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OBJECTIVE: To evaluate the frequency of cachexia and its associated factors using the Asian Working Group for Cachexia (AWGC) criteria in elderly patients with diabetes and chronic diseases. METHODS: The subjects were diabetic outpatients of ≥65 years of age who were managed at Ise Red Cross Hospital. Patients with chronic disease (chronic heart failure, cancer, or chronic renal failure). Cachexia was evaluated based on the AWGC criteria and was defined as a body mass index (BMI) <21 kg/m2 and one or more of the following: anorexia, elevated C-reactive protein, and decreased grip strength. A logistic regression analysis was used to identify cachexia-related factors, with cachexia as the dependent variable, and various variables (basic attributes, blood glucose-related parameters, diabetic complications, comorbidities, and treatment) as explanatory variables. RESULTS: Two hundred forty-two patients (male, n=164; female, n=78) were included in the study. Forty patients (16.5%) had cachexia. A logistic analysis revealed that age (odds ratio (OR), 1.16; P<0.001), type 1 diabetes (OR, 15.25; P=0.002), diabetic retinopathy (OR, 5.72; P=0.001), and physical frailty (OR, 7.06; P<0.001) were associated with cachexia. CONCLUSION: Elderly diabetics with chronic diseases were more likely to have cachexia. According to the AWGC criteria, the frequency of cachexia was 16.5% in elderly patients with diabetes and chronic diseases. Additionally, type 1 diabetes, diabetic retinopathy, age, and physical frailty were identified as factors associated with cachexia. In elderly diabetes patients with chronic diseases, it is therefore important to raise awareness regarding cachexia when these related factors are diagnosed.
Assuntos
Caquexia , Humanos , Caquexia/diagnóstico , Caquexia/etiologia , Idoso , Masculino , Feminino , Doença Crônica , Idoso de 80 Anos ou mais , Diabetes Mellitus , Complicações do DiabetesRESUMO
Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38+ CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.
Assuntos
Caquexia , Monócitos , Músculo Esquelético , Neoplasias , Neutrófilos , Caquexia/metabolismo , Caquexia/etiologia , Monócitos/metabolismo , Monócitos/imunologia , Humanos , Neoplasias/complicações , Neoplasias/metabolismo , Neoplasias/imunologia , Neutrófilos/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Camundongos , Masculino , Transdução de Sinais , Linhagem Celular Tumoral , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Camundongos Endogâmicos C57BL , Interleucinas/metabolismo , Interleucinas/genética , Feminino , Perfilação da Expressão GênicaRESUMO
Cancer cachexia manifests as whole body wasting, however, the precise mechanisms governing the alterations in skeletal muscle and cardiac anabolism have yet to be fully elucidated. In this study, we explored changes in anabolic processes in both skeletal and cardiac muscles in the Yoshida AH-130 ascites hepatoma model of cancer cachexia. AH-130 tumor-bearing rats experienced significant losses in body weight, skeletal muscle, and heart mass. Skeletal and cardiac muscle loss was associated with decreased ribosomal (r)RNA, and hypophosphorylation of the eukaryotic factor 4E binding protein 1. Endoplasmic reticulum stress was evident by higher activating transcription factor mRNA in skeletal muscle and growth arrest and DNA damage-inducible protein (GADD)34 mRNA in both skeletal and cardiac muscles. Tumors provoked an increase in tissue expression of interferon-γ in the heart, while an increase in interleukin-1ß mRNA was apparent in both skeletal and cardiac muscles. We conclude that compromised skeletal muscle and heart mass in the Yoshida AH-130 ascites hepatoma model involves a marked reduction translational capacity and efficiency. Furthermore, our observations suggest that endoplasmic reticulum stress and tissue production of pro-inflammatory factors may play a role in the development of skeletal and cardiac muscle wasting.
