeroen Van Cutsem

To systematically examine the available literature on circulating biomarkers of performance resilience in a military environment, with the goal of identifying the most promising circulating biomarkers. The construct 'resilience' is hypothesized to play an important role in increasing Special Operations Forces' and other military personnel's capacity for withstanding exposure to various military-specific stressors. However, objectively measuring resilience is challenging. Some of the most important and well-studied circulating biomarkers that affect military-specific resilience are cortisol, dehydroepiandrosterone (sulfate) [DHEA(S)], noradrenaline, serotonin, neuropeptide-Y (NPY) and brain-derived neurotrophic factor. Despite growing evidence, the available knowledge is yet to be summarized and reviewed while considering the intensity and duration of military-specific stressors, military experience, and methodological differences between studies. Cortisol, Insulin-like growth factor-1 (IGF-1), NPY and DHEA(S) provide a physiological window into military-specific resilience. In general, individuals who exhibit a pronounced but controlled biomarker response to an acute stressor, combined with a quick recovery to baseline, demonstrate physiological flexibility that is associated with greater military-specific resilience. Future research will need to determine relative thresholds for the acute stressor-related change in circulating biomarkers and relative timing to stressor, to correctly interpret 'a pronounced but controlled biomarker response' and 'quick recovery to baseline'. Show less

Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202. Show less