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Reid J, Blair C, Dempster M, McKeaveney C, Slee A, Fitzsimons D. Multimodal interventions for cachexia management. Cochrane Database Syst Rev 2025; 3:CD015749. [PMID: 40130780 PMCID: PMC11934851 DOI: 10.1002/14651858.cd015749.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
BACKGROUND Cachexia (disease-related wasting) is a complex metabolic syndrome which occurs in people with chronic illnesses, including cancer, HIV/AIDS, kidney disease, heart disease, and chronic obstructive pulmonary disease (COPD). People with cachexia experience unintentional weight loss, muscle loss, fatigue, loss of appetite, and reduced quality of life. Multimodal interventions which work synergistically to treat the syndrome could lead to benefits. OBJECTIVES To assess the benefits and harms of multimodal interventions aimed at alleviating or stabilising cachexia in people with a chronic illness. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers in July 2024, together with reference checking, citation searching, and contact with study authors to identify studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) in adults with or at risk of cachexia, comparing multimodal interventions combining two or more modalities (of pharmacology, nutrition, exercise) to treatment as usual, variation of the intervention, or unimodal intervention. DATA COLLECTION AND ANALYSIS Two review authors independently screened potentially eligible studies, extracted data, and assessed risk of bias (RoB 1). Primary outcomes were physical function, strength, and adverse events. Secondary outcomes were body composition and weight, quality of life (QoL), appetite, fatigue, and biochemical markers. We assessed the certainty of evidence with GRADE. MAIN RESULTS We included nine studies with 926 adults (mean age: 63 years). Study sample sizes ranged from 20 to 332 participants. Six studies were conducted in Europe, and one each in Turkey, New Zealand, and the USA. There were six studies in people with cancer, and one each in people with COPD, chronic kidney disease, and HIV/AIDS. We judged four studies to be at an overall high risk of bias, and five at an overall unclear risk. All outcomes in all comparisons had very low-certainty evidence, downgraded once for risk of bias and/or indirectness and twice for imprecision. Multimodal intervention (pharmacological, nutritional, and/or exercise) compared to treatment as usual One cancer study randomised 46 participants, with 41 included in all analyses except adverse events. The study assessed outcomes immediately after treatment, lasting six weeks. Compared to treatment as usual, there is no clear evidence for an effect of a multimodal intervention on: physical function (mean difference (MD) -16.10 m, 95% confidence interval (CI) -79.06 to 46.86; 41 participants); strength (MD 3.80 kg, 95% CI -3.21 to 10.81; 41 participants); adverse events (risk ratio (RR) 1.36, 95% CI 0.70 to 2.65; 46 participants); body composition (MD 7.89 cm2, 95% CI -10.43 to 26.21; 41 participants); weight (MD 5.89 kg, 95% CI -1.45 to 13.23; 41 participants); appetite (MD 0.68 points, 95% CI -0.60 to 1.96; 41 participants); fatigue (MD 0.12, 95% CI -1.05 to 1.29; 41 participants); and biochemical markers (MD 2%, 95% CI 0.99 to 3.01; 41 participants), but the evidence was very uncertain; QoL was not reported. Multimodal intervention compared to variation of the intervention Three cancer studies and one HIV/AIDS study randomised 192 participants. We could not use the available data, nor obtain additional data, from two studies (one in cancer, one in HIV/AIDS). The studies assessed outcomes immediately after treatment, ranging from three to seven months. Compared to a variation of the intervention, there is no clear evidence for an effect of a multimodal intervention on: physical function (MD 10.0 m, 95% CI -36.27 to 56.27; 1 study, 56 participants); strength (MD 0.7 kg, 95% CI -3.75 to 5.15; 1 study, 56 participants); adverse events (RR 0.87, 95% CI 0.38 to 2.02; P = 0.75, I2 = 0%; 2 studies, 95 participants); body composition (MD -2.67 kg, 95% CI -5.89 to 0.54; P = 0.10, I2 = 0%; 2 studies, 95 participants); weight (MD -2.47 kg, 95% CI -7.11 to 2.16; P = 0.30, I2 = 0%; 2 studies, 95 participants); QoL (standardised mean difference (SMD) -0.15, 95% CI -0.55 to 0.26; P = 0.47, I2 = 0%; 2 studies, 95 participants); appetite (SMD -0.34, 95% CI -1.27 to 0.59; P = 0.48, I2 = 79%; 2 studies, 95 participants); fatigue (MD 6.40 points, 95% CI -1.10 to 13.90; 1 study, 56 participants); or biochemical markers (MD 9.80 pg/mL, 95% CI -6.25 to 25.85; P = 0.23, I2 = 73%; 2 studies, 95 participants), but the evidence is very uncertain. Multimodal intervention compared to unimodal intervention We included six studies (802 participants) in this comparison: three cancer studies, and one each in people with COPD, chronic kidney disease, and HIV/AIDS. The studies assessed outcomes immediately after treatment, ranging from three to seven months. We could not use the available data, nor obtain additional data, from the HIV/AIDS study. Compared to a unimodal intervention, there is no clear evidence for an effect of a multimodal intervention on: physical function (SMD 0.02, 95% CI -0.22 to 0.26; P = 0.86, I2 = 0%; 2 studies, 348 participants); strength (SMD 0.23, 95% CI -0.81 to 1.27; P = 0.66, I2 = 0%; 2 studies, 348 participants); adverse events (RR 0.87, 95% CI -0.43 to 1.73; P = 0.68, I2 = 45%; 2 studies, 395 participants); body composition (SMD 0.11, 95% CI -0.28 to 0.50; P = 0.58, I2 = 74%; 5 studies, 742 participants); body weight (SMD -0.02, 95% CI -0.38 to 0.33; P = 0.90, I2 = 49%; 4 studies, 431 participants); QoL (SMD 0.22, 95% CI -0.29 to 0.73; P = 0.39, I2 = 61%; 3 studies, 411 participants); appetite (SMD -0.09, 95% CI -0.58 to 0.40; P = 0.72, I2 = 58%; 2 studies, 395 participants); fatigue (MD -6.80 points, 95% CI -12.44 to -1.17; 1 study, 244 participants); and biochemical markers (SMD 0.11, 95% CI -0.59 to 0.80; P = 0.76, I2 = 79%; 3 studies, 411 participants), but the evidence is very uncertain. AUTHORS' CONCLUSIONS The review found insufficient evidence to support or refute the use of multimodal interventions in managing cachexia. The certainty of the evidence was very low. Methodologically rigorous, well-powered RCTs with adequate interaction times are needed to assess the effectiveness of multimodal interventions in managing cachexia across chronic illnesses.
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Affiliation(s)
- Joanne Reid
- School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK
| | - Carolyn Blair
- School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK
| | - Martin Dempster
- School of Psychology, Queen's University Belfast, Belfast, UK
| | - Clare McKeaveney
- School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK
| | - Adrian Slee
- Division of Medicine, Faculty of Medical Sciences, University College London, London, UK
| | - Donna Fitzsimons
- School of Nursing and Midwifery, Queen's University Belfast, Belfast, UK
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Goncalves MD, Dunne RF, Moore AC, Phillips W, Heymsfield SB, Brown JC, Talbert EE, Janowitz T. Call to Improve Coding of Cancer-Associated Cachexia. JCO Oncol Pract 2025:OP2400781. [PMID: 39805066 DOI: 10.1200/op-24-00781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/05/2024] [Accepted: 12/09/2024] [Indexed: 01/16/2025] Open
Abstract
Cachexia is a systemic wasting syndrome prevalent in patients with cancer that significantly affects quality of life, health care costs, and therapeutic outcomes. Despite its clinical importance, cachexia is rarely formally diagnosed. This deficiency presents a challenge for effective patient management and care, health care resource allocation, and the advancement of therapeutic approaches. Here, we highlight impedances to the diagnosis and coding of cachexia, including the absence of standardized therapy, a lack of incentives for accurate coding, and overlapping clinical features with other conditions. We differentiate cachexia from related conditions like unintentional weight loss, sarcopenia, frailty, and protein-calorie malnutrition, outlining their distinct clinical features and inter-relations. We propose an approach to enhance diagnostic accuracy and coding for cachexia. This effort will enable better prevalence data, translation of mechanism-based therapy development, patient identification and stratification, and ultimately advanced diagnostics and US Food and Drug Administration-approved treatments for cachexia.
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Xie H, Wei L, Ruan G, Zhang H, Shi J, Lin S, Liu C, Liu X, Zheng X, Chen Y, Chen J, Shi H. AWGC2023 cachexia consensus as a valuable tool for predicting prognosis and burden in Chinese patients with cancer. J Cachexia Sarcopenia Muscle 2024; 15:2084-2093. [PMID: 39192568 PMCID: PMC11446680 DOI: 10.1002/jcsm.13555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/24/2024] [Accepted: 07/05/2024] [Indexed: 08/29/2024] Open
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 < 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.