Assuntos
Caquexia , Músculo Esquelético , Miocárdio , Resposta a Proteínas não Dobradas , Animais , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/patologia , Caquexia/genética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Ratos , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Wistar , Estresse do Retículo Endoplasmático , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Fator de Transcrição CHOP/metabolismo , Fator de Transcrição CHOP/genéticaRESUMO
INTRODUCTION: Heart failure (HF) is associated with significant alterations in body composition, including malnutrition due to insufficient intake, chronic inflammation and increased energy expenditure. Identifying the prevalence of malnutrition and the risk of sarcopenia in patients with HF is crucial to improve clinical outcomes. MATERIAL AND METHODS: This cross-sectional, single-center, observational study involved 121 outpatients diagnosed with HF. Nutritional status was assessed using the Mini Nutritional Assessment (MNA), the Malnutrition Universal Screening Tool (MUST), and the Subjective Global Rating (SGA). Sarcopenia was screened using the SARC-F (Strength, Assistance in walking, Rise from a chair, Climb stairs, Falls) questionnaire and diagnosed based on the European Working Group in Older People (EWGSOP2) criteria and functionality with the Short Performance Battery (SPPB) test. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria. RESULTS: The study found that 10.7% had cardiac cachexia and 45.4% of deceased patients had been in this condition (p = 0.002). Moderate-to-high risk of malnutrition was identified in 37.1%, 23.9%, and 31.4% of patients according to the MNA, MUST, and SGA tests, respectively. According to the GLIM criteria, 56.2% of patients were malnourished. Additionally, 24.8% of patients had a high probability of sarcopenia, and 57.8% were not autonomous according to SPPB. Patients with less than 30% quadriceps muscle contraction were at a high risk of sarcopenia. CONCLUSIONS: There is a high prevalence of malnutrition among outpatients with HF, which is associated with worse prognosis, increased risk of sarcopenia, and greater frailty. These findings underscore the importance of early nutritional and functional assessments in this population to improve clinical outcomes.
Assuntos
Insuficiência Cardíaca , Desnutrição , Avaliação Nutricional , Estado Nutricional , Pacientes Ambulatoriais , Sarcopenia , Humanos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Masculino , Feminino , Idoso , Estudos Transversais , Desnutrição/epidemiologia , Desnutrição/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/diagnóstico , Pacientes Ambulatoriais/estatística & dados numéricos , Prevalência , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Caquexia/epidemiologia , Caquexia/etiologia , Composição CorporalRESUMO
The purpose of this study was to assess the prevalence and prognosis of cachexia in patients with non-sarcopenic dysphagia. A retrospective cohort study was conducted using the Japanese sarcopenic dysphagia database. Cachexia was diagnosed using the Asian Working Group for Cachexia criteria, sarcopenia using the Asian Working Group for Sarcopenia 2019 criteria, and malnutrition using the Global Leadership Initiative on Malnutrition criteria. Outcomes were death, swallowing function (Food Intake LEVEL Scale (FILS)), and activities of daily living (Barthel Index (BI)). The mean age of the 175 non-sarcopenic dysphagia patients was 77 (±11) years; 103 (59%) were male, 30 (17%) had cachexia, 133 (76%) had whole-body sarcopenia, and 92 (53%) were malnourished. Of the 30 patients with cachexia, 4 and 11 did not have sarcopenia and malnutrition, respectively. No significant associations were found between cachexia, sarcopenia, and malnutrition. Death was notably higher in the cachexia group (5/30; 17% vs. 2/145; 1%, p = 0.002). Median FILS (7 vs. 8, p = 0.585) and median BI (35 vs. 50, p = 0.469) scores did not show significant differences based on cachexia status. The prevalence of cachexia was 17%, and mortality may be higher with cachexia in non-sarcopenic dysphagia patients.
