Cachexia, a syndrome marked by nonintentional weight loss, muscle wasting, functional decline and poor prognosis, affects 50%–80% of cancer patients, severely impacting quality of life, treatment tolerance and survival. A ‘Regulatory and Trial Update Workshop’ was organized by the Society on Cachexia and Wasting Disorders (SCWD) in December 2024 in Washington, DC, focused on clinical trial endpoints, standards of care and recent advancements. This article provides a summary of the discussions that were held during the first day of the workshop. Despite ongoing research, effective therapies for cachexia remain limited. Existing treatments, such as nutritional supplements, progestins, anti-inflammatories and anabolic agents, have shown mixed results, often improving appetite or lean mass without consistent functional benefits. Common muscle mass measurements, like CT scans of the L3 vertebra, are inadequate as primary endpoints because of biological variability and small effect sizes and because they do not necessarily translate into clinical benefit. Trials continue to face challenges in meeting regulatory requirements, which mandate improvements in both body composition and functional outcomes. Regulatory consensus emphasizes demonstrating clinically meaningful benefits in patient-reported outcomes/physical function and/or morbidity–mortality using validated instruments, adequate safety exposure, recognition that handgrip and weight alone are insufficient, feasibility in advanced disease, consideration of general activity measures, optional but informative body composition data and, for a pan-cancer label, benefits across at least three distinct cancers. Patient-centred endpoints, emphasizing real-life functioning and social participation, are essential as patients prioritize daily activity and independence over isolated physical measures. Clinical trials presented during the meeting included the MENAC trial, which tested a multimodal intervention combining nutrition, exercise, anti-inflammatory drugs and cancer therapy, achieved modest weight stabilization but no significant improvements in muscle mass or activity. In contrast, TCMCB07, an MC-4 receptor antagonist, demonstrated promising results in preclinical and early-phase human studies, showing weight stabilization and improved caloric intake with good tolerability. ART27.13, a dual CB1/CB2 receptor agonist, also demonstrated positive effects in appetite stimulation and weight stabilization. For S-pindolol, which targets appetite and metabolism, Phase IIb/III trials are to be initiated, following an earlier Phase II trial that showed improved muscle mass and muscle strength (hand grip strength). Future treatments must focus on integrating patient-centred goals, therapeutic mechanisms and meaningful clinical outcomes.
Excessive fat accumulation in muscles with disuse atrophy may impair muscle physiologic function and exacerbate the progression of atrophy, with causes largely unexplored. Evidence indicates leptin plays a crucial role in regulating skeletal muscle fat metabolism. Masticatory muscle (a special skeletal muscle) atrophy often causes aesthetic and functional problems due to various occlusal factors. This study examines leptin's role and mechanism in masseter muscle disuse atrophy and explores leptin's source.
A C57BL/6J mouse disuse atrophy model was established. The ameliorative role of leptin in masseter muscle lipid accumulation and atrophy and its local sources were explored by injection of exogenous leptin and nilotinib, which specifically induces leptin-producing fibro-adipogenic progenitor cells (FAPs). Transcriptomic sequencing revealed the molecular mechanism of lipid accumulation in the masseter muscle, which was validated by in vitro experiments.
Mice with masseter muscle disuse atrophy showed significant fat accumulation (triglycerides, TG: 3.750-fold elevation, p < 0.001). Local leptin injection reduced masseter muscle fat accumulation (TG: 2.330-fold reduction, p < 0.001) and atrophy index (MuRF-1: 2.068-fold reduction, p < 0.05). Transcriptomic analysis revealed downregulated PPAR lipid metabolism pathways, with significant repression of peroxisome proliferator-activated receptor α (PPARα) and consequent phenotypic effects. Leptin significantly upregulated PPARα expression (mRNA: 10.814-fold elevation, p < 0.001; protein: 1.843-fold elevation, p < 0.001). PPARα silencing in C2C12 cells abrogated leptin's lipid-lowering effect (TG: 3.903-fold reduction abolished, p < 0.01). Fluorescence-activated cell sorting (FACS)-isolated FAPs expressed leptin mRNA. Nilotinib-induced FAP apoptosis reduced local leptin expression (1.628-fold reduction, p < 0.05) and exacerbated masseter muscle lipid accumulation and atrophy (MuRF-1: 2.007-fold elevation, p < 0.001).
Disuse atrophy reduces leptin secreted by FAPs, triggering lipid accumulation that exacerbates muscle degeneration. This reveals the critical regulatory role of FAPs in maintaining masseter muscle homeostasis through leptin-mediated mechanisms.
The Sarcopenia and Quality of Life (SarQoL) questionnaire is recognized as the only disease-specific patient-reported outcome measure (PROM) for assessing sarcopenia-related HRQoL. This systematic review and meta-analysis aimed to provide a quantitative summary of all evidence reported on the reliability, validity, responsiveness and floor/ceiling effects of SarQoL in older adults.
Following PRISMA-COSMIN guidelines, a systematic search for studies evaluating the psychometric properties of SarQoL (i.e., reliability, validity, responsiveness and floor and ceiling effects) in older people was conducted on MEDLINE (via OVID), PsycINFO, Scopus and EMBASE. Studies published between 2013 and November 2024 using a consensual definition of sarcopenia were included. Study selection and data extraction were made by two independent reviewers. A random-effects model meta-analysis was applied. PROSPERO registration: CRD42024546880.
From 411 studies identified by the search strategy, 25 fulfilled the inclusion criteria, including 4585 community-dwelling individuals, of which 1311 were diagnosed as sarcopenic. SarQoL demonstrated high reliability (pooled Cronbach's alpha values consistently exceeding 0.80) and excellent test–retest reliability (pooled ICC = 0.98). Construct validity was confirmed with strong convergent correlations (pooled r > 0.54) with related dimensions of generic SF-36 and EQ-5D and weaker divergent correlations (pooled r < 0.47). Responsiveness, evaluated in two studies using different methodologies, supported the ability of SarQoL to detect meaningful changes in HRQoL. The certainty of evidence was rated as high for reliability, validity and responsiveness.
This meta-analysis consolidates a decade of evidence and confirms the strong psychometric properties of SarQoL, with a high level of evidence.
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