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Affiliation(s)
- Hailun Xie
- Department of Gastrointestinal Gland Surgery, First Affiliated HospitalGuangxi Medical UniversityNanningChina
| | - Lishuang Wei
- Department of Gastrointestinal Gland Surgery, First Affiliated HospitalGuangxi Medical UniversityNanningChina
| | - Guotian Ruan
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Heyang Zhang
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Jinyu Shi
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Shiqi Lin
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Chenan Liu
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Xiaoyue Liu
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Xin Zheng
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Yue Chen
- Department of Gastrointestinal Surgery, Department of Clinical NutritionBeijing Shijitan Hospital, Capital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric Diseases, Xuanwu HospitalCapital Medical UniversityBeijingChina
- Key Laboratory of Cancer FSMP for State Market RegulationBeijingChina
| | - Junqiang Chen
- Department of Gastrointestinal Gland Surgery, First Affiliated HospitalGuangxi Medical UniversityNanningChina
| | - Hanping Shi
- Department of Gastrointestinal Gland Surgery, First Affiliated HospitalGuangxi Medical UniversityNanningChina
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Tamayo-Torres E, Garrido A, de Cabo R, Carretero J, Gómez-Cabrera MC. Molecular mechanisms of cancer cachexia. Role of exercise training. Mol Aspects Med 2024; 99:101293. [PMID: 39059039 DOI: 10.1016/j.mam.2024.101293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024]
Abstract
Cancer-associated cachexia represents a multifactorial syndrome mainly characterized by muscle mass loss, which causes both a decrease in quality of life and anti-cancer therapy failure, among other consequences. The definition and diagnostic criteria of cachexia have changed and improved over time, including three different stages (pre-cachexia, cachexia, and refractory cachexia) and objective diagnostic markers. This metabolic wasting syndrome is characterized by a negative protein balance, and anti-cancer drugs like chemotherapy or immunotherapy exacerbate it through relatively unknown mechanisms. Due to its complexity, cachexia management involves a multidisciplinary strategy including not only nutritional and pharmacological interventions. Physical exercise has been proposed as a strategy to counteract the effects of cachexia on skeletal muscle, as it influences the mechanisms involved in the disease such as protein turnover, inflammation, oxidative stress, and mitochondrial dysfunction. This review will summarize the experimental and clinical evidence of the impact of physical exercise on cancer-associated cachexia.
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Affiliation(s)
- Eva Tamayo-Torres
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100, Burjassot, Spain; Freshage Research Group. Department of Physiology. Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - Amanda Garrido
- Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Rafael de Cabo
- Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Julián Carretero
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100, Burjassot, Spain.
| | - María Carmen Gómez-Cabrera
- Freshage Research Group. Department of Physiology. Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
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Shakhshir MH, Salameh HT, Amer R, Zyoud SH. Identifying correlations between nutritional impact symptoms and risk factors for malnutrition in adult cancer patients with solid tumors: a cross-sectional study from a developing country. Support Care Cancer 2024; 32:689. [PMID: 39325232 DOI: 10.1007/s00520-024-08879-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 09/12/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND Many cancer patients experience malnutrition, which can worsen their health and survival outcomes. However, limited research exists in our region on how common malnutrition is among hospitalized adults with solid tumors and what factors contribute to it. This study aimed to identify these factors and assess the effects of nutritional impact symptoms (NISs) caused by solid tumors on patients' nutritional status. METHODS Between July 2022 and February 2023, a cross-sectional study was carried out on the campuses of two major cancer treatment centers located in a national university hospital and a governmental hospital. Twelve NISs were adopted from the Patient-Generated Subjective Global Assessments (PG-SGA). The Nutrition Risk Screening 2002 (NRS-2002) instrument was used to thoroughly assess the risk of malnutrition. Multiple linear regressions were used to conduct a thorough study. RESULTS A cohort of 294 participants was included. The prevalence of malnutrition risk (NRS score ≥ 3) was 26.9%. Parameters such as age, gender, marital status, educational level, monthly income, type of cancer and treatment modality, and the need for mealtime assistance exhibited statistically significant associations with malnutrition (p < 0.05). The results revealed a substantial inverse correlation between fluid intake and the NRS-2002 score (p < 0.001). Furthermore, symptoms related to solid tumors and their treatment, including chewing difficulties, fatigue, dry mouth, anorexia, constipation, nausea, dizziness, and a sensation of fullness, were also significantly associated with malnutrition (p < 0.05). Additional insights from the regression analysis underscored the independent correlation between the risk of malnutrition in solid malignant malignancies and factors such as anorexia (p < 0.001), colorectal cancer (p = 0.003), gender (p = 0.018), educational attainment (p = 0.049), and the need for mealtime assistance among patients (p < 0.001). CONCLUSIONS Malnutrition is a major issue among adult cancer patients, particularly those with solid tumors. Anorexia, colorectal cancer, gender, educational attainment, and the need for mealtime assistance were identified as factors that led to malnutrition in our research. This study emphasizes the need for a multidisciplinary plan of care to diagnose and treat malnutrition, improve overall therapy, and reduce mortality and morbidity.
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Affiliation(s)
- Muna H Shakhshir
- Department of Nutrition, An-Najah National University Hospital, Nablus, 44839, Palestine.
- Department of Public Health, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
| | - Husam T Salameh
- Department of Hematology and Oncology, An-Najah National University Hospital, Nablus, 44839, Palestine
- Department of Medicine, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
| | - Riad Amer
- Department of Hematology and Oncology, An-Najah National University Hospital, Nablus, 44839, Palestine
- Department of Medicine, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
| | - Sa'ed H Zyoud
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
- Poison Control and Drug Information Center (PCDIC), College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
- Clinical Research Center, An-Najah National University Hospital, Nablus, 44839, Palestine.
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Khan S, Ahmad Javid S, Ur Rehman S, Akhtar Y, Amir Khan M. A Systematic Review of Cost-Effectiveness Analyses Examining Treatments for Cachexia Syndrome. Nutr Cancer 2024; 76:584-595. [PMID: 38801296 DOI: 10.1080/01635581.2024.2353939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 05/04/2024] [Accepted: 05/06/2024] [Indexed: 05/29/2024]
Abstract
OBJECTIVES This systematic review aims to critically evaluate and synthesize the economic outcomes of various therapeutic strategies employed to manage cachexia patients. METHODS A comprehensive search for randomized controlled trials and observational studies was conducted from January 1, 2000 to December 31, 2023, using PubMed, Google Scholar, Clinical Trials Registry, Cochrane Central Register of Controlled Trials, British Medical Journal, National Health Service Economic Evaluation Database, and ScienceDirect, following PRISMA guidelines. We assessed the quality of the included studies using the Consolidated Health Economic Evaluation Reporting Standards reporting guidelines. RESULTS We identified six high to medium quality economic evaluations in four countries, focusing on cancer, chronic obstructive pulmonary disease, and HIV/AIDS-associated cachexia. The results indicate that combination management strategies, specifically the use of nutritional supplements and exercise, are more cost-effective than usual care for cachexia syndrome. Additionally, two studies showed that dietary supplements alone were more cost-effective than usual care, and pharmacotherapy alone was more cost-effective than a placebo. CONCLUSION Combining several strategies, such as nutritional supplements and exercise, may be the most economically efficient method for managing cachexia compared to usual care or single treatment approaches. However, the restricted and diverse characteristics of the current research hinder the definitive conclusions.
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Affiliation(s)
- Safeer Khan
- Department of Pharmaceutical Sciences, Institute of Chemical Sciences, Government College University, Lahore, Punjab, Pakistan
| | | | - Sabi Ur Rehman
- Department of Pharmacy, Foreman Christian College (A Chartered University), Lahore, Punjab, Pakistan
| | - Yasmeen Akhtar
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Muhammad Amir Khan
- Department of Foreign Medical Education, Fergana Institute of Public Health, Fergana, Uzbekistan
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Arai H, Maeda K, Wakabayashi H, Naito T, Konishi M, Assantachai P, Auyeung WT, Chalermsri C, Chen W, Chew J, Chou M, Hsu C, Hum A, Hwang IG, Kaido T, Kang L, Kamaruzzaman SB, Kim M, Lee JSW, Lee W, Liang C, Lim WS, Lim J, Lim YP, Lo RS, Ong T, Pan W, Peng L, Pramyothin P, Razalli NH, Saitoh M, Shahar S, Shi HP, Tung H, Uezono Y, von Haehling S, Won CW, Woo J, Chen L. Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia. J Cachexia Sarcopenia Muscle 2023; 14:1949-1958. [PMID: 37667992 PMCID: PMC10570088 DOI: 10.1002/jcsm.13323] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/05/2023] [Accepted: 08/02/2023] [Indexed: 09/06/2023] Open
Abstract
Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3-6 month period and suggested a tentative cut-off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.