Assuntos
Caquexia , Transtornos de Deglutição , Desnutrição , Sarcopenia , Humanos , Caquexia/epidemiologia , Caquexia/mortalidade , Masculino , Estudos Retrospectivos , Transtornos de Deglutição/epidemiologia , Idoso , Feminino , Prevalência , Sarcopenia/epidemiologia , Sarcopenia/complicações , Sarcopenia/diagnóstico , Prognóstico , Idoso de 80 Anos ou mais , Desnutrição/epidemiologia , Desnutrição/diagnóstico , Atividades Cotidianas , Japão/epidemiologiaRESUMO
BACKGROUND: Intracranial tumors constitute a significant burden on global morbidity and disability, posing a risk for the development of cachexia. Cancer cachexia is a multi-organ syndrome of systemic inflammation and negative energy balance which may lead to diminished treatment efficacy and reduced survival rates. The association between intracranial tumor features and incidence of cachexia remains unknown. The purpose of this study is to investigate the association between the characteristics of intracranial tumors and the incidence of cachexia in patients. METHODS: We conducted a retrospective cross-sectional study to observe hospitalized intracranial tumor patients at Dr. Cipto Mangunkusumo Hospital. This study described the prevalence and the percentage of baseline characteristics, the diagnosis of cachexia was based on Evans criteria. Kolmogorov-Smirnov for the normality test. Bivariate analysis was done using the Chi-square test for qualified categorical variables, the Fischer test for unqualified categorical variables, and the Mann-Whitney test for ordinal variables. RESULTS: Our study revealed of 36 subjects with intracranial tumor diagnosis, the incidence of cachexia was higher in secondary brain tumors compared to primary brain tumors [odds ratio (OR) 5.5; 95% confidence interval (CI): 1.28-23.69; P=0.02]. Cancer cachexia occurs through inflammation, autonomic, and neuroendocrine pathways, leading to increased energy expenditure and decreased energy intake. The burden of secondary brain tumor amplifies the overall metabolic demands and systemic inflammation thus contributing to cachexia progression, which is identified by significant weight loss in patients with secondary brain tumor groups compared to primary tumors (P=0.01). Patients with cachexia tend to experience malnutrition and fatigue (P=0.04), which may interfere with their survival rates and quality of life. The most common neurological deficit observed in our subjects is headache (72.2%), while patients presenting with clinical manifestations of extremity weakness were more likely to develop cachexia (OR 6.4; 95% CI: 1.23-35.44; P=0.04). There were no significant differences in age distribution, gender, and brain tumor location among the subject groups. CONCLUSIONS: Patients with secondary brain tumors and extremity weakness are more likely to develop cachexia. The severity of cachexia can help distinguish between primary and secondary brain tumors. Clinicians should pay attention to neurological deficits, particularly extremity weakness, as it can worsen cachexia.
Assuntos
Neoplasias Encefálicas , Caquexia , Humanos , Caquexia/etiologia , Caquexia/epidemiologia , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/epidemiologia , Incidência , Idoso , AdultoRESUMO
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.
Assuntos
Caquexia , Neoplasias , Olanzapina , Humanos , Caquexia/tratamento farmacológico , Caquexia/etiologia , Hidrazinas , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Metanálise em Rede , Olanzapina/administração & dosagem , Olanzapina/efeitos adversos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
This review critically evaluates the substantial role of exercise in enhancing cancer prevention, treatment, and patient quality of life. It conclusively demonstrates that regular physical activity not only reduces cancer risk but also significantly mitigates side effects of cancer therapies. The key findings include notable improvements in fatigue management, reduction of cachexia symptoms, and enhancement of cognitive functions. Importantly, the review elucidates the profound impact of exercise on tumor behavior, modulation of immune responses, and optimization of metabolic pathways, advocating for the integration of exercise into standard oncological care protocols. This refined abstract encourages further exploration and application of exercise as a pivotal element of cancer management.
