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Background: Gastric cancer can lead to excessive catabolism in patients. After undergoing gastric surgery, patients may experience additional unintended weight loss, resulting in severe malnutrition and potentially cachexia. Methods: We selected and incorporated patients from two centers. Cohort 1 (n = 1393) served as the development cohort, while cohort 2 (n = 501) was designated as an external validation cohort. Within cohort 1, 70% of the patients were utilized for model training, with the remaining 30% reserved for internal validation. The training set initially underwent univariate logistic regression, followed by multivariate logistic regression. The factors ultimately incorporated were used to construct the model and create nomograms. The discriminative ability was assessed using ROC curves in all three datasets, calibration curves were used to evaluate consistency, and decision curves analysis was performed to assess the clinical application value. Results: The model incorporated 12 factors, specifically: age (OR = 1.07), preoperative BMI (OR = 0.89), surgery type (Total Gastrectomy (TG), OR = 1.83), chemotherapy (yes, OR = 1.52), stage (III, OR = 1.40), anastomotic obstruction (yes, OR = 6.85), Postsurgical Gastroparesis Syndrome (PGS) (yes, OR = 2.27), albumin (OR = 0.95), hemoglobin (OR = 0.98), triglycerides (OR = 0.36), CRP (OR = 1.07), and Neutrophil to Lymphocyte Ratio (NLR) (OR = 1.05). The model demonstrated robust performance in ROC with AUC values of 0.805 in the training set, 0.767 in the validation set, and 0.795 in Cohort 2. Calibration curves in all three datasets exhibited a high degree of concordance between actual and predicted probabilities. Decision curve analysis (DCA) indicated that the model holds substantial clinical utility across all three datasets. Conclusions: We have developed a predictive model for cachexia in patients undergoing gastric cancer surgery. This model enables healthcare professionals to accurately estimate the risk of cachexia in postoperative patients with nutritional deficits, allowing for timely nutritional interventions to enhance patient quality of life and prognosis. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Cachexia is a complex and multifactorial syndrome, which is a current, worldwide treatment challenge, and concerns most of the patients with cancer. The issue is characterized by anorexia, skeletal muscle loss, adipose tissue wasting, involuntary weight loss, malnutrition, and poor appetite due to dysfunction of metabolism and chronic, systemic inflammation. Additionally, it impacts oncological treatment and a decline in Quality of Life. The review aims to explore the latest research, innovations, and potentials in the treatment of cachexia. Material and methods: The review was based on research of articles published from 2019 to 2024 on the PubMed database using the following keywords: cancer cachexia, palliative care, and cachexia pharmacotherapy. Results: Anamorelin, a selective ghrelin receptor agonist showed effectiveness in weight gain and appetite improvement. Also, myostatin inhibitors protect muscles and promote their growth due to suppression of myostatin. Ponsegromab, a GDF-15 inhibitor, significantly and directly enhanced muscle mass, appetite, and quality of life, with good safety. Modern antiinflammatory medications like momelotynib or tocilizumab, reduced the concentration of proinflammatory cytokines and improved quality of life, however, but posed immunosuppression risk. Pentoxifylline declined inflammation and chemotherapy toxicity, and improved body weight and survival. Cannabinoids alleviated chemotherapy-induced nausea but were ineffective for weight and quality of life. Conclusions: Therapeutic approaches target various aspects of cachexia due to its complex pathophysiology. Anamorelin, ponsegromab, and myostatin inhibitors have clinical potential. Modern antiinflammatory drugs and pentoxifylline offer supportive benefits. Further research is vital for developing effective and safe treatment guidelines for cancer cachexia. [ABSTRACT FROM AUTHOR]