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Affiliation(s)
- Hidenori Arai
- National Center for Geriatrics and GerontologyObuJapan
| | - Keisuke Maeda
- Nutrition Therapy Support CenterAichi Medical University HospitalNagakuteJapan
- Department of Geriatric MedicineNational Center for Geriatrics and GerontologyObuJapan
| | - Hidetaka Wakabayashi
- Department of Rehabilitation MedicineTokyo Women's Medical University HospitalTokyoJapan
| | - Tateaki Naito
- Division of Thoracic OncologyShizuoka Cancer CenterShizuokaJapan
| | - Masaaki Konishi
- Department of CardiologyYokohama City University School of MedicineYokohamaJapan
| | | | - Wai Tung Auyeung
- Jockey Club Institute of AgeingThe Chinese University of Hong KongShatinHong KongChina
| | - Chalobol Chalermsri
- Department of Preventive and Social Medicine, Division of Geriatric Medicine, Faculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand
- Department of Women's and Children's HealthUppsala UniversityUppsalaSweden
| | - Wei Chen
- Department of Clinical Nutrition, Department of Health MedicinePeking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Justin Chew
- Department of Geriatric MedicineTan Tock Seng HospitalSingapore
- Institute of Geriatrics and Active AgeingTan Tock Seng HospitalSingapore
| | - Ming‐Yueh Chou
- Center for Geriatrics and GerontologyKaohsiung Veterans General HospitalKaohsiung CityTaiwan
| | - Chih‐Cheng Hsu
- National Center for Geriatrics and Welfare ResearchMiaoli CountyTaiwan
| | - Allyn Hum
- Department of Geriatrics and Palliative CareTan Tock Seng HospitalSingapore
| | - In Gyu Hwang
- Department of Internal MedicineChung‐Ang University Hospital, Chung‐Ang University College of MedicineSeoulRepublic of Korea
| | - Toshimi Kaido
- Department of Gastroenterological and General SurgerySt. Luke's International HospitalTokyoJapan
| | - Lin Kang
- Department of Geriatric MedicinePeking Union Medical College HospitalBeijingChina
| | | | - Miji Kim
- Department of Biomedical Science and Technology, College of Medicine, East‐West Medical Research InstituteKyung Hee UniversitySeoulRepublic of Korea
| | - Jenny Shun Wah Lee
- Institute of AgingThe Chinese University of Hong Kong, Department of Medicine, Alice Ho Miu Ling Nethersole HospitalTai PoHong Kong
| | - Wei‐Ju Lee
- Aging and Health Research CenterNational Yang Ming Chiao Tung UniversityTaipei CityTaiwan
| | - Chih‐Kuang Liang
- Center for Geriatrics and GerontologyKaohsiung Veterans General HospitalKaohsiung CityTaiwan
- Center for Healthy Longevity and Aging SciencesNational Yang Ming Chiao Tung UniversityTaipei CityTaiwan
| | - Wee Shiong Lim
- Department of Geriatric Medicine, Institute of Geriatric MedicineTan Tock Seng HospitalSingapore
- Lee Kong Chian School of MedicineNanyang Technological UniversitySingapore
| | - Jae‐Young Lim
- Department of Rehabilitation MedicineSeoul National University College of Medicine, Seoul National University Bundang HospitalSeongnamRepublic of Korea
| | - Yen Peng Lim
- Department of Nutrition and DieteticsTan Tock Seng HospitalSingapore
| | - Raymond See‐Kit Lo
- Department of Medicine and TherapeuticsChinese University of Hong Kong, Shatin HospitalMa On ShanHong Kong
| | - Terence Ong
- Department of Medicine, Faculty of MedicineUniversity MalayaKuala LumpurMalaysia
| | - Wen‐Harn Pan
- Institute of Biomedical SciencesAcademia Sinica, TaiwanTaipei CityTaiwan
| | - Li‐Ning Peng
- Aging and Health Research CenterNational Yang Ming Chiao Tung UniversityTaipei CityTaiwan
| | - Pornpoj Pramyothin
- Division of Nutrition, Department of Medicine, Faculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand
| | - Nurul Huda Razalli
- Centre for Healthy Aging and Wellness (H‐CARE), Faculty of Health SciencesUniversiti Kebangsaan Malaysia, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul AzizKuala LumpurMalaysia
| | - Masakazu Saitoh
- Department of Physical Therapy, Faculty of Health ScienceJuntendo UniversityTokyoJapan
| | - Suzana Shahar
- Center for Healthy Aging and Wellness, Faculty Health SciencesUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Han Ping Shi
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan HospitalCapital Medical University of ChinaBeijingChina
| | - Heng‐Hsin Tung
- National Yang Ming Chiao Tung UniversityTaipei CityTaiwan
| | - Yasuhito Uezono
- Department of Pain Control ResearchThe Jikei University School of MedicineTokyoJapan
| | - Stephan von Haehling
- Department of Cardiology and PneumologyUniversity of Goettingen Medical Center, Georg‐August‐University GoettingenGoettingenGermany
- German Center for Cardiovascular Research (DZHK), partner site GöttingenGöttingenGermany
| | - Chang Won Won
- Department of Family MedicineCollege of Medicine, Kyung Hee UniversitySeoulRepublic of Korea
| | - Jean Woo
- Department of Medicine & TherapeuticsThe Chinese University of Hong Kong, Prince of Wales HospitalHong Kong SARChina
| | - Liang‐Kung Chen
- Center for Healthy Longevity and Aging SciencesNational Yang Ming Chiao Tung UniversityTaipei CityTaiwan
- Center for Geriatrics and GerontologyTaipei Veterans General Hospital; Taipei Municipal Gan‐Dau HospitalTaipei CityTaiwan
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8
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Cunningham P, Unger CA, Patton EA, Aiken A, Browne A, James E, Aladhami AK, Hope 3rd MC, VanderVeen BN, Cardaci TD, Murphy EA, Enos RT, Velázquez KT. Platelet status in cancer cachexia progression in Apc Min/+ mice. Front Immunol 2023; 14:1253587. [PMID: 37701438 PMCID: PMC10493779 DOI: 10.3389/fimmu.2023.1253587] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/10/2023] [Indexed: 09/14/2023] Open
Abstract
Cachexia, a complex wasting syndrome, significantly affects the quality of life and treatment options for cancer patients. Studies have reported a strong correlation between high platelet count and decreased survival in cachectic individuals. Therefore, this study aimed to investigate the immunopathogenesis of cancer cachexia using the ApcMin/+ mouse model of spontaneous colorectal cancer. The research focused on identifying cellular elements in the blood at different stages of cancer cachexia, assessing inflammatory markers and fibrogenic factors in the skeletal muscle, and studying the behavioral and metabolic phenotype of ApcMin/+ mice at the pre-cachectic and severely cachectic stages. Platelet measurements were also obtained from other animal models of cancer cachexia - Lewis Lung Carcinoma and Colon 26 adenocarcinoma. Our study revealed that platelet number is elevated prior to cachexia development in ApcMin/+ mice and can become activated during its progression. We also observed increased expression of TGFβ2, TGFβ3, and SMAD3 in the skeletal muscle of pre-cachectic ApcMin/+ mice. In severely cachectic mice, we observed an increase in Ly6g, CD206, and IL-10 mRNA. Meanwhile, IL-1β gene expression was elevated in the pre-cachectic stage. Our behavioral and metabolic phenotyping results indicate that pre-cachectic ApcMin/+ mice exhibit decreased physical activity. Additionally, we found an increase in anemia at pre-cachectic and severely cachectic stages. These findings highlight the altered platelet status during early and late stages of cachexia and provide a basis for further investigation of platelets in the field of cancer cachexia.
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Affiliation(s)
- Patrice Cunningham
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Christian A. Unger
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Emma A. Patton
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Akyla Aiken
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
- Columbia Department of Veterans Affairs Health Care System, Columbia, SC, United States
| | - Alea Browne
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Ella James
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Ahmed K. Aladhami
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Marion C. Hope 3rd
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Brandon N. VanderVeen
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Thomas D. Cardaci
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - E. Angela Murphy
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Reilly T. Enos
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Kandy T. Velázquez
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
- Columbia Department of Veterans Affairs Health Care System, Columbia, SC, United States
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9
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Schmich SKP, Keck J, Bonaterra GA, Bertoune M, Adam A, Wilhelm B, Slater EP, Schwarzbach H, Fendrich V, Kinscherf R, Hildebrandt W. Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice. Biomedicines 2023; 11:biomedicines11030912. [PMID: 36979889 PMCID: PMC10046345 DOI: 10.3390/biomedicines11030912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B).
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Affiliation(s)
- Simon K. P. Schmich
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Jan Keck
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Gabriel A. Bonaterra
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Mirjam Bertoune
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Anna Adam
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Beate Wilhelm
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Emily P. Slater
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Hans Schwarzbach
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Volker Fendrich
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Ralf Kinscherf
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Wulf Hildebrandt
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
- Correspondence: ; Tel.: +49-6421-2864042; Fax: +49-6421-2868983
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10
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Eljalby M, Huang X, Becher T, Wibmer AG, Jiang CS, Vaughan R, Schöder H, Cohen P. Brown adipose tissue is not associated with cachexia or increased mortality in a retrospective study of patients with cancer. Am J Physiol Endocrinol Metab 2023; 324:E144-E153. [PMID: 36576355 PMCID: PMC9902220 DOI: 10.1152/ajpendo.00187.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/28/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022]
Abstract
Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and β-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia.NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.
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Affiliation(s)
- Mahmoud Eljalby
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Xiaojing Huang
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Tobias Becher
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
- DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
- First Department of Medicine (Division of Cardiology), University Medical Center Mannheim, Mannheim, Germany
| | - Andreas G Wibmer
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Caroline S Jiang
- Center for Clinical and Translational Science, The Rockefeller University, New York City, New York
| | - Roger Vaughan
- Center for Clinical and Translational Science, The Rockefeller University, New York City, New York
- Graduate School of Medical Sciences, Weill Cornell Medicine, New York City, New York
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
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11
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VanderVeen BN, Cardaci TD, Cunningham P, McDonald SJ, Bullard BM, Fan D, Murphy EA, Velázquez KT. Quercetin Improved Muscle Mass and Mitochondrial Content in a Murine Model of Cancer and Chemotherapy-Induced Cachexia. Nutrients 2022; 15:102. [PMID: 36615760 PMCID: PMC9823918 DOI: 10.3390/nu15010102] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
A cachexia diagnosis is associated with a doubling in hospital stay and increased healthcare cost for cancer patients and most cachectic patients do not survive treatment. Unfortunately, complexity in treating cachexia is amplified by both the underlying malignancy and the anti-cancer therapy which can independently promote cachexia. Quercetin, an organic polyphenolic flavonoid, has demonstrated anti-inflammatory and antioxidant properties with promise in protecting against cancer and chemotherapy-induced dysfunction; however, whether quercetin is efficacious in maintaining muscle mass in tumor-bearing animals receiving chemotherapy has not been investigated. C26 tumor-bearing mice were given 5-fluorouracil (5FU; 30 mg/kg of lean mass i.p.) concomitant with quercetin (Quer; 50 mg/kg of body weight via oral gavage) or vehicle. Both C26 + 5FU and C26 + 5FU + Quer had similar body weight loss; however, muscle mass and cross-sectional area was greater in C26 + 5FU + Quer compared to C26 + 5FU. Additionally, C26 + 5FU + Quer had a greater number and larger intermyofibrillar mitochondria with increased relative protein expression of mitochondrial complexes V, III, and II as well as cytochrome c expression. C26 + 5FU + Quer also had increased MFN1 and reduced FIS1 relative protein expression without apparent benefits to muscle inflammatory signaling. Our data suggest that quercetin protected against cancer and chemotherapy-induced muscle mass loss through improving mitochondrial homeostatic balance.