Assuntos
Exercício Físico , Neoplasias , Qualidade de Vida , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Exercício Físico/fisiologia , Terapia por Exercício , Caquexia/etiologia , Caquexia/terapia , Animais , Fadiga/etiologiaRESUMO
Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that are characteristically different from other malignancies. The difference is not only in the prognosis, which is usually more favorable in such patients, but also in the high clinical progression of the disease, where NET patients do not experience the cachexia typical of other malignancies. The purposes of this study were to evaluate the ghrelin and leptin levels in a group of patients diagnosed with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and bronchopulmonary neuroendocrine tumors (BP-NETs) and to analyze the relationship between the body mass index (BMI), cachexia and selected NET markers. The study group comprised 52 patients with GEP-NETs and BP-NETs, while the controls comprised 67 healthy volunteers. The ghrelin and leptin concentrations were determined in both groups. The concentrations of chromogranin A, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), total cholesterol, triglycerides and glucose were determined in the study group. Characteristics of the study group and of the controls were defined by age, sex and BMI, and the effects of these factors on the ghrelin and leptin concentrations were assessed. The data obtained were subject to statistical analysis. The study cohort showed higher levels of ghrelin as compared to the controls (142.31 ± 26.00 vs. 121.49 ± 35.45, p = 0.016), and no statistical difference in the levels of leptin (11.15 ± 9.6 vs. 12.94 ± 20.30, p = 0.439) were observed. Significantly lower levels of leptin were found in patients with the small intestine primary location, as compared to individuals with primary locations in the lungs and the pancreas (4.9 ± 6.49 vs. 16.97 ± 15.76, p = 0.045, and 4.9 ± 6.49 vs. 12.89 ± 8.56, p = 0.016, respectively). A positive correlation was observed between the leptin levels and the BMIs in both the study group (rS = 0.33, p = 0.016) and the controls (rS = 0.41, p = 0.001). The study group showed a negative correlation between the leptin levels and 5-HIAA (rS = -0.32, p = 0.026) and a negative correlation between the leptin levels and Ki-67 (rS = -0.33, p = 0.018). The control group showed negative correlations between the ghrelin and the volunteer age (rS = -0.41, p = 0.008), the leptin and the volunteer age (rS = -0.44, p < 0.001), the leptin and total cholesterol (rS = -0.24, p < 0.049) as well as the leptin and triglycerides (rS = -0.33, p < 0.006). The current study emphasized the importance of the markers' determination, where ghrelin appears as a valuable diagnostic biomarker in NETs, probably responsible for maintaining a normal BMI, despite the progression of the disease.
Assuntos
Índice de Massa Corporal , Grelina , Leptina , Tumores Neuroendócrinos , Humanos , Grelina/sangue , Leptina/sangue , Feminino , Masculino , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/diagnóstico , Pessoa de Meia-Idade , Adulto , Idoso , Neoplasias Gástricas/sangue , Neoplasias Gástricas/diagnóstico , Adipocinas/sangue , Estudos de Casos e Controles , Biomarcadores Tumorais/sangue , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Caquexia/sangue , Neoplasias Intestinais/sangue , Neoplasias Intestinais/diagnósticoRESUMO
Cachexia, which affects 50-80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75-ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.
Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Caquexia , Proteínas de Choque Térmico HSP70 , Neoplasias , Animais , Caquexia/genética , Caquexia/patologia , Caquexia/metabolismo , Camundongos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Translocador 2 do Nucleotídeo Adenina/genética , Translocador 2 do Nucleotídeo Adenina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, we used a murine cancer cachexia model to investigate the effects of a nutritional formula (NuF) rich in fish oil and selenium yeast as an adjuvant to enhance the drug efficacy of an EGFR inhibitor (Tarceva). In contrast to the healthy control, tumor-bearing mice exhibited severe cachexia symptoms, including tissue wasting, hypoalbuminemia, and a lower food efficiency ratio. Experimentally, Tarceva reduced pEGFR and HIF-1α expression. NuF decreased the expression of pEGFR and HIF-2α, suggesting that Tarceva and NuF act differently in prohibiting tumor growth and subsequent metastasis. NuF blocked LLC tumor-induced PTHrP and expression of thermogenic factor UCP1 and lipolytic enzymes (ATGL and HSL) in WAT. NuF attenuated tumor progression, inhibited PTHrP-induced adipose tissue browning, and maintained adipose tissue integrity by modulating heat shock protein (HSP) 72. Added together, Tarceva in synergy with NuF favorably improves cancer cachexia as well as drug efficacy.
