A comprehensive review of animal models for cancer cachexia: Implications for translational research.

Cancer cachexia is a multifactorial syndrome characterized by progressive weight loss and a disease process that nutritional support cannot reverse. Although progress has been made in preclinical research, there is still a long way to go in translating research findings into clinical practice. One of the main reasons for this is that existing preclinical models do not fully replicate the conditions seen in clinical patients. Therefore, it is important to understand the characteristics of existing preclinical models of cancer cachexia and pay close attention to the latest developments in preclinical models. The main models of cancer cachexia used in current research are allogeneic and xenograft models, genetically engineered mouse models, chemotherapy drug-induced models, Chinese medicine spleen deficiency models, zebrafish and Drosophila models, and cellular models. This review aims to revisit and summarize the commonly used animal models of cancer cachexia by evaluating existing preclinical models, to provide tools and support for translational medicine research.

Efficacy and safety of pharmacotherapy for cancer cachexia: A systematic review and network meta-analysis.

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.

Machine learning to identify precachexia and cachexia: a multicenter, retrospective cohort study.

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.

Nutritional Mechanisms of Cancer Cachexia.

Cancer cachexia is a complex systemic wasting syndrome. Nutritional mechanisms that span energy intake, nutrient metabolism, body composition, and energy balance may be impacted by, and may contribute to, the development of cachexia. To date, clinical management of cachexia remains elusive. Leaning on discoveries and novel methodologies from other fields of research may bolster new breakthroughs that improve nutritional management and clinical outcomes. Characteristics that compare and contrast cachexia and obesity may reveal opportunities for cachexia research to adopt methodology from the well-established field of obesity research. This review outlines the known nutritional mechanisms and gaps in the knowledge surrounding cancer cachexia. In parallel, we present how obesity may be a different side of the same coin and how obesity research has tackled similar research questions. We present insights into how cachexia research may utilize nutritional methodology to expand our understanding of cachexia to improve definitions and clinical care in future directions for the field.

High-Protein Nutritional Supplements Improve Nutritional Status in Malnourished Patients with Systemic Sclerosis.

(1) Background: Impaired nutritional status in systemic sclerosis (SSc) is prevalent. (2) Objective: This study aimed to identify pre-cachexia and malnutrition in SSc patients and to estimate the effectiveness of a high-protein oral nutritional supplement (ONS) in improving their nutritional status. (3) Materials and methods: The SSc population comprised 56 patients and a control group of 49 healthy persons. After a baseline clinical evaluation, bioelectrical impedance analysis (BIA), and laboratory tests, SSc patients were divided into well-nourished, pre-cachectic, and malnourished categories. SSc patients with a nutritional disbalance received a high-protein ONS once daily for 3 months. Patients were reassessed at 3 and 12 months after inclusion in the study. (4) Results: SSc patients, in comparison to the control group, had a significantly lower seven-point SGA value [6(0) vs. 7(1), p < 0.001)], lean tissue mass [LTM, 35.1 (10.5) vs. 40.1 (10.10), p = 0.008], and lean tissue index [LTI, 13.5 (3) vs. 14.9 (4), p = 0.009]. Of the 56 SSc patients, 40 (71.4%) were well nourished, 5 (8.9%) had pre-cachexia, and 11 (19.7%) were malnourished. A high-protein ONS in the pre-cachexia group stabilized the SGA value, anthropometric measurements, and BIA after 3 and 12 months. In malnourished patients, it significantly improved the SGA value [5(0) vs. 6(0), p = 0.002], LTI [12.1 (2.1) vs. 12.7 (3.2), p = 0.021] and LTM [31.1 (7.7) vs. 35.1 (9.1), p = 0.021], and that effect remained stable at 12 months. (5) Conclusion: Malnutrition is a common complication of SSc that can be improved with nutritional intervention.

Circulating adipose-tissue miRNAs in gastrointestinal cancer patients and their association with the level and type of adiposity at body composition analysis.