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Affiliation(s)
- Brandon N. VanderVeen
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
- AcePre, LLC, Columbia, SC 29209, USA
| | - Thomas D. Cardaci
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Patrice Cunningham
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Sierra J. McDonald
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Brooke M. Bullard
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Daping Fan
- AcePre, LLC, Columbia, SC 29209, USA
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - E. Angela Murphy
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
- AcePre, LLC, Columbia, SC 29209, USA
| | - Kandy T. Velázquez
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
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12
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Murphy BT, Mackrill JJ, O'Halloran KD. Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise. J Physiol 2022; 600:4979-5004. [PMID: 36251564 PMCID: PMC10091733 DOI: 10.1113/jp283569] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/09/2022] [Indexed: 01/05/2023] Open
Abstract
Cancer cachexia is defined as a multi-factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50-80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focusing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia and subsequently explores the available respiratory- and exercise-focused literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise-induced support of muscle via antioxidant and anti-inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function and muscle glucose uptake provide avenues for interventional studies. Currently available pre-clinical mouse models including novel transgenic animals provide a platform for the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer.
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Affiliation(s)
- Ben T. Murphy
- Department of PhysiologySchool of MedicineCollege of Medicine and HealthUniversity College CorkCorkIreland
| | - John J. Mackrill
- Department of PhysiologySchool of MedicineCollege of Medicine and HealthUniversity College CorkCorkIreland
| | - Ken D. O'Halloran
- Department of PhysiologySchool of MedicineCollege of Medicine and HealthUniversity College CorkCorkIreland
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13
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Yin L, Cui J, Lin X, Li N, Fan Y, Zhang L, Liu J, Chong F, Wang C, Liang T, Liu X, Deng L, Yang M, Yu J, Wang X, Cong M, Li Z, Weng M, Yao Q, Jia P, Guo Z, Li W, Song C, Shi H, Xu H. Identifying cancer cachexia in patients without weight loss information: machine learning approaches to address a real-world challenge. Am J Clin Nutr 2022; 116:1229-1239. [PMID: 36095136 DOI: 10.1093/ajcn/nqac251] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 09/07/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Diagnosing cancer cachexia relies extensively on patient-reported historic weight, and failure to accurately recall this information can lead to severe underestimation of cancer cachexia. OBJECTIVES The present study aimed to develop inexpensive tools to facilitate the identification of cancer cachexia in patients without weight loss information. METHODS This multicenter cohort study included 12,774 patients with cancer. Cachexia was retrospectively diagnosed using Fearon et al.'s framework. Baseline clinical features, excluding weight loss, were modeled to mimic a situation where the patient is unable to recall their weight history. Multiple machine learning (ML) models were trained using 75% of the study cohort to predict cancer cachexia, with the remaining 25% of the cohort used to assess model performance. RESULTS The study enrolled 6730 males and 6044 females (median age = 57.5 y). Cachexia was diagnosed in 5261 (41.2%) patients and most diagnoses were made based on the weight loss criterion. A 15-variable logistic regression (LR) model mainly comprising cancer types, gastrointestinal symptoms, tumor stage, and serum biochemistry indexes was selected among the various ML models. The LR model showed good performance for predicting cachexia in the validation data (AUC = 0.763; 95% CI: 0.747, 0.780). The calibration curve of the model demonstrated good agreement between predictions and actual observations (accuracy = 0.714, κ = 0.396, sensitivity = 0.580, specificity = 0.808, positive predictive value = 0.679, negative predictive value = 0.733). Subgroup analyses showed that the model was feasible in patients with different cancer types. The model was deployed as an online calculator and a nomogram, and was exported as predictive model markup language to permit flexible, individualized risk calculation. CONCLUSIONS We developed an ML model that can facilitate the identification of cancer cachexia in patients without weight loss information, which might improve decision-making and lead to the development of novel management strategies in cancer care. This trial was registered at https://www.chictr.org.cn as ChiCTR1800020329.
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Affiliation(s)
- Liangyu Yin
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China; Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xin Lin
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Na Li
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yang Fan
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ling Zhang
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jie Liu
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Feifei Chong
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chang Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Tingting Liang
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiangliang Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Li Deng
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mei Yang
- Department of Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Jiami Yu
- Department of Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Xiaojie Wang
- Department of Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Minghua Cong
- Department of Comprehensive Oncology, National Cancer Center or Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zengning Li
- Department of Clinical Nutrition, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Min Weng
- Department of Clinical Nutrition, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Qinghua Yao
- Department of Integrated Chinese and Western Medicine, Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
| | - Pingping Jia
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer Food for Special Medical Purposes (FSMP) for State Market Regulation, Beijing, China
| | - Zengqing Guo
- Department of Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Wei Li
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chunhua Song
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Hanping Shi
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer Food for Special Medical Purposes (FSMP) for State Market Regulation, Beijing, China.
| | - Hongxia Xu
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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14
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Clark BC, Grooms DR, Etheridge T, Wilkinson DJ, Zhu S, Arnold WD, Szewczyk NJ. Editorial: Integrative Physiology of Common Chronic Musculoskeletal Disorders. Front Physiol 2022; 13:971103. [PMID: 35899027 PMCID: PMC9310779 DOI: 10.3389/fphys.2022.971103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Brian C. Clark
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, OH, United States
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
- *Correspondence: Brian C. Clark,
| | - Dustin R. Grooms
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, OH, United States
- School of Rehabilitation and Communication Sciences, Ohio University, Athens, OH, United States
| | - Timothy Etheridge
- Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom
| | - Daniel J. Wilkinson
- MRC-ARUK Centre for Musculoskeletal Aging Research and National Institute of Health Research, Biomedical Research Centre, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, United Kingdom
| | - Shouan Zhu
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, OH, United States
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
| | - W. David Arnold
- Department of Neurology, Ohio State University, Columbus, OH, United States
| | - Nathaniel J. Szewczyk
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, OH, United States
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
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15
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Factors Affecting the Assessment of Cancer Cachexia by Nurses Caring for Patients with Advanced Cancer Undergoing Chemotherapy: A Cross-Sectional Survey. Asia Pac J Oncol Nurs 2022; 9:100075. [PMID: 35669286 PMCID: PMC9163426 DOI: 10.1016/j.apjon.2022.100075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022] Open
Abstract
Objective This study aimed to identify the awareness, knowledge, and assessment of cancer cachexia among nurses who cared for patients with advanced cancer undergoing chemotherapy. In addition, we identified the factors that affected their assessments. Methods A cross-sectional survey was conducted among nurses who cared for patients with advanced cancer undergoing chemotherapy at designated cancer care hospitals and regional cancer care cooperation hospitals between June and September 2020. We applied Bandura's triadic reciprocal causation as the research framework. The questionnaire consisted of questions on awareness, knowledge, and assessment of cancer cachexia. Single and multiple regression analyses were conducted on the relationship between each variable and the number of assessment items. Results Questionnaires were sent to 1026 nurses, 403 of whom responded (response rate: 39.3%). Among these, 299 responses were valid, being a 74.1% valid response rate. The average age was 39.74 ± 9.65 years and the mean work experience as a nurse was 16.50 ± 9.14 years. In respect of the awareness of cancer cachexia, 93.3% of the participants answered “assessment of cancer cachexia was needed,” and 75.2% answered “a nurse's role includes assessing for cancer cachexia.” Only 15.4% responded positively regarding “confidence in the assessment of cancer cachexia.” Regarding knowledge of cancer cachexia, the percentage of correct answers to questions about the definition of cachexia and diagnostic criteria ranged from 45.5% to 53.8%. With regard to cancer cachexia assessments, the participants assessed “weight loss or rate of weight loss (56.9%),” “symptoms affecting nutritional status (54.2%),” and “anorexia (46.2%).” Factors affecting the assessment of cancer cachexia were higher knowledge scores on cancer cachexia (P = 0.039), routine assessment of cancer cachexia (P < 0.001), experiences of participating in in-hospital training on cancer cachexia (P = 0.027), and collaborating with physical/occupational therapists in the nutritional management of patients (P = 0.025). Conclusions Nurses held the view that their role required them to assess for cancer cachexia, but they did not feel confident in doing so. In addition, they lacked knowledge of reversible “cancer cachexia;” hence, the assessments were not routinely completed. Education on these topics and the development and standardization of tools to assess or collaborate with other professions are required.
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Parra-Peralbo E, Talamillo A, Barrio R. Origin and Development of the Adipose Tissue, a Key Organ in Physiology and Disease. Front Cell Dev Biol 2022; 9:786129. [PMID: 34993199 PMCID: PMC8724577 DOI: 10.3389/fcell.2021.786129] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/01/2021] [Indexed: 12/17/2022] Open
Abstract
Adipose tissue is a dynamic organ, well known for its function in energy storage and mobilization according to nutrient availability and body needs, in charge of keeping the energetic balance of the organism. During the last decades, adipose tissue has emerged as the largest endocrine organ in the human body, being able to secrete hormones as well as inflammatory molecules and having an important impact in multiple processes such as adipogenesis, metabolism and chronic inflammation. However, the cellular progenitors, development, homeostasis and metabolism of the different types of adipose tissue are not fully known. During the last decade, Drosophila melanogaster has demonstrated to be an excellent model to tackle some of the open questions in the field of metabolism and development of endocrine/metabolic organs. Discoveries ranged from new hormones regulating obesity to subcellular mechanisms that regulate lipogenesis and lipolysis. Here, we review the available evidences on the development, types and functions of adipose tissue in Drosophila and identify some gaps for future research. This may help to understand the cellular and molecular mechanism underlying the pathophysiology of this fascinating key tissue, contributing to establish this organ as a therapeutic target.