Assuntos
Caquexia , Suplementos Nutricionais , Receptores ErbB , Óleos de Peixe , Lipólise , Selênio , Termogênese , Animais , Caquexia/tratamento farmacológico , Caquexia/patologia , Camundongos , Selênio/farmacologia , Selênio/uso terapêutico , Lipólise/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Termogênese/efeitos dos fármacos , Óleos de Peixe/farmacologia , Óleos de Peixe/uso terapêutico , Camundongos Endogâmicos C57BL , Masculino , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismoRESUMO
Cancer cachexia mouse models are needed to recapitulate the clinical features of patients with cachexia. Here, we present a protocol for the establishment and evaluation of cancer cachexia mouse models. We delineate the steps in preparing tumor cells for inoculation and surgical procedures. After the establishment of these mouse models, we describe essential techniques to assess cancer cachexia, including grip strength evaluation, tissue collection, and the calculation of cross-sectional areas of muscle tissue. For complete details on the use and execution of this protocol, please refer to Liu et al.,1 Yang et al.,2 Shi et al.,3 and Zhou et al.4.
Assuntos
Caquexia , Modelos Animais de Doenças , Neoplasias , Caquexia/etiologia , Animais , Camundongos , Neoplasias/complicações , Neoplasias/patologia , Músculo Esquelético/patologiaRESUMO
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.
Assuntos
Caquexia , Aprendizado de Máquina , Neoplasias , Humanos , Caquexia/etiologia , Caquexia/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias/complicações , Idoso , Estudos de Coortes , Proteína C-Reativa/análise , AdultoRESUMO
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.
Assuntos
Caquexia , Neoplasias , Humanos , Caquexia/diagnóstico , Caquexia/etiologia , Neoplasias/complicações , Neoplasias/mortalidade , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , Idoso , Estudos Retrospectivos , Consenso , Biomarcadores , Estudos Transversais , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , População do Leste AsiáticoRESUMO
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.
Assuntos
Caquexia , Neoplasias , Humanos , Caquexia/epidemiologia , Caquexia/etiologia , Neoplasias/complicações , Neoplasias/mortalidade , PrevalênciaRESUMO
A model for accelerated aging in mice was developed: CB6F2 mice aged 39-45 days were exposed to fractionated 4-fold relatively uniform γ-radiation (137Cs, 0.98 Gy/min) at a total dose of 6.8 Gy. Radiation exposure led to delayed active growth, leukopenia, and lymphopenia for over 1 year during the post-radiation period. The death of irradiated males and females occurred significantly earlier than in control group animals. Median lifespans in the experimental group were 35-38% lower than in the control group (p<0.001). Ionizing radiation exposure led to the early development of hair depigmentation, cachexia, and the development of aging-associated diseases. In irradiated mice, oncological pathology constituted 30-35% in the mortality structure, which is twice as often as in the control group. The developed model can be used to study the pathogenesis of accelerated aging under radiation exposure and the search for means of its prevention and treatment.