Background: Adipose tissue (AT) wasting in cancer is an early catabolic event with negative impact on outcomes. Circulating miRNAs may promote body weight loss and cachexia. We measured circulating miRNAs linked to AT alterations and compared their levels between i) gastrointestinal (GI) cancer patients and controls, ii) cachectic and non-cachectic cancer patients, and iii) according to adiposity level and its distribution. Methods: Patients with GI cancer and subjects with benign diseases as controls were considered. Cachexia was assessed and adiposity evaluated by CT-scan for subcutaneous AT area (SAT), visceral AT area and the total AT area (TAT). MiRNAs involved were measured in plasma by RT-qPCR. Results: 37 naïve GI cancer patients and 14 controls were enrolled. Patients with cachexia presented with lower SAT compared to non-cachectic (p < 0.05). In cancer patients, we found higher levels of miR-26a, miR-128, miR-155 and miR-181a vs. controls (p < 0.05). Cancer patients with BMI < 25 kg/m2 showed higher levels of miR-26a vs. those with BMI ≥ 25 (p = 0.035). MiR-26a and miR-181a were higher in cachectic and non-cachectic vs. controls (p < 0.05). Differences between cachectic and controls were confirmed for miR-155 (p < 0.001) but not between non-cachectic vs. control (p = 0.072). MiR-155 was higher in cachectic patients with low TAT vs. those without cachexia and high TAT (p = 0.036). Conclusion: Our data confirm a modulation of specific and different miRNAs involved in AT metabolism in cancer and cachexia. MiR-155 levels were higher in patients presenting with cachexia and low adiposity with implications in the pathogenic mechanisms and clinical consequences of GI cancer patients.

The left ventricular assist device 'skeleton man': case report-simple tools for skeletal muscle evaluation and very early aerobic/resistance/inspiratory training in cardiac cachexia.

Background: Skeletal muscle wasting (SMW) is highly prevalent in patients with heart failure (HF) at left ventricular assist device (LVAD) implantation and is associated with morbidity and mortality. At the same time, SMW is clinically under-recognized, while exercise training (ET) studies in weak LVAD patients are lacking. Case summary: A 60-year-old man with advanced HF, SMW, cardiac cachexia, and frailty was confined in bed for 6 months initially supported with intravenous inotropes and subsequently with an intra-aortic balloon pump. His frailty was recognized as an LVAD-responsive frailty, and patient was successfully implanted with a HeartWare (Medtronic). Post-surgery, patient was very weak, unable even to move in bed without assistance. We evaluated skeletal muscle using simple tools such as the Oxford scale, mid-thigh circumference, hand-held dynamometry, and maximum inspiratory pressure. Physical performance was assessed with the sit to stand test, gait speed test, pedal bike timing, and the 6 min walk test. On top of routine physiotherapy, patient underwent an 8-week modified aerobic/resistance/inspiratory (ARIS) ET programme at moderate intensity and showed significant improvements in skeletal muscle mass and strength and physical and functional capacity. Discussion: We want to emphasize the importance of skeletal muscle evaluation at LVAD implantation and the feasibility and effectiveness of early ARIS training in very weak patients.

Multiple thoracolumbar compression fractures induced by glucocorticoid-induced osteoporosis and cachexia in a young adult female patient with systemic lupus erythematosus: a case report with a 5-year follow-up.

BACKGROUND: High doses of glucocorticoids and severe weight loss can cause osteoporosis. We present a case of glucocorticoid-induced osteoporosis and cachexia in an 18-year-old woman who experienced severe appetite loss leading to weight loss, amenorrhea, and multiple thoracolumbar compression fractures. CASE PRESENTATION: The patient had been receiving high-dose glucocorticoid treatment for systemic lupus erythematosus since the age of 13 and developed unexplained appetite loss since the age of 16. She subsequently developed thoracolumbar compression fractures, which necessitated repeated hospitalization. Gradual glucocorticoid tapering using belimumab and weight regain were achieved through high-calorie nutrition administration via the central vein, which helped the patient overcome her cachexic state. Romosozumab administration increased bone mineral density. CONCLUSION: Long-term administration of glucocorticoids may lead to osteoporosis and cachexia, resulting in amenorrhea, especially in young adults. Approaches that taper glucocorticoids and promote weight regain may be helpful in the management of such patients.

Co-morbid sarcopenia and low bone mineral density in young paediatric cancer survivors.