Adverse events (AEs) induced by cancer chemotherapy reduce not only patient quality of life (QOL) but also the efficacy of treatment. Management of AEs can therefore improve both the efficacy and safety of cancer chemotherapy. This review describes the contribution of pharmacists to the management of adverse events aimed at improving the treatment efficacy of cancer chemotherapy. Efforts to improve the evidence-practice gap are a useful approach to countermeasures against AEs. Pharmacists can intervene in these efforts in the course of their daily practice. Here, we made undertook to improve the evidence-practice gap in prophylaxis pharmacotherapy for chemotherapy-induced nausea and vomiting (CINV) and anti-EGFR antibody-induced acneiform rash. After intervention by pharmacists, the rate of adherence to prophylaxis pharmacotherapy for these AEs was significantly improved, and the incidence of CINV and acneiform rash was significantly decreased. Notably, time to treatment failure (TTF) with anti-EGFR antibody therapy tended to be increased, and may have contributed to an improvement in therapeutic effect. Next, we examined adverse events associated with anti-cancer drugs related to the therapeutic effect of cancer chemotherapy. Incidence of hypomagnesemia in patients receiving anti-EGFR antibodies and neutropenia in patients receiving TAS-102 was significantly associated with the therapeutic effect of cancer chemotherapy. Moreover, we examined the impact of cancer cachexia, a cancer-associated AE, on the therapeutic effect of immune checkpoint inhibitors. In patients receiving nivolumab, the presence of cancer cachexia prior to treatment initiation was associated with shorter OS and TTF. In summary, pharmacist management of AEs was shown to improve treatment response. Further, AEs which are predictive of treatment response in cancer chemotherapy were identified. Management of these AEs is an important role for pharmacists aiming to improve patient QOL and treatment efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer patients frequently develop a syndrome named cachexia that causes severe muscle loss and frailty, eventually representing the cause of death. Muscle atrophy and muscle weakness are characterized by massive degradation of endogenous proteins, potentially consequent to excessive disposal of mitochondria through the selective autophagic process of mitophagy. This study explored whether selectively silencing BNIP3, a mitophagy-related protein upregulated in the muscle of both mouse and human cancer hosts, could help in preventing muscle loss. Two distinct methodological silencing approaches were tested, either by electroporation of a plasmid or via adenoviral particle injection. Although the first method was ineffective in tumor-bearing mice, the adenovirus-based approach significantly reduced BNIP3 levels and moderately increased muscle fiber size, suggesting partial prevention of muscle atrophy. BNIP3 silencing also maintained mitochondrial mass without disrupting oxidative balance, highlighting BNIP3's central role in cancer cachexia and suggesting that targeting BNIP3 may help in supporting muscle health in cancer patients. Background and Aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia. Methods: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection. Results: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance. Conclusions: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Patients and Methods Results Conclusions Cachexia is a poor prognostic factor in many advanced cancers. Cachexia diagnostic criteria of the European Palliative Care Research Collaboration (EPCRC) may underestimate cachexia in Asians; therefore, new criteria have been proposed by the Asian Working Group for Cachexia (AWGC). We compared both criteria to determine differences in diagnostic rates and their association with lung cancer prognosis.This single‐center, retrospective cohort study considered lung cancer outpatients receiving chemotherapy. Survival was analyzed using Kaplan–Meier curves and log‐rank tests. The association between cachexia diagnosis and prognosis was examined for each set of criteria using a Cox proportional hazards model. C‐statistic analysis was performed to compare the discriminative power for prognosis.Among the 106 participants analyzed (median age, 75 [71–79] years; 75 males [70.8%]; 91 [85.9%] with performance status [PS] 0–1), 58 (54.7%) and 77 (72.6%) cachexia cases were diagnosed using the EPCRC and AWGC criteria, respectively. The latter encompassed all but one patient diagnosed using the EPCRC criteria. Patients with cachexia had a significantly poorer prognosis according to both criteria (EPCRC, p = 0.002; AWGC, p = 0.001). Both criteria had almost equal discriminative power for prognosis (EPCRC, C‐statistic = 0.658; AWGC, C‐statistic = 0.658). CRP in the AWGC criteria was most strongly related to prognosis.Cachexia was an independent poor prognostic factor in lung cancer patients receiving chemotherapy under the AWGC and EPCRC criteria, both of which had similar prognostic discriminatory power. Among CRP, anorexia, and grip strength, elevated CRP may be the most prognostically relevant parameter in the AWGC criteria. [ABSTRACT FROM AUTHOR]

Introduction: Cancer cachexia is associated with various metabolic mechanisms such as inflammatory response, insulin resistance, and increased muscle proteolysis. However, effective treatment methods have not yet been standardized. Chrysanthemum indicum L. (CI) is a perennial plant belonging to the Asteraceae family, and its flowers have been used for the treatment of headaches, colds, and rhinitis in Asia. Methods: This study investigated the effect of CI on cancer cachexia. We subcutaneously injected CT26 colon cancer cells (5 × 105 cells/mouse) into the right flank of BALB/c mice. After 1 week, the mice were orally administered vehicle, CI (100 mg/kg), or Celecoxib (50 mg/kg) for 3 weeks. Results: CI improved loss of body weight and impaired glucose tolerance, but celecoxib did not recover the body weight and glucose intolerance. CI not only improved the decreased myofiber diameters but also inhibited muscle protein degradation factors, MAFbx and MuRF1. CI also increased cellular membrane GLUT4 in CT26 conditioned medium-treated C2C12 myofibers and cancer cachexia-induced mice. Furthermore, we found that linarin, a constituent of CI, was responsible for the improvement of muscle atrophy. Conclusion: Our findings indicate that CI can ameliorate muscle atrophy by improving glucose uptake, suggesting that CI could be a therapeutic agent for cancer cachexia. [ABSTRACT FROM AUTHOR]

Introduction: Cancer cachexia (CC) is characterized by weight loss with specifically reduced skeletal muscles and adipose tissues in patients with late-stage cancer. Dihydroartemisinin (DHA), an effective antimalarial derivative of artemisinin, has been demonstrated to have anti-inflammatory and antitumor properties. Materials and Methods: This study examined the effects of DHA on the Lewis lung carcinoma (LLC)-induced CC mouse model. Results: DHA treatment significantly increases tumor-free body weight and food intake but decreases serum interleukin-6 level and tumor weight in CC mice. In addition, DHA treatment relieves muscle atrophy and decreases muscle ring finger 1 (MuRF1) and F-box-only protein 32 (Fbx32) expressions in CC mice. In vitro , DHA reverses the reduction in myotube formation induced by an LLC-conditioned medium and increases Fbx32 expression in C2C12 mouse myotubular cells. Conclusions: Our study demonstrated that DHA ameliorates the cachectic state and skeletal muscle atrophy in LLC-induced cachectic mouse models, suggesting its therapeutic potential for CC. [ABSTRACT FROM AUTHOR]

Circadian rhythms are ∼24 h cycles evident in behaviour, physiology and metabolism. The molecular mechanism directing circadian rhythms is the circadian clock, which is composed of an interactive network of transcription–translation feedback loops. The core clock genes include Bmal1, Clock, Rev‐erbα/β, Per and Cry. In addition to keeping time, the core clock regulates a daily programme of gene expression that is important for overall cell homeostasis. The circadian clock mechanism is present in all cells, including skeletal muscle fibres, and disruption of the muscle clock is associated with changes in muscle phenotype and function. Skeletal muscle atrophy is largely associated with a lower quality of life, frailty and reduced lifespan. Physiological and genetic modification of the core clock mechanism yields immune dysfunction, alters inflammatory factor expression and secretion and is associated with skeletal muscle atrophy in multiple conditions, such as ageing and cancer cachexia. Here, we summarize the possible interplay between the circadian clock modulation of immune cells, systemic inflammatory status and skeletal muscle atrophy in chronic inflammatory conditions. Although there is a clear disruption of circadian clocks in various models of atrophy, the mechanism behind such alterations remains unknown. Understanding the modulatory potential of muscle and immune circadian clocks in inflammation and skeletal muscle health is essential for the development of therapeutic strategies to protect skeletal muscle mass and function of patients with chronic inflammation. [ABSTRACT FROM AUTHOR]