Assuntos
Senilidade Prematura , Raios gama , Animais , Camundongos , Masculino , Feminino , Raios gama/efeitos adversos , Senilidade Prematura/patologia , Senilidade Prematura/genética , Senilidade Prematura/etiologia , Longevidade/efeitos da radiação , Radiação Ionizante , Envelhecimento/efeitos da radiação , Caquexia/patologia , Caquexia/etiologia , Radioisótopos de CésioRESUMO
Oxidative stress contributes to the loss of skeletal muscle mass and function in cancer cachexia. However, this outcome may be mitigated by an improved endogenous antioxidant defence system. Here, using the well-established oxidative stress-inducing muscle atrophy model of Lewis lung carcinoma (LLC) in 13-week-old male C57BL/6J mice, we demonstrate that extracellular superoxide dismutase (EcSOD) levels increase in the cachexia-prone extensor digitorum longus muscle. LLC transplantation significantly increased interleukin-1ß (IL-1ß) expression and release from extensor digitorum longus muscle fibres. Moreover, IL-1ß treatment of C2C12 myotubes increased NBR1, p62 phosphorylation at Ser351, Nrf2 nuclear translocation and EcSOD protein expression. Additional studies in vivo indicated that intramuscular IL-1ß injection is sufficient to stimulate EcSOD expression, which is prevented by muscle-specific knockout of p62 and Nrf2 (i.e. in p62 skmKO and Nrf2 skmKO mice, respectively). Finally, since an increase in circulating IL-1ß may lead to unwanted outcomes, we demonstrate that targeting this pathway at p62 is sufficient to drive muscle EcSOD expression in an Nrf2-dependent manner. In summary, cancer cachexia increases EcSOD expression in extensor digitorum longus muscle via muscle-derived IL-1ß-induced upregulation of p62 phosphorylation and Nrf2 activation. These findings provide further mechanistic evidence for the therapeutic potential of p62 and Nrf2 to mitigate cancer cachexia-induced muscle atrophy. KEY POINTS: Oxidative stress plays an important role in muscle atrophy during cancer cachexia. EcSOD, which mitigates muscle loss during oxidative stress, is upregulated in 13-week-old male C57BL/6J mice of extensor digitorum longus muscles during cancer cachexia. Using mouse and cellular models, we demonstrate that cancer cachexia promotes muscle EcSOD protein expression via muscle-derived IL-1ß-dependent stimulation of the NBR1-p62-Nrf2 signalling pathway. These results provide further evidence for the potential therapeutic targeting of the NBR1-p62-Nrf2 signalling pathway downstream of IL-1ß to mitigate cancer cachexia-induced muscle atrophy.
Assuntos
Caquexia , Interleucina-1beta , Camundongos Endogâmicos C57BL , Músculo Esquelético , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Superóxido Dismutase , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/genética , Masculino , Interleucina-1beta/metabolismo , Músculo Esquelético/metabolismo , Camundongos , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/genética , Camundongos Knockout , Estresse OxidativoRESUMO
GDF15 (growth differentiation factor 15), also known as macrophage inhibitory cytokine 1 (MIC-1), is a circulating protein involved in the regulation of energy balance and weight control. Elevated levels of GDF15 have been associated with cachexia and reduced survival rates in cancer patients. Through the activation of the GFRAL (GDNF-family receptor α-like)-RET (Rearranged during Transfection) signaling pathway, GDF15 can induce weight loss, making it a potential target for treating cachexia. Currently, there are no approved antibody drugs specifically targeting GDF15 for cancer cachexia treatment. However, efforts have been made to develop antibody-based therapeutics against this emerging target. In this study, we generated a monoclonal antibody KY-NAb-GDF15 against GDF15 that effectively blocks downstream signaling mediated by GFRAL upon stimulation by GDF15. This antibody demonstrates robust neutralizing activity and exhibits high binding specificity. Importantly, our findings indicate that this antibody holds promise in alleviating cancer-induced cachexia and mitigating chemotherapy-induced weight loss, thereby offering significant therapeutic potential for managing cancer cachexia.
Assuntos
Anticorpos Neutralizantes , Caquexia , Fator 15 de Diferenciação de Crescimento , Neoplasias , Caquexia/tratamento farmacológico , Caquexia/imunologia , Anticorpos Neutralizantes/uso terapêutico , Humanos , Neoplasias/complicações , Neoplasias/imunologia , Animais , Camundongos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismoRESUMO
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.
Assuntos
Caquexia , Progressão da Doença , Camundongos Endogâmicos BALB C , Sistema Nervoso Simpático , Animais , Caquexia/metabolismo , Caquexia/patologia , Caquexia/etiologia , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Masculino , Camundongos , Proteína Desacopladora 1/metabolismo , Linhagem Celular Tumoral , Canais Iônicos/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Oxidopamina , Simpatectomia Química , Interleucina-6/metabolismo , Índice de Massa Corporal , Neoplasias/complicações , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
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 16â h and muscle fiber hypertrophy after 3 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.