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Affiliation(s)
| | - Ana Talamillo
- Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Rosa Barrio
- Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
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17
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De Brandt J, Beijers RJHCG, Chiles J, Maddocks M, McDonald MLN, Schols AMWJ, Nyberg A. Update on the Etiology, Assessment, and Management of COPD Cachexia: Considerations for the Clinician. Int J Chron Obstruct Pulmon Dis 2022; 17:2957-2976. [PMID: 36425061 PMCID: PMC9680681 DOI: 10.2147/copd.s334228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 10/31/2022] [Indexed: 11/19/2022] Open
Abstract
Cachexia is a commonly observed but frequently neglected extra-pulmonary manifestation in patients with chronic obstructive pulmonary disease (COPD). Cachexia is a multifactorial syndrome characterized by severe loss of body weight, muscle, and fat, as well as increased protein catabolism. COPD cachexia places a high burden on patients (eg, increased mortality risk and disease burden, reduced exercise capacity and quality of life) and the healthcare system (eg, increased number, length, and cost of hospitalizations). The etiology of COPD cachexia involves a complex interplay of non-modifiable and modifiable factors (eg, smoking, hypoxemia, hypercapnia, physical inactivity, energy imbalance, and exacerbations). Addressing these modifiable factors is needed to prevent and treat COPD cachexia. Oral nutritional supplementation combined with exercise training should be the primary multimodal treatment approach. Adding a pharmacological agent might be considered in some, but not all, patients with COPD cachexia. Clinicians and researchers should use longitudinal measures (eg, weight loss, muscle mass loss) instead of cross-sectional measures (eg, low body mass index or fat-free mass index) where possible to evaluate patients with COPD cachexia. Lastly, in future research, more detailed phenotyping of cachectic patients to enable a better comparison of included patients between studies, prospective longitudinal studies, and more focus on the impact of exacerbations and the role of biomarkers in COPD cachexia, are highly recommended.
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Affiliation(s)
- Jana De Brandt
- Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Physiotherapy, Umeå University, Umeå, Sweden
| | - Rosanne J H C G Beijers
- Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Joe Chiles
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Matthew Maddocks
- Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, King's College London, London, UK
| | - Merry-Lynn N McDonald
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Annemie M W J Schols
- Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - André Nyberg
- Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Physiotherapy, Umeå University, Umeå, Sweden
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18
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Lakshman Kumar P, Wilson AC, Rocco A, Cho MH, Wan E, Hobbs BD, Washko GR, Ortega VE, Christenson SA, Li X, Wells JM, Bhatt SP, DeMeo DL, Lutz SM, Rossiter H, Casaburi R, Rennard SI, Lomas DA, Labaki WW, Tal‐Singer R, Bowler RP, Hersh CP, Tiwari HK, Dransfield M, Thalacker‐Mercer A, Meyers DA, Silverman EK, McDonald MN. Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease. J Cachexia Sarcopenia Muscle 2021; 12:1803-1817. [PMID: 34523824 PMCID: PMC8718068 DOI: 10.1002/jcsm.12782] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach. METHODS Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2 ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data. RESULTS At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10-8 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling. CONCLUSIONS The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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Affiliation(s)
- Preeti Lakshman Kumar
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
| | - Ava C. Wilson
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
| | - Alison Rocco
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
| | - Michael H. Cho
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Emily Wan
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Veterans Affairs Boston Health Care System, Jamaica PlainBostonMAUSA
| | - Brian D. Hobbs
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - George R. Washko
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Victor E. Ortega
- Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic DiseasesWake Forest School of MedicineWinston‐SalemNCUSA
| | - Stephanie A. Christenson
- Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of MedicineUniversity of California San FranciscoSan FranciscoCAUSA
| | - Xingnan Li
- Department of MedicineUniversity of Arizona College of MedicineTucsonAZUSA
| | - J. Michael Wells
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
| | - Surya P. Bhatt
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
| | - Dawn L. DeMeo
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Sharon M. Lutz
- Department of Population MedicineHarvard Medical SchoolBostonMAUSA
| | - Harry Rossiter
- Rehabilitation Clinical Trials CenterLos Angeles Biomedical Research Institute at Harbor Harbor‐UCLA Medical CenterTorranceCAUSA
| | - Richard Casaburi
- Rehabilitation Clinical Trials CenterLos Angeles Biomedical Research Institute at Harbor Harbor‐UCLA Medical CenterTorranceCAUSA
| | | | | | - Wassim W. Labaki
- Division of Pulmonary and Critical Care MedicineUniversity of MichiganAnn ArborMIUSA
| | | | - Russel P. Bowler
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep MedicineNational Jewish HealthDenverCOUSA
| | - Craig P. Hersh
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Hemant K. Tiwari
- Department of BiostatisticsUniversity of Alabama at BirminghamBirminghamALUSA
| | - Mark Dransfield
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
| | - Anna Thalacker‐Mercer
- Department of Cell Development and Integrative BiologyUniversity of Alabama at BirminghamBirminghamALUSA
| | - Deborah A. Meyers
- Department of MedicineUniversity of Arizona College of MedicineTucsonAZUSA
| | - Edwin K. Silverman
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Merry‐Lynn N. McDonald
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of MedicineUniversity of Alabama at BirminghamBirminghamALUSA
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
- Department of GeneticsUniversity of Alabama at BirminghamBirminghamALUSA
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Gerrard JC, Hay JP, Adams RN, Williams JC, Huot JR, Weathers KM, Marino JS, Arthur ST. Current Thoughts of Notch's Role in Myoblast Regulation and Muscle-Associated Disease. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182312558. [PMID: 34886282 PMCID: PMC8657396 DOI: 10.3390/ijerph182312558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 12/25/2022]
Abstract
The evolutionarily conserved signaling pathway Notch is unequivocally essential for embryogenesis. Notch’s contribution to the muscle repair process in adult tissue is complex and obscure but necessary. Notch integrates with other signals in a functional antagonist manner to direct myoblast activity and ultimately complete muscle repair. There is profound recent evidence describing plausible mechanisms of Notch in muscle repair. However, the story is not definitive as evidence is slowly emerging that negates Notch’s importance in myoblast proliferation. The purpose of this review article is to examine the prominent evidence and associated mechanisms of Notch’s contribution to the myogenic repair phases. In addition, we discuss the emerging roles of Notch in diseases associated with muscle atrophy. Understanding the mechanisms of Notch’s orchestration is useful for developing therapeutic targets for disease.
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Affiliation(s)
- Jeffrey C. Gerrard
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Jamison P. Hay
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Ryan N. Adams
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - James C. Williams
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Joshua R. Huot
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Kaitlin M. Weathers
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Joseph S. Marino
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Susan T. Arthur
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
- Correspondence:
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20
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Virgens IPA, Santana NM, Lima SCVC, Fayh APT. Can COVID-19 be a risk for cachexia for patients during intensive care? Narrative review and nutritional recommendations. Br J Nutr 2021; 126:552-560. [PMID: 33261670 PMCID: PMC7711335 DOI: 10.1017/s0007114520004420] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 01/08/2023]
Abstract
Although increased weight, and particularly obesity, has been associated with a more severe clinical course of COVID-19 and risk of fatality, the course of the illness can lead to prolonged length of stay. Changes in nutritional status and weight loss during hospitalisation are largely reported in some populations, but still not explored in COVID-19 patients. Considering that patients with COVID-19 show an increased inflammatory response, other signs and symptoms, which can lead to weight and muscle loss, should be monitored. The aim of this article was to establish possible connections between COVID-19, prolonged hospitalisation and muscle wasting, as well as to propose nutritional recommendations for the prevention and treatment of cachexia, through a narrative review. Identification of risk and presence of malnutrition should be an early step in general assessment of all patients, with regard to more at-risk categories including older adults and individuals suffering from chronic and acute disease conditions, such as COVID-19. The deterioration of nutritional status, and consequently cachexia, increases the risk of mortality and needs to be treated with attention as other complications. There is, however, little hard evidence of nutritional approaches in assisting COVID-19 treatment or its management including cachexia.
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Affiliation(s)
- Isabel P. A. Virgens
- Graduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte59078-970, Brazil
| | - Natália M. Santana
- Graduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte59078-970, Brazil
| | - Severina C. V. C. Lima
- Graduate Program in Nutrition, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte59078-970, Brazil
| | - Ana P. T. Fayh
- Graduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte59078-970, Brazil
- Graduate Program in Nutrition, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte59078-970, Brazil
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21
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Widner DB, Liu C, Zhao Q, Sharp S, Eber MR, Park SH, Files DC, Shiozawa Y. Activated mast cells in skeletal muscle can be a potential mediator for cancer-associated cachexia. J Cachexia Sarcopenia Muscle 2021; 12:1079-1097. [PMID: 34008339 PMCID: PMC8350201 DOI: 10.1002/jcsm.12714] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Eighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer-associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle-resident immune cells could be a source of inflammation. This study explores the efficacy of cancer activated skeletal muscle-resident mast cells as a biomarker and mediator of cachexia. METHODS Individual gene markers for immune cells were assessed in a publicly available colon carcinoma cohort of normal (n = 3), moderate cachexia (n = 3), and severe cachexia (n = 4) mice. Lewis lung carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and a combination of toluidine blue staining, immunofluorescence, quantitative polymerase chain reaction, and western blots measured innate immune cell expression in hind limb muscles. In vitro measurements included C2C12 myotube diameter before and after treatment with media from primary murine mast cells activated with LL/2 conditioned media. To assess translational potential in human samples, innate immune cell signatures were assessed for correlation with skeletal muscle atrophy and apoptosis, dietary excess, and cachexia signatures in normal skeletal muscle tissue. Gene set enrichment analysis was performed with innate immune cell signatures in publicly available cohorts for upper gastrointestinal (GI) cancer and pancreatic ductal adenocarcinoma (PDAC) patients (accession: GSE34111 and GSE130563, respectively). RESULTS Individual innate immunity genes (TPSAB1 and CD68) showed significant increases in severe cachexia (weight loss > 15%) mice in a C26 cohort (GSE24112). Induction of cachexia in C57BL/6 mice with LL/2 subcutaneous injection significantly increased the number of activated skeletal muscle-resident degranulating mast cells. Murine mast cells activated with LL/2 conditioned media decreased C2C12 myotube diameter (P ≤ 0.05). Normal human skeletal muscle showed significant positive correlations between innate immune cell signatures and muscle apoptosis and atrophy, dietary excess, and cachexia signatures. The mast cell signature was up-regulated (positive normalized enrichment score and false discovery rate ≤ 0.1) in upper GI cachectic patients (n = 12) compared with control (n = 6), as well as in cachectic PDAC patients (n = 17) compared with control patients (n = 16). CONCLUSIONS Activated skeletal muscle-resident mast cells are enriched in cachectic muscles, suggesting skeletal-muscle resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis.