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. Abbreviations: DEAF1: Deformed epidermal autoregulatory factor-1; FOXO: Forkhead box O; MuSC: Muscle Stem Cell; PAX7: Paired box 7; PIK3C3: Phosphatidylinositol 3-kinase catalytic subunit type 3. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Cancer cachexia complicates advanced non‐small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first‐line systemic therapy. Methods We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first‐line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first‐line systemic therapy. Results A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0–2 who were initiated on first‐line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first‐line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy‐associated emesis affecting early appetite‐related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: −3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (−1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression‐free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003). Conclusions Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite‐related QOL trends vary based on the type of first‐line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter.

Abstract Background The primary objective of this study was to assess the frequency of body composition increases and their relationships to changes in body weight in two cohorts of real world, treatment‐naïve, advanced non‐small cell lung cancer (NSCLC) patients. One cohort received the current standard of care (CSOC), which consisted of immunotherapy and newer chemotherapy regimens, and the other cohort was treated with the former standard of care (FSOC), consisting only of older platinum‐containing regimens. Methods CSOC (n = 106) and FSOC (n = 88) cohorts of advanced NSCLC patients were included in this study. Weights were collected at each clinical visit, and body composition analysis from routine chest computed tomography via automated segmentation software assessed at baseline and at 6 and 12 weeks. Standard statistical methods were used to calculate relationships between changes in weight and in body composition. Results The CSOC cohort contained 106 stage IV NSCLC patients treated between 16/12/2014 and 22/10/2020 while the FSOC cohort contained 88 stage III/IV NSCLC patients treated between 16/6/2006 and 18/11/2014. While each cohort exhibited decreases in median weight, body mass index (BMI), mean skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI) at the 6 and 12 week time points, a subset of patients experienced increases in these parameters. Using a threshold of ≥2.5% increase for weight, BMI, SMI, and SATI at the 12 week time point, both cohorts showed similar (20.5% and 27.3%) increases in these parameters. With a cut point of ≥5% increase at 12 weeks follow‐up, 8.0% to 25.0% of the patients gained ≥5% in weight, BMI, SMI and SATI. Comparing these results in each cohort showed no significant differences. Pearson coefficients for weight change related to changes in SMI and SATI at 6 and 12 weeks ranged from 0.31 to 0.58 with all P values

Cancer cachexia is a debilitating syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite the prevalence and severe consequences of cancer cachexia, effective treatments for this syndrome remain elusive. Therefore, there is a greater need for well-characterized animal models to identify novel therapeutic targets. Certain manifestations of cachexia, such as pain and depression, have been extensively studied using animal models of cancer-induced bone pain (CIBP). In contrast, other aspects of cachexia have received less attention in these models. To address this issue, we established the CIBP model by injecting Lewis lung carcinoma into the intramedullary cavity of the femur, observed cachexia-related symptoms, and demonstrated the utility of this model as a preclinical platform to study cancer cachexia. This model accurately recapitulates key features of cancer cachexia, including weight loss, muscle atrophy, adipose tissue depletion, CIBP, and anxiety. These findings suggest that psychological factors, in addition to physiological and metabolic factors, play significant roles in cancer cachexia development. Our model offers a valuable resource for investigating the underlying mechanisms of cancer cachexia and for developing innovative therapeutic strategies that target physical and psychological components.

Abstract Background The Asian Working Group for Cachexia (AWGC) proposed the first consensus report on diagnostic criteria for cachexia in Asians in 2023. However, the current consensus lacks cohort evidence to validate its effectiveness and practicality. We aimed to explore the value of the AWGC2023 criteria for predicting the prognosis and medical burden of patients with cancer through a retrospective post hoc cross‐sectional analysis of the Investigation on Nutrition Status and its Clinical Outcome of Common Cancers (INSCOC) project in China. Methods Cox regression analyses were performed to assess the independent association between cachexia and long‐term survival. We utilized C‐reactive protein (CRP), neutrophil‐to‐lymphocyte ratio (NLR), inflammatory burden index (IBI), albumin (ALB) and Glasgow prognostic score (GPS) as diagnostic markers for cachexia, designating them as CRP‐based cachexia, NLR‐based cachexia, IBI‐based cachexia, ALB‐based cachexia and GPS‐based cachexia, respectively. Additionally, we diagnosed cachexia using body mass index (BMI) cutoff values of 18.5, 20, 21 and 22 kg/m2, respectively, and subsequently compared their prognostic predictive value through Harrell's concordance index (C‐index). Logistic regression models were used to assess the association between cachexia and medical burden. Results A total of 5426 patients with cancer were enrolled in this study. Cox regression analysis confirmed that cachexia based on the AWGC2023 criteria was an independent predictor of long‐term survival in patients with cancer. Patients with cachexia had significantly poorer long‐term survival than patients without cachexia (66.4% vs. 49.7%, P

Abstract Background Cancer cachexia‐induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l‐Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia‐associated fibrosis and the involvement of Runx2 in the process remain unexplored. Methods Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l‐carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1‐stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real‐time PCR, western blot analysis, co‐immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model. Results l‐Carnitine supplementation reduced cancer cachexia‐induced declines in grip strength (>88.2%, P 57.9%, P

Abstract 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.

