BACKGROUND: Cachexia is associated with poor survival rates. In the clinical setting, the diagnosis of cancer cachexia is challenging. The cachexia index (CXI), a new index for predicting survival time, is a promising tool for diagnosing cancer cachexia; however, its efficacy in predicting patient survival has not been validated.
OBJECTIVE: This meta-analysis and systematic review aimed to explore the CXI\'s prognostic value in patients with cancer.
METHODS: The PubMed, Embase, MEDLINE, and Cochrane Library databases were searched for relevant studies to determine the association between CXI findings and prognosis.
METHODS: The outcomes were overall survival (OS), progression-, disease-, and recurrence-free survival (PFS/DFS/RFS) rates, and the rate of complete response.
METHODS: The QUality In Prognostic Studies (QUIPS) tool was used to evaluate the quality of the included trials. This meta-analysis comprised 14 studies involving 2777 patients. A low CXI was associated with decreased OS (hazard ratio [HR] 2.34, 95% confidence interval [CI] 2.01-2.72; P < .001), PFS/DFS/RFS (HR 1.93, 95% CI 1.68-2.22; P < .001), and complete response (odds ratio [OR] 0.49, 95% CI 0.36-0.66; P < .001). Patients with a low CXI had a lower body mass index (mean difference [MD] -0.75, 95% CI -1.00 to 0.50; P < .001), skeletal muscle index (standardized MD -0.80, 95% CI -0.98 to -0.61; P < .001), and serum albumin level (MD -0.23, 95% CI -0.26 to -0.20; P < .001); and a higher neutrophil-lymphocyte ratio (MD 1.88, 95% CI 1.29-2.47; P < .001) and more advanced disease stages (OR 0.80, 95% CI 0.71-0.91; P = .001).
CONCLUSIONS: A low CXI was found to be associated with poor survival in patients with cancer. While the CXI is a promising marker for predicting cancer cachexia, further studies are required to verify its usefulness.

BACKGROUND: Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.
METHODS: Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer\'s guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.
RESULTS: Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.
CONCLUSIONS: This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body\'s dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.

OBJECTIVE: Exocrine pancreatic insufficiency (EPI) contributes to malnutrition, marked by muscle loss during chemotherapy for advanced pancreatic cancer (aPC). Pancreatic enzyme replacement therapy (PERT) is recommended for patients with EPI; however, it\'s efficacy for attenuating muscle loss has not been demonstrated. We aimed to delineate the impact of PERT dose on muscle loss using a 7-year population-based cohort with aPC who were provided PERT at the discretion of their oncologist or dietitian according to clinical indications of EPI.
METHODS: All patients treated with chemotherapy for aPC from 2013 to 2019 in Alberta, Canada (population ∼4.3 million) were included if they had computed tomography (CT) scans both prior to and 12 ± 4 weeks after chemotherapy initiation. Change in muscle area (cm2) was measured at 3rd lumbar level on repeated CT scans. Muscle loss was defined by measurement error (loss >2.3 cm2). Clinical and pharmaceutical data were retrieved from provincial registries. For patients who were dispensed PERT -8 to +6 weeks from chemo start (PERT users), estimated dose consumed per day was calculated as: (total dose dispensed) / (days, first to last dispensation). PERT users were categorized as high dose or low dose users according to the median estimated dose consumed. Non-users were classified as No PERT. Association between PERT use and muscle loss was analyzed with multivariable logistic regression.
RESULTS: Among 210 patients, 81 (39%) were PERT users. Median estimated dose consumed per day of 75 000 USP lipase units defined the cutoff between low dose and high dose uses. There were no significant differences in baseline characteristics between high dose and low dose groups. Muscle loss was more prevalent among low dose compared to both high dose and No PERT groups (88% vs. 58% and 67%, p < 0.05). In the multivariable model predicting muscle loss, low dose PERT was independently associated with greater odds of muscle loss (OR 5.4, p = 0.004) vs. high dose, independent of tumour response, disease stage, and chemotherapy regimen.
CONCLUSIONS: In patients with clinical indications of EPI during chemotherapy for aPC, low doses of PERT were insufficient to prevent muscle loss. Patients with EPI consuming higher doses of PERT had similar odds of muscle maintenance to patients without clinical indications of EPI. Provider education for optimal PERT dosing in patients with EPI should be prioritized, and resources must be allocated to support dose titration.