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Affiliation(s)
- D Brooke Widner
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
| | - Chun Liu
- Internal Medicine-Sections in Pulmonary and Critical Care Medicine and Geriatrics and the Critical Illness Injury and Recovery Research Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
| | - Qingxia Zhao
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
| | - Sarah Sharp
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA.,Department of Biology, Wake Forest University, Winston-Salem, NC, USA
| | - Matthew R Eber
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
| | - Sun H Park
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
| | - D Clark Files
- Internal Medicine-Sections in Pulmonary and Critical Care Medicine and Geriatrics and the Critical Illness Injury and Recovery Research Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
| | - Yusuke Shiozawa
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA
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22
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Shin DW, Kim MA, Lee JC, Kim J, Hwang JH. Maintenance of skeletal muscle mass during FOLFIRINOX is a favorable prognostic factor in pancreatic cancer patients. BMC Res Notes 2021; 14:272. [PMID: 34266478 PMCID: PMC8281692 DOI: 10.1186/s13104-021-05681-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 07/05/2021] [Indexed: 12/15/2022] Open
Abstract
Objective The study aimed to investigate the effect of body composition changes during chemotherapy on clinical outcomes in patients with pancreatic cancer. Results In patients with locally advanced pancreatic cancer (LAPC), the cross-sectional area of skeletal muscle (SM) and adipose tissue (AT) at the level of third lumbar vertebra was measured. The SM and AT ratios indicated the changes during chemotherapy. The patients were classified into three groups based on these ratios: group 1, ≥ 1.00; group 2, 0.85–0.99; group 3, < 0.85. The overall survival (OS) and surgical resection rates were estimated. Fifty-eight patients with LAPC who received first-line FOLFIRINOX were analyzed. Fifteen (25.9%) patients who underwent resection showed maintained BMI, SM, and AT as compared to the patients who did not undergo resection. As the SM ratio decreased, the risk for death increased significantly. Further, the resection rate was significantly higher in patients with maintained SM compared to those with low SM ratio. On the contrary, the change in AT ratio was not associated with OS and resection rate; however, significant decrease in AT more than 15% showed poor clinical outcomes. Maintenance of SM during chemotherapy is a reliable prognostic factor indicating longer OS and higher resection rate. Supplementary Information The online version contains supplementary material available at 10.1186/s13104-021-05681-x.
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Affiliation(s)
- Dong Woo Shin
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, South Korea.,Division of Gastroenterology, Department of Internal Medicine, Keimyung University School of Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Minseok Albert Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jong-Chan Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, South Korea
| | - Jaihwan Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, South Korea
| | - Jin-Hyeok Hwang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, South Korea.
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23
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Visavadiya NP, Rossiter HB, Khamoui AV. Distinct glycolytic pathway regulation in liver, tumour and skeletal muscle of mice with cancer cachexia. Cell Biochem Funct 2021; 39:802-812. [PMID: 34129243 DOI: 10.1002/cbf.3652] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/13/2021] [Accepted: 05/25/2021] [Indexed: 12/31/2022]
Abstract
Energetically inefficient inter-organ substrate shuttles are proposed contributors to cachexia-related weight loss. Here, we examined glycolytic pathway metabolites, enzyme activity and transport proteins in skeletal muscle, liver and tumours of mice with cachexia-related weight loss induced by colon-26 cancer cells. Skeletal muscle of cachexic mice had increased [L-lactate]/[pyruvate], LDH activity and lactate transporter MCT1. Cachexic livers also showed increased MCT1. This is consistent with the proposal that the rate of muscle-derived lactate shuttling to liver for use in gluconeogenesis is increased, that is, an increased Cori cycle flux in weight-losing cachexic mice. A second shuttle between liver and tumour may also contribute to disrupted energy balance and weight loss. We found increased high-affinity glucose transporter GLUT1 in tumours, suggesting active glucose uptake, tumour MCT1 detection and decreased intratumour [L-lactate]/[pyruvate], implying increased lactate efflux and/or intratumour lactate oxidation. Last, high [L-lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle-derived lactate supply for the tumour (a 'reverse Warburg effect'), supporting tumour growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss. Therapies that aim to normalize dysregulated substrate shuttling among energy-regulating tissues may alleviate unintended weight loss in cancer cachexia. SIGNIFICANCE OF THE STUDY: Cachexia is a serious complication of cancer characterized by severe weight loss, muscle atrophy and frailty. Cachexia occurs in roughly half of all cancer patients, and in up to 80% of patients with advanced disease. Cachexia independently worsens patient prognosis, lowers treatment efficacy, increases hospitalization cost and length of stay, and accounts for 20-30% of cancer-related deaths. There are no effective treatments. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss in cancer cachexia. Identifying therapies that normalize dysregulated substrate shuttling among energy-regulating tissues may protect against cachexia-related weight loss.
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Affiliation(s)
- Nishant P Visavadiya
- Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida, USA
| | - Harry B Rossiter
- Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Andy V Khamoui
- Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida, USA.,Institute for Human Health and Disease Intervention, Florida Atlantic University, Jupiter, FL, USA.,Brain Institute, Florida Atlantic University, Jupiter, Florida, USA
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24
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Avancini A, Trestini I, Tregnago D, Lanza M, Menis J, Belluomini L, Milella M, Pilotto S. A multimodal approach to cancer-related cachexia: from theory to practice. Expert Rev Anticancer Ther 2021; 21:819-826. [PMID: 33971783 DOI: 10.1080/14737140.2021.1927720] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Cachexia represents a relevant issue in oncological care, which is still lacking effective therapies. Although the incidence of cancer cachexia varies across cancer types, it is responsible for approximately a quarter of cancer-related deaths. The pathophysiology of this syndrome is multifactorial, including weight loss, muscle atrophy and impairment of the pro-/anti-inflammatory balance.Areas covered: Diagnostic criteria and optimal endpoints for cachexia-dedicated trials are still debated, slowing the identification of interventions counteracting cachexia sequaele. The multifaceted features of this syndrome support the rationale for personalized therapy. A multimodal approach is likely to offer the best option to address key cachexia-related issues. Pharmacologic agents, physical exercise, nutritional and psycho-social interventions may have a synergistic effect, and improve quality of life.Expert opinion: A personalized multimodal intervention could be the best strategy to effectively manage cancer cachexia. To offer such a comprehensive approach, a specialized staff, including health professionals with different expertise, is necessary. Each specialist plays a specific role inside the multimodal intervention, with the aim of delivering the best cancer care and access to the most effective therapeutic options for each patient.
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Affiliation(s)
- Alice Avancini
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
| | - Ilaria Trestini
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
| | - Daniela Tregnago
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
| | - Massimo Lanza
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Jessica Menis
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
| | - Lorenzo Belluomini
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
| | - Michele Milella
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
| | - Sara Pilotto
- Medical Oncology, Department of Medicine, University of Verona Hospital Trust, Verona, Italy
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25
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Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments. Cells 2021; 10:cells10030516. [PMID: 33671024 PMCID: PMC7997313 DOI: 10.3390/cells10030516] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.
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26
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Beltrami M, Fumagalli C, Milli M. Frailty, sarcopenia and cachexia in heart failure patients: Different clinical entities of the same painting. World J Cardiol 2021; 13:1-10. [PMID: 33552398 PMCID: PMC7821009 DOI: 10.4330/wjc.v13.i1.1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/25/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Heart Failure (HF) in elderly patients is a systemic syndrome where advanced age, comorbidities with organ system deterioration, frailty and impaired cognition significantly impact outcome. Cardiac cachexia, sarcopenia and frailty despite overlap in definitions are different clinical entities that frequently coexist in HF patients. However, these co-factors often remain unaddressed, resulting in poor quality-of-life, prolonged physical disability and exercise intolerance and finally with higher rehospitalization rates and mortality. Strategy aim to increase muscle mass and muscle strength and delay the occurrence of frailty state appear essential in this regard. Common HF drugs therapy (b-blockers, angiotensin-converting enzyme inhibitors) and prescription of physical exercise program remain the cornerstone of therapeutic approach in HF patients with new promising data regarding nutritional supplementation. However, the treatment of all these conditions still remain debated and only a profound knowledge of the specific mechanisms and patterns of disease progression will allow to use the appropriate therapy in a given clinical setting. For all these reasons we briefly review current knowledge on frailty, sarcopenia and cachexia in HF patients with the attempt to define clinically significant degrees of multiorgan dysfunction, specific "red alert" thresholds in clinical practice and therapeutic approach.