Abstract Studies have shown that the cachexia index (CXI) is a useful predictor of cachexia in patients with colorectal cancer. However, the application of the CXI is limited stemming from the intricacy and additional cost of radiographic examinations. This study aimed to develop an easy-to-use and practical CXI based on fat-free mass index (FFMI-CXI) to evaluate the prognostic value of FFMI-CXI in CRC. A total of 656 patients with CRC were enrolled in the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) study. The FFMI-CXI was calculated as [FFMI (kg)/height (m)2 × serum albumin (g/L)]/neutrophil-lymphocyte ratio. The cutoff value for FFMI-CXI was determined through the analysis of ROC curves and Youden’s index for both male and female cohorts. Kaplan–Meier survival curves with log-rank tests were conducted to compare time–event relationships between different groups. Cox proportional hazards regression models incorporating both univariate and multivariate variables were employed to explore the independent prognostic factors associated with OS. Logistic regression analysis was performed to assess the association of the FFMI-CXI with secondary outcomes. The major outcome was 5-year overall survival (OS). Based on the cutoff values, 331 patients had low FFMI-CXI, and 325 patients had high FFMI-CXI. Patients in the low FFMI-CXI subgroup were significantly older and had advanced TNM stage, malnutrition, high systemic inflammation, long hospitalizations, high hospitalization costs, adverse short-term outcomes, and all-cause mortality. Multivariate Cox regression analyses revealed that FFMI-CXI (HR 0.47, 95% CI 0.33–0.66; p

Pharmacists’ roles in cachexia care are unclear. This study aimed to clarify the knowledge and practice of cachexia care and identify factors related to the practice of cachexia care among pharmacists. Information on the knowledge and practice of cachexia care was obtained. Components of practicing multimodal care were evaluated. Participants were categorized into two groups according to practicing multimodal care levels. Comparisons were made between the groups, and multiple regression analysis was employed. Of the 451 pharmacists, 243 responded. They were categorized into the Practicing group (n = 119) and Not practicing group (n = 124). Significant differences were observed for the number of advanced cancer patients/month, frequency of caring for them, and involvement in training programs on cachexia. The Practicing group had significantly better knowledge about cachexia. The Practicing group used guidelines, items, and symptoms more frequently to detect cachexia. The Practicing group tended to detect cachexia and initiate interventions in earlier phases and in patients with a better status. Multivariate logistic regression analysis showed that the most significant factor was the regular provision of care (odds ratio, 2.07; 95% confidence interval, 1.10–3.92). The regular provision of care was associated with the practice of multimodal care.

Purpose: Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [18F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia. Methods: [18F]FDG PET/MRI imaging was performed in cachexia-inducing tumour models versus models that do not induce cachexia. SUVaverage was calculated for all tumours via volume of interest (VOI) analysis of PET/MRI overlay images using PMOD software. Results: [18F]FDG PET imaging demonstrated increased tumour and brain uptake in cachectic versus non-cachectic tumour-bearing mice. Therapy with mAb 002 was able to reduce [18F]FDG uptake in tumours (P < 0.05, n = 3). Fn14 KO tumours did not induce body weight loss and did not show an increase in [18F]FDG tumour and brain uptake over time. In non-cachectic mice bearing Fn14 KO tumours, [18F]FDG tumour uptake was significantly lower (P < 0.01) than in cachectic mice bearing Fn14 WT counterparts. As a by-product of glucose metabolism, l-lactate production was also increased in cachexia-inducing tumours expressing Fn14. Conclusion: Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours. [ABSTRACT FROM AUTHOR]

Background: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non‐small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. Methods: This prospective cohort study included 55 metastatic NSCLC patients and seven age‐matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. Results: We observed a higher survival rate in NSCLC patients with high performance in the timed up‐and‐go (+320%; p =.007), sit‐to‐stand (+256%; p =.01) and six‐minute walking (+323%; p =.002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p >.05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (−54.2%; p <.0001) and cell proliferation (−44.9%; p =.007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. Conclusion: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism. We found that patients with better performance in the timed up‐and‐go, sit‐to‐stand and six‐minutes walking test lived longer in this cohort. Moreover, plasma from NSCLC patients with low physical performance impaired oxygen consumption and extracellular acidification rate and decreased the proliferation of primary human myotubes. Unbiased metabolomics revealed several metabolites differentially expressed in the plasma of NSCLC patients with low physical performance compared to healthy control subjects, with serine and M22G being the most reduced and increased metabolites, respectively. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1 × 106 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (∼250 nmol/kg body wt/day) and administered to mice beginning 7 days following tumor induction, whereas control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover, and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post hoc test when interactions were significant (P ≤ 0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis, and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females, SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1, Serca1, and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC. NEW & NOTEWORTHY: Herein, we assess the efficacy of the mitochondria-targeted antioxidant SkQ1 to mitigate cancer cachexia (CC) in both biological sexes. We demonstrate that SkQ1 administration attenuates muscle wasting induced by C26 tumors in male, but not female, mice. Conversely, we identify that in females, SkQ1 improves muscle contractility. These phenotypic adaptations to SkQ1 are aligned with respective responses in muscle protein synthesis, mitochondrial respiration, and mRNA content of protein turnover, as well as mitochondrial and calcium handling-related markers. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cancer cachexia is a multifactorial syndrome characterized by the progressive loss of skeletal muscle mass and adipose tissue. Dalbergia odorifer is widely used in traditional medicine in Korea and China to treat various diseases. However, its exact role and underlying mechanism in regulating cancer cachexia have not been elucidated yet. This research was conducted to investigate the effect of D. odorifer extract (DOE) in preventing the development of cancer-induced cachexia symptoms and figure out the relevant mechanisms. Methods: A cancer cachexia model was established in Balb/c mice using the CT26 colon carcinoma cell line. To evaluate the anti-cachexia effect of Dalbergia odorifer extract (DOE), CT26-bearing mice were orally administered with DOE at concentrations of 50 and 100 mg/kg BW for 14 days. C2C12 myotubes and 3T3L1 adipocytes were treated with 80% CT26 conditioned medium, DOE, and wortmannin, a particular AKT inhibitor to determine the influence of DOE in the AKT signaling pathway. Mice body weight, food intake, myofiber cross-sectional area, adipocyte size, myotube diameter, lipid accumulation, and relevant gene expression were analyzed. Results: The oral administration of DOE at doses of 50 and 100 mg/kg body weight to CT26 tumor-bearing mice resulted in a significant reduction in body weight loss, an increase in food intake, and a decrease in serum glycerol levels. Furthermore, DOE treatment led to an increase in muscle mass, larger muscle fiber diameter, and elevated expression levels of MyH2 and Igf1, while simultaneously reducing the expression of Atrogin1 and MuRF1. DOE also attenuated adipose tissue wasting, as evidenced by increased epididymal fat mass, enlarged adipocyte size, and upregulated Pparγ expression, alongside a reduction in Ucp1 and IL6 levels. In cachectic C2C12 myotubes and 3T3-L1 adipocytes induced by the CT26 conditioned medium, DOE significantly inhibited muscle wasting and lipolysis by activating the AKT signaling pathway. The treatment of wortmannin, a specific AKT inhibitor, effectively neutralized DOE's impact on the AKT pathway, myotube diameter, and lipid accumulation. Conclusions: DOE ameliorates cancer cachexia through the expression of genes involved in protein synthesis and lipogenesis, while suppressing those related to protein degradation, suggesting its potential as a plant-derived therapeutic agent in combating cancer cachexia. [ABSTRACT FROM AUTHOR]