BACKGROUND: Sarcopenia and low areal bone mineral density (aBMD) are prevalent musculoskeletal complications after paediatric cancer treatment. However, their relationship has not been examined in young paediatric cancers survivors. This study aimed to evaluate aBMD differences according to sarcopenia status and the risk of low aBMD Z-score in young paediatric cancer survivors with sarcopenia confirmed/probable. METHODS: This cross-sectional study included 116 paediatric cancer survivors (12.1 ± 3.3 years old; 42.2% female). Handgrip strength was used to assessed muscle strength. Dual-energy X-ray absorptiometry estimated aBMD (g/cm2) and appendicular lean mass index (ALMI, kg/m2). 'No sarcopenia' was defined when muscle strength was >decile 2. 'Sarcopenia probable' was defined when muscle strength was ≤ decile 2 and ALMI Z-score was > -1.5 standard deviation (SD). 'Sarcopenia confirmed' was defined when muscle strength was ≤ decile 2 and ALMI Z-score ≤ -1.5 SD. Analysis of covariance and logistic regression, adjusted for time from treatment completion, radiotherapy exposure, calcium intake, and physical activity, was used to evaluate aBMD and estimate the odds ratios (ORs) of low aBMD (aBMD Z-score < -1.0). RESULTS: Survivors with sarcopenia confirmed had significantly lower aBMD than those without sarcopenia at total body (-1.2 [95% CI: -1.5 to -0.8] vs. 0.2 [-0.2 to 0.6], P < 0.001), lumbar spine (-0.7 [-1.1 to -0.3] vs. 0.4 [0.0 to 0.8], P < 0.001), total hip (-0.5 [-0.9 to -0.2] vs. 0.4 [0.1 to 0.8], P < 0.001), and femoral neck (-1.0 [-1.4 to -0.6] vs. 0.1 [-0.3 to 0.4], P = 0.001). Compared with survivors with sarcopenia probable, survivors with sarcopenia confirmed had significantly lower aBMD Z-score at total body (-1.2 [-1.5 to -0.8] vs. -0.2 [-0.7 to 0.4], P = 0.009), total hip (-0.5 [-0.9 to -0.2] vs. 0.5 [-0.1 to 1.0], P = 0.010), and femoral neck (-1.0 [-1.4 to -0.6] vs. 0.1 [-0.5 to 0.7], P = 0.014). Survivors with sarcopenia confirmed were at higher risk of low aBMD Z-score at the total body (OR: 6.91, 95% CI: 2.31-24.15), total hip (OR: 2.98, 1.02-9.54), and femoral neck (OR: 4.72, 1.72-14.19), than those without sarcopenia. Survivors with sarcopenia probable were at higher risk of low aBMD Z-score at the total body (OR: 4.13, 1.04-17.60) than those without sarcopenia. CONCLUSIONS: Young paediatric cancer survivors with sarcopenia present higher risk of low aBMD. Resistance training-based interventions designed to mitigate osteosarcopenia in this population should be implemented at early stages.

Detection of cancer-associated cachexia in lung cancer patients using whole-body [18F]FDG-PET/CT imaging: A multi-centre study.

BACKGROUND: Cancer-associated cachexia (CAC) is a metabolic syndrome contributing to therapy resistance and mortality in lung cancer patients (LCP). CAC is typically defined using clinical non-imaging criteria. Given the metabolic underpinnings of CAC and the ability of [18F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computer tomography (CT) to provide quantitative information on glucose turnover, we evaluate the usefulness of whole-body (WB) PET/CT imaging, as part of the standard diagnostic workup of LCP, to provide additional information on the onset or presence of CAC. METHODS: This multi-centre study included 345 LCP who underwent WB [18F]FDG-PET/CT imaging for initial clinical staging. A weight loss grading system (WLGS) adjusted to body mass index was used to classify LCP into 'No CAC' (WLGS-0/1 at baseline prior treatment and at first follow-up: N = 158, 51F/107M), 'Dev CAC' (WLGS-0/1 at baseline and WLGS-3/4 at follow-up: N = 90, 34F/56M), and 'CAC' (WLGS-3/4 at baseline: N = 97, 31F/66M). For each CAC category, mean standardized uptake values (SUV) normalized to aorta uptake () and CT-defined volumes were extracted for abdominal and visceral organs, muscles, and adipose-tissue using automated image segmentation of baseline [18F]FDG-PET/CT images. Imaging and non-imaging parameters from laboratory tests were compared statistically. A machine-learning (ML) model was then trained to classify LCP as 'No CAC', 'Dev CAC', and 'CAC' based on their imaging parameters. SHapley Additive exPlanations (SHAP) analysis was employed to identify the key factors contributing to CAC development for each patient. RESULTS: The three CAC categories displayed multi-organ differences in . In all target organs, was higher in the 'CAC' cohort compared with 'No CAC' (P < 0.01), except for liver and kidneys, where in 'CAC' was reduced by 5%. The 'Dev CAC' cohort displayed a small but significant increase in of pancreas (+4%), skeletal-muscle (+7%), subcutaneous adipose-tissue (+11%), and visceral adipose-tissue (+15%). In 'CAC' patients, a strong negative Spearman correlation (ρ = -0.8) was identified between and volumes of adipose-tissue. The machine-learning model identified 'CAC' at baseline with 81% of accuracy, highlighting of spleen, pancreas, liver, and adipose-tissue as most relevant features. The model performance was suboptimal (54%) when classifying 'Dev CAC' versus 'No CAC'. CONCLUSIONS: WB [18F]FDG-PET/CT imaging reveals groupwise differences in the multi-organ metabolism of LCP with and without CAC, thus highlighting systemic metabolic aberrations symptomatic of cachectic patients. Based on a retrospective cohort, our ML model identified patients with CAC with good accuracy. However, its performance in patients developing CAC was suboptimal. A prospective, multi-centre study has been initiated to address the limitations of the present retrospective analysis.