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Affiliation(s)
- Matteo Beltrami
- Cardiology Unit, San Giovanni di Dio Hospital, Florence 50142, Italy
| | - Carlo Fumagalli
- Cardiomyopathy Unit, Careggi University Hospital, Florence 50139, Italy
| | - Massimo Milli
- Cardiology Unit, San Giovanni di Dio Hospital, Florence 50142, Italy
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27
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Singh GB, Cowan DB, Wang DZ. Tiny Regulators of Massive Tissue: MicroRNAs in Skeletal Muscle Development, Myopathies, and Cancer Cachexia. Front Oncol 2020; 10:598964. [PMID: 33330096 PMCID: PMC7719840 DOI: 10.3389/fonc.2020.598964] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
Skeletal muscles are the largest tissues in our body and the physiological function of muscle is essential to every aspect of life. The regulation of development, homeostasis, and metabolism is critical for the proper functioning of skeletal muscle. Consequently, understanding the processes involved in the regulation of myogenesis is of great interest. Non-coding RNAs especially microRNAs (miRNAs) are important regulators of gene expression and function. MiRNAs are small (~22 nucleotides long) noncoding RNAs known to negatively regulate target gene expression post-transcriptionally and are abundantly expressed in skeletal muscle. Gain- and loss-of function studies have revealed important roles of this class of small molecules in muscle biology and disease. In this review, we summarize the latest research that explores the role of miRNAs in skeletal muscle development, gene expression, and function as well as in muscle disorders like sarcopenia and Duchenne muscular dystrophy (DMD). Continuing with the theme of the current review series, we also briefly discuss the role of miRNAs in cancer cachexia.
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Affiliation(s)
- Gurinder Bir Singh
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Douglas B Cowan
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
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28
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Hadzibegovic S, Sikorski P, Potthoff SK, Springer J, Lena A, Anker MS. Clinical problems of patients with cachexia due to chronic illness: a congress report. ESC Heart Fail 2020; 7:3414-3420. [PMID: 33012131 PMCID: PMC7754899 DOI: 10.1002/ehf2.13052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Indexed: 12/28/2022] Open
Affiliation(s)
- Sara Hadzibegovic
- Division of Cardiology and Metabolism, Department of Cardiology, Charité - Campus Virchow Klinikum (CVK), Berlin, Germany.,Department of Cardiology, Campus Benjamin Franklin (CBF), Charité University Medicine, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Philipp Sikorski
- Division of Cardiology and Metabolism, Department of Cardiology, Charité - Campus Virchow Klinikum (CVK), Berlin, Germany.,Department of Cardiology, Campus Benjamin Franklin (CBF), Charité University Medicine, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Sophia K Potthoff
- Division of Cardiology and Metabolism, Department of Cardiology, Charité - Campus Virchow Klinikum (CVK), Berlin, Germany.,Department of Cardiology, Campus Benjamin Franklin (CBF), Charité University Medicine, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Jochen Springer
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Alessia Lena
- Division of Cardiology and Metabolism, Department of Cardiology, Charité - Campus Virchow Klinikum (CVK), Berlin, Germany.,Department of Cardiology, Campus Benjamin Franklin (CBF), Charité University Medicine, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Markus S Anker
- Division of Cardiology and Metabolism, Department of Cardiology, Charité - Campus Virchow Klinikum (CVK), Berlin, Germany.,Department of Cardiology, Campus Benjamin Franklin (CBF), Charité University Medicine, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany
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29
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Mallard J, Hucteau E, Schott R, Petit T, Demarchi M, Belletier C, Ben Abdelghani M, Carinato H, Chiappa P, Fischbach C, Kalish-Weindling M, Bousinière A, Dufour S, Favret F, Pivot X, Hureau TJ, Pagano AF. Evolution of Physical Status From Diagnosis to the End of First-Line Treatment in Breast, Lung, and Colorectal Cancer Patients: The PROTECT-01 Cohort Study Protocol. Front Oncol 2020; 10:1304. [PMID: 32903594 PMCID: PMC7438727 DOI: 10.3389/fonc.2020.01304] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 06/23/2020] [Indexed: 01/06/2023] Open
Abstract
Background: Cancer cachexia and exacerbated fatigue represent two hallmarks in cancer patients, negatively impacting their exercise tolerance and ultimately their quality of life. However, the characterization of patients' physical status and exercise tolerance and, most importantly, their evolution throughout cancer treatment may represent the first step in efficiently counteracting their development with prescribed and tailored exercise training. In this context, the aim of the PROTECT-01 study will be to investigate the evolution of physical status, from diagnosis to the end of first-line treatment, of patients with one of the three most common cancers (i.e., lung, breast, and colorectal). Methods: The PROTECT-01 cohort study will include 300 patients equally divided between lung, breast and colorectal cancer. Patients will perform a series of assessments at three visits throughout the treatment: (1) between the date of diagnosis and the start of treatment, (2) 8 weeks after the start of treatment, and (3) after the completion of first-line treatment or at the 6-months mark, whichever occurs first. For each of the three visits, subjective and objective fatigue, maximal voluntary force, body composition, cachexia, physical activity level, quality of life, respiratory function, overall physical performance, and exercise tolerance will be assessed. Discussion: The present study is aimed at identifying the nature and severity of maladaptation related to exercise intolerance in the three most common cancers. Therefore, our results should contribute to the delineation of the needs of each group of patients and to the determination of the most valuable exercise interventions in order to counteract these maladaptations. This descriptive and comprehensive approach is a prerequisite in order to elaborate, through future interventional research projects, tailored exercise strategies to counteract specific symptoms that are potentially cancer type-dependent and, in fine, to improve the health and quality of life of cancer patients. Moreover, our concomitant focus on fatigue and cachexia will provide insightful information about two factors that may have substantial interaction but require further investigation. Trial registration: This prospective study has been registered at ClinicalTrials.gov (NCT03956641), May, 2019.
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Affiliation(s)
- Joris Mallard
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France.,EA 3072: Mitochondria, Oxidative Stress and Muscular Protection Laboratory, Faculty of Medicine, Faculty of Sports Sciences, University of Strasbourg, Strasbourg, France
| | - Elyse Hucteau
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France.,EA 3072: Mitochondria, Oxidative Stress and Muscular Protection Laboratory, Faculty of Medicine, Faculty of Sports Sciences, University of Strasbourg, Strasbourg, France
| | - Roland Schott
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Thierry Petit
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Martin Demarchi
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | | | | | - Hélène Carinato
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Pascale Chiappa
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Cathie Fischbach
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | | | - Audren Bousinière
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Stéphane Dufour
- EA 3072: Mitochondria, Oxidative Stress and Muscular Protection Laboratory, Faculty of Medicine, Faculty of Sports Sciences, University of Strasbourg, Strasbourg, France
| | - Fabrice Favret
- EA 3072: Mitochondria, Oxidative Stress and Muscular Protection Laboratory, Faculty of Medicine, Faculty of Sports Sciences, University of Strasbourg, Strasbourg, France
| | - Xavier Pivot
- Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Thomas J Hureau
- EA 3072: Mitochondria, Oxidative Stress and Muscular Protection Laboratory, Faculty of Medicine, Faculty of Sports Sciences, University of Strasbourg, Strasbourg, France
| | - Allan F Pagano
- EA 3072: Mitochondria, Oxidative Stress and Muscular Protection Laboratory, Faculty of Medicine, Faculty of Sports Sciences, University of Strasbourg, Strasbourg, France
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30
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Mitochondrial dynamics and quality control are altered in a hepatic cell culture model of cancer cachexia. Mol Cell Biochem 2020; 476:23-34. [PMID: 32797334 DOI: 10.1007/s11010-020-03882-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/07/2020] [Indexed: 01/06/2023]
Abstract
Hepatic mitochondrial function loss is associated with cancer cachexia pathology in vivo. Here, we examined if hepatic mitochondrial defects observed in vivo in the cachexic liver also recapitulate during the in vitro treatment of mouse hepatocytes with tumor conditioned media. In vitro experiments were combined with proteome-wide expression analysis of cachexic liver tissue curated for mitochondrial dynamics and quality control proteins, to determine the fidelity of hepatic mitochondrial maladaptation in cancer cachexia pathology. AML12 hepatocytes were exposed to colon-26 (C26) and Lewis lung carcinoma (LLC) conditioned media for 6-72 h and assayed for cell viability, membrane potential, respiratory function, H2O2 production, total ROS/RNS, and mitochondrial dynamics and quality control proteins by immunoblotting. Liver tissue from cachexic C26 mice was analyzed by TMT-based quantitative proteomics for in vivo comparison. Cell viability, membrane potential, H2O2 production, total ROS/RNS, and respiration were decreased 48-72 h after exposure to C26 and/or LLC. Protein expression of treated hepatocytes and cachexic liver tissue showed altered mitochondrial dynamics and quality control, in a manner that suggests limited fusion and content mixing, but also impaired ability to fragment and clear damaged mitochondria. Two strategies to maintain mitochondrial health, therefore, may not be functioning sufficiently in the cachexic liver. Together these findings imply adverse effects of C26 and LLC exposure on hepatocyte health, due to impaired mitochondrial function and remodeling. Exposure of mouse hepatocytes to tumor conditioned media models aspects of cachexic liver mitochondria dysfunction in vivo and validates the importance of hepatic mitochondrial maladaptation in cancer cachexia pathology.