BACKGROUND: Anamorelin is expected to improve cancer cachexia by increasing lean body mass (LBM) due to increased appetite and protein synthesis. However, the effect of anamorelin on cancer cachexia in real-world practice is unclear. The purpose of this study was to evaluate the efficacy and safety of anamorelin and to identify predictors of efficacy on treatment with anamorelin.
METHODS: We retrospectively analyzed data from patients with cancer cachexia treated with chemotherapy between May 2021 and August 2022. Efficacy of anamorelin was evaluated using LBM, with \"12-week sustained effective response\" to anamorelin treatment defined as maintenance or an increase in LBM for 12 weeks. We examined factors associated with \"12-week sustained effective response\" to anamorelin treatment using a multivariable logistic model that included controlling nutritional status (CONUT) score, an objective assessment of nutritional disorders, and the modified Glasgow prognostic score (mGPS), which scores the cachexia status of cancer patients. To assess patient subjective quality of life (QOL) changes related to eating after starting anamorelin treatment, we used a questionnaire (QOL-ACD appetite-related items: Q8, 9, 11). Adverse events were evaluated in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
RESULTS: On analysis of data from 40 patients, 23 patients showed a 12-week sustained effective response to anamorelin (57.5%). At 12 weeks, LBM significantly increased by 1.63 ± 3.73 kg (mean ± SD). Multivariable logistic analysis revealed that a low CONUT score was significantly associated with \"12-week sustained effective response\" to anamorelin treatment (adjusted odds ratio: 13.5, 95% confidence intervals: 2.2-84.2, P = 0.004). QOL assessment showed a trend toward increased appetite and enjoyment of meals after anamorelin initiation. Five patients (12.5%) had an increase in HbA1c of more than 1.0% during the 12 weeks after the start of anamorelin. No patient had QT interval prolongation or grade 3 or higher hepatic transaminase elevation.
CONCLUSIONS: Anamorelin may maintain or increase LBM with tolerable safety in patients with cancer cachexia undergoing chemotherapy. A low CONUT score, despite meeting criteria for cancer cachexia, is suggested as a predictor for the efficacy of anamorelin, indicating that patients with a low CONUT score may benefit from early introduction of anamorelin.

Cachexia is a wasting syndrome that manifests in more than half of all cancer patients. Cancer-associated cachexia negatively influences the survival of patients and their quality of life. It is characterized by a rapid loss of adipose and skeletal muscle tissues, which is partly mediated by inflammatory cytokines. Here, we explored the crucial roles of interleukin-6 (IL-6) family cytokines, including IL-6, leukemia inhibitory factor, and oncostatin M, in the development of cancer cachexia. These cytokines have been shown to exacerbate cachexia by promoting the wasting of adipose and muscle tissues, activating mechanisms that enhance lipolysis and proteolysis. Overlapping effects of the IL-6 family cytokines depend on janus kinase/signal transducer and activator of transcription 3 signaling. We argue that the blockade of these cytokine pathways individually may fail due to redundancy and future therapeutic approaches should target common downstream elements to yield effective clinical outcomes.

Cancer cachexia is an involuntary loss of body weight, mostly of skeletal muscle. Previous research favors the existence of a microbiota-muscle crosstalk, so the aim of the study was to evaluate the impact of microbiota alterations induced by antibiotics on skeletal muscle proteins expression. Skeletal muscle proteome changes were investigated in control (CT) or C26 cachectic mice (C26) with or without antibiotic treatment (CT-ATB or C26-ATB, n = 8 per group). Muscle protein extracts were divided into a sarcoplasmic and myofibrillar fraction and then underwent label-free liquid chromatography separation, mass spectrometry analysis, Mascot protein identification, and METASCAPE platform data analysis. In C26 mice, the atrogen mafbx expression was 353% higher than CT mice and 42.3% higher than C26-ATB mice. No effect on the muscle protein synthesis was observed. Proteomic analyses revealed a strong effect of antibiotics on skeletal muscle proteome outside of cachexia, with adaptative processes involved in protein folding, growth, energy metabolism, and muscle contraction. In C26-ATB mice, proteome adaptations observed in CT-ATB mice were blunted. Differentially expressed proteins were involved in other processes like glucose metabolism, oxidative stress response, and proteolysis. This study confirms the existence of a microbiota-muscle axis, with a muscle response after antibiotics that varies depending on whether cachexia is present.

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.

UNASSIGNED: Cancer cachexia is associated with poor prognosis in patients with metastatic urothelial carcinoma (mUC). The objective of the study was to assess the cachexia index (CXI), which is a new indicator assessing the status of cancer cachexia, as a prognostic indicator for mUC patients treated with gemcitabine plus cisplatin (GC) chemotherapy.
UNASSIGNED: The study included 55 patients with mUC who underwent GC chemotherapy between 2008 and 2022 as first-line chemotherapy. The CXI at the start of chemotherapy was determined as follows: CXI=(serum albumin × skeletal muscle mass index)/ (neutrophil count/lymphocyte count). Patients were categorized into two groups based on a median CXI value (CXI-high and CXI low). We used Kaplan-Meier curves and multivariate Cox proportional hazards regression models to assess the association between the CXI and overall survival (OS).
UNASSIGNED: At the start of GC chemotherapy, significant differences were not found in patients\' characteristics. The median OS was significantly shorter in the CXI-low group [10.0 months (95% confidence interval (CI)=5.1-12.8)] than in the CXI-high group [22.3 months (95% CI=13.6-NA), p<0.05]. Multivariate analysis revealed that low CXI was a predictor of a poor prognosis [hazard ratio (HR)=2.25, 95% CI=1.12-4.52, p<0.05].
UNASSIGNED: CXI might be useful as a prognostic indicator for patients with mUC undergoing first-line GC chemotherapy.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.