Understanding cachexia and its impact on lung cancer and beyond.

Cancer cachexia is a multifactorial syndrome characterized by loss of body weight secondary to skeletal muscle atrophy and adipose tissue wasting. It not only has a significant impact on patients' quality of life but also reduces the effectiveness and tolerability of anticancer therapy, leading to poor clinical outcomes. Lung cancer is a prominent global health concern, and the prevalence of cachexia is high among patients with lung cancer. In this review, we integrate findings from studies of lung cancer and other types of cancer to provide an overview of recent advances in cancer cachexia. Our focus includes topics such as the clinical criteria for diagnosis and staging, the function and mechanism of selected mediators, and potential therapeutic strategies for clinical application. A comprehensive summary of current studies will improve our understanding of the mechanisms underlying cachexia and contribute to the identification of high-risk patients, the development of effective treatment strategies, and the design of appropriate therapeutic regimens for patients at different disease stages.

Prevalence of and Survival with Cachexia among Patients with Cancer: A Systematic Review and Meta-Analysis.

Cachexia is associated with lower overall survival (OS) in patients with cancer; however, the relationship between the two is reported to differ according to the definitive criteria for diagnosing cachexia. We aimed to investigate 1) the difference in the prevalence of cachexia in patients with cancer and 2) the association between cachexia and OS, depending on the definitive criteria for diagnosing cachexia in patients with cancer. We searched PubMed and Web of Science from their inception until July 31, 2023, to identify eligible studies. We conducted a systematic review of the prevalence of cachexia in patients with cancer and performed a meta-analysis to investigate its relationship with OS. A total of 125 articles comprising 137,960 patients were included in the systematic review, and 26 articles consisting of 11,118 patients underwent meta-analysis. The overall prevalence of cachexia in patients with cancer was 33.0% (95% confidence interval [CI]: 32.8, 33.3); however, it varied according to the definitive criteria for diagnosing cachexia (13.9%-56.5%). According to the Fearon 2011 criteria, the prevalence of cachexia was associated with a high hazard ratio (HR) for OS compared with that of noncachexia [HR: 1.58 (95% CI: 1.45, 1.73)]; according to the other criteria, the HR was 2.78 (95% CI: 1.88, 4.11), indicating significant subgroup differences (P = 0.006). The dose-response curve indicated that the HR for OS plateaued at a cachexia prevalence range of 40%-50% (l-shaped relationship). The prevalence of cachexia in patients with cancer may vary depending on the definitive criteria used to diagnose cachexia. The HR for OS was higher for low cachexia prevalence. The definitive criteria should be carefully considered when assessing cachexia in patients with cancer. This trial was registered at the PROSPERO as CRD42023435474.

Development of a malnutrition model in mice: Comparative evaluation of food restriction percentage and different diets.

Malnutrition is a complicated illness that affects people worldwide and is linked to higher death rates, a heightened vulnerability to infections, and delayed cognitive development. Experimental models have been constructed to comprehend the mechanisms associated with hunger. In this regard, the current study used two different types of food aiming to validate a murine model of malnutrition based on dietary restriction. The study was conducted with fifty-six Swiss male mice (eight-week-old) divided into eight groups (n=7 each) and fed the following experimental diets (10 weeks): Standard Diet (ST) ad libitum; ST 20% dietary restriction; ST 40% dietary restriction; ST 60% dietary restriction; AIN93-M diet ad libitum; AIN93-M 20% dietary restriction; AIN93-M 40% dietary restriction; AIN93-M 60% dietary restriction. Body, biochemical, and histological parameters were measured, and the restriction effects on genes related to oxidative stress (GPX1 and GPX4) in epididymal adipose tissue were evaluated. The results obtained showed that 20%, 40%, and 60% of dietary restrictions were able to reduce body weight when compared to controls, highlighting the accentuated weight loss in animals with 60% restrictions, especially those fed with AIN-93 M, which showed physical changes such as whitish skin and dull coat, voracious eating, and hunched posture. The present animal model also showed biochemical changes with hypoalbuminemia, as well as histological epididymal adipose tissue modulation. The presence of increased oxidative stress was observed when evaluating the GPX4 gene. Given the results, 60% food restriction using the AIN93-M diet was the best protocol for inducing malnutrition.