Studies have shown that the cachexia index (CXI) is a useful predictor of cachexia in patients with colorectal cancer. However, the application of the CXI is limited stemming from the intricacy and additional cost of radiographic examinations. This study aimed to develop an easy-to-use and practical CXI based on fat-free mass index (FFMI-CXI) to evaluate the prognostic value of FFMI-CXI in CRC. A total of 656 patients with CRC were enrolled in the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) study. The FFMI-CXI was calculated as [FFMI (kg)/height (m)2 × serum albumin (g/L)]/neutrophil-lymphocyte ratio. The cutoff value for FFMI-CXI was determined through the analysis of ROC curves and Youden's index for both male and female cohorts. Kaplan–Meier survival curves with log-rank tests were conducted to compare time–event relationships between different groups. Cox proportional hazards regression models incorporating both univariate and multivariate variables were employed to explore the independent prognostic factors associated with OS. Logistic regression analysis was performed to assess the association of the FFMI-CXI with secondary outcomes. The major outcome was 5-year overall survival (OS). Based on the cutoff values, 331 patients had low FFMI-CXI, and 325 patients had high FFMI-CXI. Patients in the low FFMI-CXI subgroup were significantly older and had advanced TNM stage, malnutrition, high systemic inflammation, long hospitalizations, high hospitalization costs, adverse short-term outcomes, and all-cause mortality. Multivariate Cox regression analyses revealed that FFMI-CXI (HR 0.47, 95% CI 0.33–0.66; p < 0.001) and TNM stage (HR 3.38, 95% CI 2.63–4.35; p < 0.001) were independently associated with OS in CRC patients. K-M survival curves revealed that the CRC patients with a high FFMI-CXI had significantly more favorable OS than those with low FFMI-CXI (62.84% vs. 84.31%; log-rank p < 0.001). Furthermore, the FFMI-CXI was valuable for predicting 90-day outcomes, malnutrition, cancer cachexia, length of hospitalization, and hospitalization expenses. This study revealed that the FFMI-CXI can be used as a prognostic indicator in patients with CRC. Patients with low FFMI-CXI should receive more attention. [ABSTRACT FROM AUTHOR]

Background: More than 50% of people with advanced cancer suffer from cancer-related cachexia (CC) -- a major contributor to morbidity and mortality. Despite the lack of local guidelines on CC diagnosis and management in Uganda, the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO) and the Global Leadership Initiative on Malnutrition (GLIM) developed guidelines on CC screening and management. However, the level of knowledge on CC and compliance with the available guidelines among Ugandan oncology health professionals is unknown. This study aimed to assess the level of awareness and knowledge of CC diagnosis and management and compliance with the ASCO/ESMO/GLIM guidelines on CC among healthcare professionals (HCPs) involved in the care of cancer patients. Methods: In this phase one, a self-administered structured questionnaire developed using the ASCO/ESMO and GLIM guidelines on diagnosis and management of CC was used to assess the level of awareness, and knowledge of 200 health professionals from three hospital settings on CC, and compliance with the ASCO/ESMO/GLIM guidelines on CC related core communication, barriers to communication, clinician training in communication, discussing goals of care, treatment options and meeting the needs of the underserved populations. The data were entered into Research Electronic Data Capture software analysed using STATA version 18.0 software. Results: The overall objectively correct knowledge score of CC diagnosis criteria was 67.5% (n = 135), yet there was a much lower level of awareness about ASCO/ESMO/GLIM guidelines on CC at 30% (n = 60) and only 21% (n = 42) of the HCPs have ever assessed Quality of life of CC patients. The compliance with ASCO/ESMO/GLIM guidelines on nutritional interventions for patients with CC varied across the variables markedly, ranging from 25.1% (n = 50) to 81% (n = 162) for the specific ASCO/ESMO/GLIM guidelines' recommendations. Whereas compliance with the guidelines on discussing goals of care, prognosis, treatment options and end-of-life care scored the highest in most variables, most HCPs exhibited low compliance with the discussion about patients' end-of-life preferences early in the course of incurable illness (49.8%, n = 99). There were statistically significant differences between the mean scores of only two variables among the three hospitals in compliance with ASCO/ESMO/GLIM guidelines on the provision of additional calories by feeding tubes (p = 0.038), and the available evidence to recommend medication to improve CC outcomes (p = 0.0286). On discussing goals of care, prognosis, treatment options and end-of-life care there was a statistically significant difference between the mean scores of only one variable; clinician's simplicity of providing information to patients (p = 0.0132) among the HCPs in the three hospital settings. Conclusion: This study indicated that the overall objectively correct knowledge of CC diagnosis criteria was inadequate, with a much lower level of awareness about the ASCO/ESMO/GLIM guidelines on CC and a handful of the HCPs have ever assessed the quality of life of CC patients. Quality improvement interventions on CC diagnosis and management should prioritize improving the level of knowledge on CC, diagnostic criteria and patient-clinician communication, including discussion about patients' end-of-life care using standardised tools such as ASCO/ESMO or GLIM guidelines on CC using a multidisciplinary team approach. [ABSTRACT FROM AUTHOR]