Omega-3 Fatty Acids Increase Weight and Quality of Life Scores in Patients With Advanced Non-Small Cell Lung Cancer and Cancer Cachexia: A Meta-Analysis.

BACKGROUND: Cancer cachexia is a common debilitating weight loss syndrome in advanced cancer, particularly lung cancer. Omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, with their immune-modulating effects, have been used to improve the nutritional status of patients with cancer cachexia. AIM: Evaluate the effects of omega-3 fatty acids in change in weight and lean body/skeletal mass, and health-related quality of life scores (HRQoL) in patients with advanced non-small cell lung cancer and cancer cachexia. DESIGN AND DATA SOURCES: Clinical trials from electronic databases and unpublished literature (date of last search 20 December 2023) were independently reviewed and evaluated by authors for their methodological quality. Data from eligible trials were extracted and analyzed in a meta-analysis. RESULTS: Six trials were included. Five trials (354 patients) assessed change in weight; 2 trials (132 patients) assessed change in lean body/skeletal mass and HRQoL scores (Global Health and Physical Functioning subscales). There is a significant difference in change in weight (mean difference [MD]: 1.22, 95% CI: 1.05-1.38, P < .01) and HRQoL scores (Global Health [MD: 14.40, 95% CI: 9.22-19.59, P < .01] and Physical Functioning [MD: 10.38, 95% CI: 8.50-12.27, P < .01] subscales) favoring the omega-3 fatty acids group. The change in lean body/skeletal mass is not significant (MD: 2.05, 95% CI: -0.55 to 4.66, P = .12). CONCLUSIONS: Among patients with advanced non-small cell lung cancer and cancer cachexia, supplementation with omega-3 fatty acids leads to a significant increase in weight and HRQoL scores but not in change in lean body/skeletal mass.

Analysis of potential TAK1/Map3k7 phosphorylation targets in hypertrophy and cachexia models of skeletal muscle.

TGFß-activated kinase-1 (TAK1) is phosphorylated during both muscle growth and muscle wasting. To understand how this can lead to such opposite effects, we first performed multiplex kinase array of mouse embryonic stem cells with and without stimulation of TAK1 to determine its potential downstream targets. The phosphorylation of these targets was then compared in three different models: hypertrophic longissimus muscle of Texel Sheep, tibialis anterior muscle of mice with cancer-induced cachexia and C2C12-derived myofibers, with and without blockade of TAK1 phosphorylation. In both Texel sheep and in cancer-induced cachexia, phosphorylation of both TAK1 and p38 was increased. Whereas p90RSK was increased in Texel sheep but not cachexia and the phosphorylation of HSP27 and total Jnk were increased in cachexia but not Texel. To understand this further, we examined the expression of these proteins in C2C12 cells as they differentiated into myotubes, with and without blockade of TAK1 phosphorylation. In C2C12 cells, decreased phosphorylation of TAK1 leads to reduced phosphorylation of p38, JNK, and HSP27 after 16 hours and muscle fiber hypertrophy after three days. However, continuous blockade of this pathway leads to muscle fiber failure, suggesting that the timing of TAK1 activation controls the expression of context-dependent targets.

A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.

Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

AWGC2023 cachexia consensus as a valuable tool for predicting prognosis and burden in Chinese patients with cancer.

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 < 0.001). Inflammatory biomarker-based cachexia was as an independent predictor of prognosis in patients with cancer, with inflammatory burden index (IBI)-based cachexia demonstrating the optimal prognostic discriminatory ability. The C-index indicated that cachexia based on BMI cutoff values of 18.5, 20, and 22 kg/m2 did not perform as well as a BMI cutoff value of 21 kg/m2. Logistic regression models revealed that using the AWGC2023 criteria, patients with cachexia had a 16.6% higher risk of prolonged hospitalization and a 16.0% higher risk of high medical expenses than patients without cachexia. CONCLUSION: The AWGC2023 criteria represent a valuable tool for predicting survival and medical burden among Chinese patients with cancer. Encouragement for further validation in other Asian populations is warranted for the AWGC2023 criteria.