Background: Detection of precachexia is important for the prevention and treatment of cachexia. However, how to identify precachexia is still a challenge. Objective: This study aimed to detect cancer precachexia using a simple method and distinguish the different characteristics of precachexia and cachexia. Methods: We included 3896 participants in this study. We used all baseline characteristics as input variables and trained machine learning (ML) models to calculate the importance of the variables. After filtering the variables based on their importance, the models were retrained. The best model was selected based on the receiver operating characteristic value. Subsequently, we used the same method and process to identify patients with precachexia in a noncachexia population using the same method and process. Results: Participants in this study included 2228 men (57.2%) and 1668 women (42.8%), of whom 471 were diagnosed with precachexia, 1178 with cachexia, and the remainder with noncachexia. The most important characteristics of cachexia were eating changes, arm circumference, high-density lipoprotein (HDL) level, and C-reactive protein albumin ratio (CAR). The most important features distinguishing precachexia were eating changes, serum creatinine, HDL, handgrip strength, and CAR. The two logistic regression models for screening for cachexia and diagnosing precachexia had the highest area under the curve values of 0.830 and 0.701, respectively. Calibration and decision curves showed that the models had good accuracy. Conclusion: We developed two models for identifying precachexia and cachexia, which will help clinicians detect and diagnose precachexia. [ABSTRACT FROM AUTHOR]

Pharmacists' roles in cachexia care are unclear. This study aimed to clarify the knowledge and practice of cachexia care and identify factors related to the practice of cachexia care among pharmacists. Information on the knowledge and practice of cachexia care was obtained. Components of practicing multimodal care were evaluated. Participants were categorized into two groups according to practicing multimodal care levels. Comparisons were made between the groups, and multiple regression analysis was employed. Of the 451 pharmacists, 243 responded. They were categorized into the Practicing group (n = 119) and Not practicing group (n = 124). Significant differences were observed for the number of advanced cancer patients/month, frequency of caring for them, and involvement in training programs on cachexia. The Practicing group had significantly better knowledge about cachexia. The Practicing group used guidelines, items, and symptoms more frequently to detect cachexia. The Practicing group tended to detect cachexia and initiate interventions in earlier phases and in patients with a better status. Multivariate logistic regression analysis showed that the most significant factor was the regular provision of care (odds ratio, 2.07; 95% confidence interval, 1.10–3.92). The regular provision of care was associated with the practice of multimodal care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cachexia is a complex metabolic condition that is often overlooked and recognized in a late irreversible phase. There is a continuing effort to discover and define a biochemical biomarker of the condition. In this study, we have chosen interleukin-13 (IL-13) and transforming growth factor beta (TGF-β), i.e., two cytokines with presumed roles in the development of cancer cachexia, and we measured their concentrations in the serum and saliva of cachectic patients with metastatic solid tumors, non-cachectic patients with metastatic solid tumors, and healthy individuals. We have demonstrated the role of saliva cytokine measurement as a potential sample for cachexia investigations as opposed to the standard approach to biomarker research, which is serum measurement. We have also found that the salivary IL-13 and TGF-ß are independent risk factors and thus could serve as potential biomarkers of the condition, a fact that warrants further research and confirmation. Cancer cachexia is a syndrome characterized by weight and muscle loss and functional impairment, strongly influencing survival in cancer patients. In this study, we aimed to establish the role of saliva cytokine measurement in cancer cachexia investigation and define two potential independent salivary biomarkers of the condition. Methods: serum and saliva specimens were obtained from 78 patients. Forty-six patients were non-cachectic, and 32 patients were cachectic (per SCRINIO group criteria), all with metastatic solid tumors. Commercial ELISA kits were used to determine the salivary and serum concentrations of interleukin 13 (IL-13) and transforming growth factor beta (TGF-β) in two patient groups and healthy controls. Laboratory values were obtained from the hospital information system, and weight and height were measured at the time of sampling. Results: A statistically significant difference was observed between the groups in saliva IL-13 concentrations but no difference in serum concentrations. Statistically significant differences were also observed between the groups in saliva and serum concentrations of TGF-β. Logistic regression analysis has identified salivary IL-13 and TGF-β as independent factors for cancer cachexia. Conclusions: We demonstrated saliva as a valuable specimen for cachexia investigation and established IL-13 and TGF-β as potential cancer cachexia biomarkers. Further research is needed to evaluate these findings. [ABSTRACT FROM AUTHOR]

Background: Cancer cachexia affects more than half of all cancer patients, reducing survival rates. Evidence‐based approaches are urgently needed to optimize treatment. Methods: A systematic review and network meta‐analysis were conducted to assess the effectiveness and safety of different pharmacotherapies for cancer cachexia. Three databases (PubMed, Cochrane Library, and Web of Science) were searched for the period from January 1, 2000, to March 20, 2024. The netmeta package in R software was used to calculate the pooled effect, employing a random effects model. Results: Seven placebo‐controlled randomized trials involving 1421 patients were analyzed. Pairwise analysis showed that body weight increases were 4.6 kg (95% confidence interval [CI] 0.83–8.37 kg) for olanzapine, 3.82 kg (95% CI 0.73–6.91 kg) for espindolol (20 mg), 2.36 kg (95% CI 1.84–2.89 kg) for anamorelin (100 mg), and 1.31 kg (95% CI 0.42–2.19 kg) for anamorelin (50 mg). In terms of safety profiles, olanzapine demonstrated the lowest odds ratio when compared to placebo, at 0.26 (95% CI 0.07–0.94), followed by anamorelin (50 mg) at 0.86 (95% CI 0.30–2.48), and anamorelin (100 mg) at 0.89 (95% CI 0.42–1.88). However, network meta‐analysis could not confirm the superiority of olanzapine over anamorelin in terms of efficacy and safety. Conclusion: Both olanzapine and anamorelin are useful in improving body weight in patients with cancer cachexia. Personalization may be helpful for different patients. [ABSTRACT FROM AUTHOR]

Purpose: of review Accurate assessment of dietary intake, especially energy and protein intake, is crucial for optimizing nutritional care and outcomes in patients with cancer. Validation of dietary assessment methods is necessary to ensure accuracy, but the validity of these methods in patients with cancer, and especially in those with cancer cachexia, is uncertain. Validating nutritional intake is complex because of the variety of dietary methods, lack of a gold standard method, and diverse validation measures. Here, we review the literature on validations of dietary intake methods in patients with cancer, including those with cachexia, and highlight the gap between current validation efforts and the need for accurate dietary assessment methods in this population. Recent findings: We analyzed eight studies involving 1479 patients with cancer to evaluate the accuracy and reliability of 24-hour recalls, food records, and food frequency questionnaires in estimating energy and protein intake. We discuss validation methods, including comparison with biomarkers, indirect calorimetry, and relative validation of dietary intake methods. Summary: Few have validated dietary intake methods against objective markers in patients with cancer. While food records and 24-hour recalls show potential accuracy for energy and protein intake, this may be compromised in hypermetabolic patients. Additionally, under- and overreporting of intake may be less frequent, and the reliability of urinary nitrogen as a protein intake marker in patients with cachexia needs further investigation. Accurate dietary assessment is important for enhancing nutritional care outcomes in cachexia trials, requiring validation at multiple time points throughout the cancer trajectory. [ABSTRACT FROM AUTHOR]

Purpose: of review Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy. Recent findings: Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumorinduced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptordeficient mice were resistant to muscle wasting. Summary: Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancerassociated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health. [ABSTRACT FROM AUTHOR]

Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients' prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for therapeutic targeting. Because monoamine oxidase-A (MAO-A) is a myocardial source of H2O2 and implicated in myofibrillar protein catabolism and heart failure, we presently studied myocardial MAO-A expression, inflammatory cells, and capillarization together with transcripts of pro-inflammatory, -angiogenic, -apoptotic, and -proteolytic signals (by qRT-PCR) in a 3x-transgenic (LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre) mouse model of orthotopic pancreatic ductal adenoarcinoma (PDAC) compared to wild-type (WT) mice. Moreover, we evaluated the effect of MAO-A inhibition by application of harmine hydrochloride (HH, 8 weeks, i.p., no sham control) on PDAC-related myocardial alterations. Myocardial MAO-A protein content was significantly increased (1.69-fold) in PDAC compared to WT mice. PDAC was associated with an increased percentage of atrogin-1+ (p < 0.001), IL-1β+ (p < 0.01), COX2+ (p < 0.001), and CD68+ (p > 0.05) cells and enhanced transcripts of pro-inflammatory IL-1β (2.47-fold), COX2 (1.53-fold), TNF (1.87-fold), and SOCS3 (1.64-fold). Moreover, PDAC was associated with a reduction in capillary density (−17%, p < 0.05) and transcripts of KDR (0.46-fold) but not of VEGFA, Notch1, or Notch3. Importantly, HH treatment largely reversed the PDAC-related increases in atrogin-1+, IL-1β+, and TNF+ cell fraction as well as in COX2, IL-1β, TNF, and SOCS3 transcripts, whereas capillary density and KDR transcripts failed to improve. In mice with PDAC, increased myocardial pro-atrophic/-inflammatory signals are attributable to increased expression of MAO-A, because they are significantly improved with MAO-A inhibition as a potential novel therapeutic option. The PDAC-related loss in myocardial capillary density may be due to other mechanisms awaiting evaluation with consideration of cardiomyocyte size, cardiac function and physical activity. [ABSTRACT FROM AUTHOR]