Leveraging real-world data to predict cancer cachexia stage, quality of life, and survival in a racially and ethnically diverse multi-institutional cohort of treatment-naïve patients with pancreatic ductal adenocarcinoma.

Introduction: Cancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management. Objectives: The main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS). Materials and methods: A population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations. Results: CC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS. Conclusions: Using clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.

Real-world data of anamorelin in advanced gastrointestinal cancer patients with cancer cachexia.

BACKGROUND: Cancer cachexia is characterized by the loss of body weight (BW) and anorexia. Anamorelin (ANAM) is a selective ghrelin receptor agonist with appetite-enhancing anabolic action. The ONO-7643-05 trial demonstrated that ANAM increased lean body mass and improved anorexia in a Japanese population. However, the clinical outcomes of patients on ANAM have not yet been reported. PATIENTS AND METHODS: We investigated the clinical outcomes of patients with unresectable, advanced, or recurrent gastrointestinal cancer (colorectal, gastric, or pancreatic cancer) who were treated with ANAM between April 2017 and August 2022. Cachexia was defined as the presence of anorexia and a loss of ≥ 5% of BW within 6 months. To evaluate the response to ANAM, the patients who had discontinued ANAM within 3 weeks were excluded. Response to ANAM was defined as maintenance of or increase in BW and improved appetite from baseline at every 3-week evaluation. We also collected data on the reasons for the discontinuation of ANAM and the correlation between clinical factors and ANAM response. Safety analysis of ANAM was performed for all patients who received ANAM. RESULTS: Seventy-four patients were included in this study (49 males and 25 females), with a median age of 67.1 years (range, 36-83). The primary tumors were colorectal cancer in 27 (36.5%), gastric cancer in 20 (27.0%), and pancreatic cancer in 27 (36.5%). The Eastern Cooperative Oncology Group performance status was 0 in 10 (13.5%), 1 in 44 (59.5%), and ≥ 2 in 20 (27.0%). The number of previous chemotherapy regimens was 0 in 20 (27.0%), 1 in 22 (29.7%), and ≥ 2 in 32 (43.2%). ANAM was discontinued within 3 weeks in 28 patients for the following reasons: low-grade (grade 1 or 2) adverse events in 15 patients, ileus in three, grade 3 fatigue in one, progressive disease in one, censored follow-up in six, and unknown reasons in three. The proportion of ANAM responders was 63.6% (95% confidence interval, 47.8-77.6%). Among baseline characteristics, age ≥ 75 attenuated the ANAM response (p = 0.03). ANAM responders showed better disease control with chemotherapy than non-responders (75.0% vs. 37.5%, p = 0.02). CONCLUSIONS: ANAM may improve the outcomes of patients with gastrointestinal cancer cachexia in clinical practice.

Determination of anamorelin concentration in human plasma using a simple high-performance liquid chromatography-ultraviolet detection method.

Anamorelin, a non-peptide ghrelin analog and growth hormone secretagogue, is a novel oral drug used to treat cancer cachexia. Patients with cancer cachexia frequently use several drugs and anamorelin is a substrate of cytochrome P450 (CYP) 3A4; therefore, drug-drug interactions with CYP3A4 inhibitors and inducers pose a clinical problem. In this study, we aimed to determine the concentration of anamorelin in human plasma using a simple high-performance liquid chromatography-ultraviolet (HPLC-UV)-based method. The analysis involved extracting a 200-µL plasma sample and protein precipitation using solid-phase extraction. Anamorelin was isocratically separated using a mobile phase consisting of 0.5% potassium dihydrogen phosphate (pH 4.5) and acetonitrile (61:39, v/v) on a Capcell Pack C18 MG II column (250 mm × 4.6 mm) at a flow rate of 1.0 mL/min and monitored at a detection wavelength of 220 nm. The calibration curve was linear within a plasma concentration range of 12.5-1,500 ng/mL, with a coefficient of determination of 0.9999. The intra- and inter-day coefficients of variation were 0.37-6.71% and 2.05-4.77%, respectively. The accuracy of the assay and recovery were 85.25-112.94% and > 86.58%, respectively. This proposed HPLC-UV method is simple and can be applied in clinical settings.