Introduction and purpose Cachexia is a complex and multifactorial syndrome, which is a current, worldwide treatment challenge, and concerns most of the patients with cancer. The issue is characterized by anorexia, skeletal muscle loss, adipose tissue wasting, involuntary weight loss, malnutrition, and poor appetite due to dysfunction of metabolism and chronic, systemic inflammation. Additionally, it impacts oncological treatment and a decline in Quality of Life. The review aims to explore the latest research, innovations, and potentials in the treatment of cachexia. Material and methods The review was based on research of articles published from 2019 to 2024 on the PubMed database using the following keywords: cancer cachexia, palliative care, and cachexia pharmacotherapy. Results Anamorelin, a selective ghrelin receptor agonist showed effectiveness in weight gain and appetite improvement. Also, myostatin inhibitors protect muscles and promote their growth due to suppression of myostatin. Ponsegromab, a GDF-15 inhibitor, significantly and directly enhanced muscle mass, appetite, and quality of life, with good safety. Modern anti-inflammatory medications like momelotynib or tocilizumab, reduced the concentration of pro-inflammatory cytokines and improved quality of life, however, but posed immunosuppression risk. Pentoxifylline declined inflammation and chemotherapy toxicity, and improved body weight and survival. Cannabinoids alleviated chemotherapy-induced nausea but were ineffective for weight and quality of life. Conclusions Therapeutic approaches target various aspects of cachexia due to its complex pathophysiology. Anamorelin, ponsegromab, and myostatin inhibitors have clinical potential. Modern anti-inflammatory drugs and pentoxifylline offer supportive benefits. Further research is vital for developing effective and safe treatment guidelines for cancer cachexia.

This report describes the case of a 59-year-old man with poorly differentiated lung adenocarcinoma and cachexia who completed chemoradiation therapy for stage III lung cancer following the administration of anamorelin. Anamorelin, a ghrelin receptor agonist, effectively improved his appetite and performance status, thereby enabling the continuation of treatment. The role of anamorelin in enhancing appetite during acute-phase treatment is promising; however, further studies must be conducted to elucidate its interaction with chemoradiation therapy. This case report highlights the potential of anamorelin as a therapeutic option for the management of cancer-related cachexia during curative treatment for lung cancer.

The article published in the Journal of Physiology explores the role of interleukin-1β (IL-1β) in muscle atrophy in cancer cachexia, emphasizing the complex interplay between inflammation, sex-specific responses, and exercise. IL-1β is found to have both pro-inflammatory and antioxidant properties, impacting muscle protein synthesis and degradation. The study highlights the potential therapeutic implications of understanding IL-1β signaling pathways and the protective role of muscle-specific IL-1β expression in combating muscle atrophy. Additionally, the article discusses the differential expression of EcSOD across muscle types and the influence of ovarian hormones on IL-1β-mediated signaling in cancer cachexia, suggesting avenues for future research and potential therapeutic interventions. [Extracted from the article]

Abstract Background Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia. Methods Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP

Abstract Background Adipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting. Methods We sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression. Results Tumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group. Conclusion The SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model.

Abstract 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. Conclusion 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.

Abstract Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small‐molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.

Abstract Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of

Background: Adipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting. Methods: We sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression. Results: Tumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group. Conclusion: The SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model. [ABSTRACT FROM AUTHOR]

The experience of bearing witness to the lack of appetite and involuntary weight loss that characterizes cancer anorexia–cachexia syndrome (CACS) is reported to be stressful for family members. Research identifies that family members engage in a wide range of behaviors in response to a relative who shows minimal interest in eating and is literally 'wasting away' before their eyes. Some families, though concerned about the symptoms of CACS, do not dwell excessively on the patient's nutritional intake while others continually harass the patient to eat and petition health care providers for aggressive nutritional interventions to eat in an attempt to stave off further physical deterioration. While studies have detailed how family members respond to a terminally ill relative with CACS, empirical work explicating the explanatory models of CACS that they hold is lacking. Explanatory models (EMs) reflect the beliefs and ideas that families have about why illness and symptoms occur, the extent to which they can be controlled, how they should be treated, and how interventions should be evaluated. To address this gap in the literature, a grounded theory study guided by Kleinman's Explanatory Model questions was conducted with 25 family members of advanced cancer patients. The core category of 'Wayfaring' integrates the key categories of the model and maps onto Kleinman's questions about CACS onset, etiology, natural course, physiological processes/anatomical structures involved, treatment, and the impacts of disease on patient and family. Findings suggest that a divergence between some biomedical constructions of CACS and explanatory models held by family members may fuel the family–health care provider conflict, thereby providing direction for communication with families about care of the patient with anorexia–cachexia. [ABSTRACT FROM AUTHOR]

Background: Anamorelin is a selective ghrelin receptor agonist approved for cancer cachexia in Japan. Little is known about predictors of anamorelin efficacy. This study aimed to assess the effect of diabetes on the efficacy and safety of anamorelin in patients with cancer cachexia. Methods: Medical records of patients with advanced non-small-cell lung, gastric, pancreatic, or colorectal cancer who received anamorelin between January 2021 and March 2023 were retrospectively reviewed. The diabetic (DM) group included patients with a confirmed diagnosis of type 2 diabetes mellitus, random plasma glucose of ≥ 200 mg/dL, or hemoglobin A1c of ≥ 6.5%. The maximum body weight gain and adverse events during anamorelin administration were compared between the DM and non-DM groups. Patients with a maximum body weight gain ≥ 0 kg were classified as the responders. Results: Of 103 eligible patients, 31 (30.1%) were assigned to the DM group. The DM group gained less weight (median of −0.53% vs. + 3.00%, p < 0.01) and had fewer responders (45.2% vs. 81.9%, p < 0.01) than the non-DM group. The odds ratio for non-response in the DM group was 6.55 (95% confidential interval 2.37–18.06, p < 0.01), adjusted by age and performance status. The DM group had a higher cumulative incidence of hyperglycaemic adverse events (72.2% vs. 6.3%, p < 0.01) and more discontinuations due to hyperglycaemic adverse events (25.8% vs. 4.2%, p < 0.01) than the non-DM group. Conclusions: Patients with diabetes and cancer cachexia are less likely to gain weight with anamorelin despite a high risk of hyperglycaemic adverse events. [ABSTRACT FROM AUTHOR]