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31
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Leucine-Rich Diet Modulates the Metabolomic and Proteomic Profile of Skeletal Muscle during Cancer Cachexia. Cancers (Basel) 2020; 12:cancers12071880. [PMID: 32668598 PMCID: PMC7408981 DOI: 10.3390/cancers12071880] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background: Cancer-cachexia induces a variety of metabolic disorders, including skeletal muscle imbalance. Alternative therapy, as nutritional supplementation with leucine, shows a modulatory effect over tumour damage in vivo and in vitro. Method: Adult rats distributed into Control (C), Walker tumour-bearing (W), control fed a leucine-rich diet (L), and tumour-bearing fed a leucine-rich diet (WL) groups had the gastrocnemius muscle metabolomic and proteomic assays performed in parallel to in vitro assays. Results: W group presented an affected muscle metabolomic and proteomic profile mainly related to energy generation and carbohydrates catabolic processes, but leucine-supplemented group (WL) recovered the energy production. In vitro assay showed that cell proliferation, mitochondria number and oxygen consumption were higher under leucine effect than the tumour influence. Muscle proteomics results showed that the main affected cell component was mitochondria, leading to an impacted energy generation, including impairment in proteins of the tricarboxylic cycle and carbohydrates catabolic processes, which were modulated and improved by leucine treatment. Conclusion: In summary, we showed a beneficial effect of leucine upon mitochondria, providing information about the muscle glycolytic pathways used by this amino acid, where it can be associated with the preservation of morphometric parameters and consequent protection against the effects of cachexia.
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32
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Attaway AH, Welch N, Hatipoğlu U, Zein JG, Dasarathy S. Muscle loss contributes to higher morbidity and mortality in COPD: An analysis of national trends. Respirology 2020; 26:62-71. [PMID: 32542761 DOI: 10.1111/resp.13877] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 05/06/2020] [Accepted: 05/18/2020] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND OBJECTIVE COPD is the third most common cause of death worldwide and fourth most common in the United States. In hospitalized patients with COPD, mortality, morbidity and healthcare resource utilization are high. Skeletal muscle loss is frequent in patients with COPD. However, the impact of muscle loss on adverse outcomes has not been systematically evaluated. We tested the hypothesis that patients hospitalized for COPD exacerbation with, compared to those without, a secondary diagnosis of muscle loss phenotype (all ICD-9 codes associated with muscle loss including cachexia) will have higher mortality and cost of care. METHODS The NIS database of hospitalized patients in 2011 (1 January-31 December) in the United States was used. The impact of a muscle loss phenotype on in-hospital mortality, LOS and cost of care for each of the 174 808 hospitalizations for COPD exacerbations was analysed. RESULTS Of the subjects admitted for a COPD exacerbation, 12 977 (7.4%) had a secondary diagnosis of muscle loss phenotype. A diagnosis of muscle loss phenotype was associated with significantly higher in-hospital mortality (14.6% vs 5.7%, P < 0.001), LOS (13.3 + 17.1 vs 5.7 + 7.6, P < 0.001) and median hospital charge per patient ($13 947 vs $6610, P < 0.001). Multivariate regression analysis showed that muscle loss phenotype increased mortality by 111% (95% CI: 2.0-2.2, P < 0.001), LOS by 68.4% (P < 0.001) and the direct cost of care by 83.7% (P < 0.001) compared to those without muscle loss. CONCLUSION In-hospital mortality, LOS and healthcare costs are higher in patients with COPD exacerbations and a muscle loss phenotype.
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Affiliation(s)
- Amy H Attaway
- Department of Pulmonology, Cleveland Clinic, Cleveland, OH, USA.,Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Nicole Welch
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA.,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Umur Hatipoğlu
- Department of Pulmonology, Cleveland Clinic, Cleveland, OH, USA
| | - Joe G Zein
- Department of Pulmonology, Cleveland Clinic, Cleveland, OH, USA.,Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA.,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
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33
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Gokuladhas S, Schierding W, Cameron-Smith D, Wake M, Scotter EL, O’Sullivan J. Shared Regulatory Pathways Reveal Novel Genetic Correlations Between Grip Strength and Neuromuscular Disorders. Front Genet 2020; 11:393. [PMID: 32391060 PMCID: PMC7194178 DOI: 10.3389/fgene.2020.00393] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/30/2020] [Indexed: 12/13/2022] Open
Abstract
Muscle weakness is a common consequence of both aging (sarcopenia) and neuromuscular disorders (NMD). Whilst genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS; measure of muscle strength/weakness) and NMDs, including multiple sclerosis (MS), myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS), it is not known whether there are common mechanisms between these phenotypes. To examine this, we have integrated GS and NMD associated genetic variants (single nucleotide polymorphisms; SNPs) in a multimorbid analysis that leverages high-throughput chromatin interaction (Hi-C) data and expression quantitative trait loci data to identify target genes (i.e., SNP-mediated gene regulation). Biological pathways enriched by these genes were then identified using next-generation pathway enrichment analysis. Lastly, druggable genes were identified using drug gene interaction (DGI) database. We identified gene regulatory mechanisms associated with GS, MG, MS, and ALS. The SNPs associated with GS regulate a subset of genes that are also regulated by the SNPs of MS, MG, and ALS. Yet, we did not find any genes commonly regulated by all four phenotype associated SNPs. By contrast, we identified significant enrichment in three pathways (mTOR signaling, axon guidance, and alcoholism) that are commonly affected by the gene regulatory mechanisms associated with all four phenotypes. 13% of the genes we identified were known drug targets, and GS shares at least one druggable gene and pathway with each of the NMD phenotypes. We have identified significant biological overlaps between GS and NMD, demonstrating the potential for spatial genetic analysis to identify common mechanisms between potential multimorbid phenotypes. Collectively, our results form the foundation for a shift from a gene to a pathway-based approach to the rationale design of therapeutic interventions and treatments for NMD.
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Affiliation(s)
| | | | - David Cameron-Smith
- Liggins Institute, The University of Auckland, Auckland, New Zealand
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Melissa Wake
- Murdoch Children’s Research Institute, The University of Melbourne, Parkville, VIC, Australia
| | - Emma L. Scotter
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Justin O’Sullivan
- Liggins Institute, The University of Auckland, Auckland, New Zealand
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da Fonseca GWP, Farkas J, Dora E, von Haehling S, Lainscak M. Cancer Cachexia and Related Metabolic Dysfunction. Int J Mol Sci 2020; 21:ijms21072321. [PMID: 32230855 PMCID: PMC7177950 DOI: 10.3390/ijms21072321] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/20/2020] [Accepted: 03/25/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer-dependent on the underlying type of cancer-and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
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Affiliation(s)
- Guilherme Wesley Peixoto da Fonseca
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo SP 05403-900, Brazil or
- Department of Cardiology and Pneumology, University Medicine Göttingen (UMG), DE-37075 Goettingen, Germany
| | - Jerneja Farkas
- Research Unit, General Hospital Murska Sobota, SI-9000 Murska Sobota, Slovenia;
- National Institute of Public Health, SI-1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Eva Dora
- Division of Cardiology, General Hospital Murska Sobota, SI-9000 Murska Sobota, Slovenia;
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University Medicine Göttingen (UMG), DE-37075 Goettingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Goettingen, DE-37099 Goettingen, Germany
- Correspondence: (S.v.H.); (M.L.); Tel.: +49-551-3920-911 (S.v.H.); +386-251-23-733 (M.L.); Fax: +49-551-3920-918 (S.v.H.); Fax: +386-252-11-007 (M.L.)
| | - Mitja Lainscak
- Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
- Division of Cardiology, General Hospital Murska Sobota, SI-9000 Murska Sobota, Slovenia;
- Correspondence: (S.v.H.); (M.L.); Tel.: +49-551-3920-911 (S.v.H.); +386-251-23-733 (M.L.); Fax: +49-551-3920-918 (S.v.H.); Fax: +386-252-11-007 (M.L.)
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35
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Siddiqui JA, Pothuraju R, Jain M, Batra SK, Nasser MW. Advances in cancer cachexia: Intersection between affected organs, mediators, and pharmacological interventions. Biochim Biophys Acta Rev Cancer 2020; 1873:188359. [PMID: 32222610 DOI: 10.1016/j.bbcan.2020.188359] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/10/2020] [Accepted: 03/23/2020] [Indexed: 02/06/2023]
Abstract
Advanced cancer patients exhibit cachexia, a condition characterized by a significant reduction in the body weight predominantly from loss of skeletal muscle and adipose tissue. Cachexia is one of the major causes of morbidity and mortality in cancer patients. Decreased food intake and multi-organ energy imbalance in cancer patients worsen the cachexia syndrome. Cachectic cancer patients have a low tolerance for chemo- and radiation therapies and also have a reduced quality of life. The presence of tumors and the current treatment options for cancer further exacerbate the cachexia condition, which remains an unmet medical need. The onset of cachexia involves crosstalk between different organs leading to muscle wasting. Recent advancements in understanding the molecular mechanisms of skeletal muscle atrophy/hypertrophy and adipose tissue wasting/browning provide a platform for the development of new targeted therapies. Therefore, a better understanding of this multifactorial disorder will help to improve the quality of life of cachectic patients. In this review, we summarize the metabolic mediators of cachexia, their molecular functions, affected organs especially with respect to muscle atrophy and adipose browning and then discuss advanced therapeutic approaches to cancer cachexia.
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Affiliation(s)
- Jawed A Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Mohd W Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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36
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Mckeaveney C, Noble H, de Barbieri I, Strini V, Maxwell AP, Reid J. Awareness, Understanding and Treatment Practices when Managing Cachexia in End-Stage Kidney Disease. J Ren Care 2019; 46:35-44. [PMID: 31642200 DOI: 10.1111/jorc.12301] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Cachexia is a wasting syndrome found within a range of chronic illnesses/life-limiting conditions, however awareness and understanding of cachexia amongst renal Health Care Professionals has not been investigated. OBJECTIVES To ascertain the awareness, understanding and treatment practices of Health Care Professionals who provide care for people with cachexia and end-stage renal disease. METHODS Health Care Professionals were recruited via the European Dialysis and Transplant Nurses Association/European Renal Care Association in September 2018. This was an exploratory study using a mixed-methods approach with those who provide care for patients with end-stage renal disease and cachexia. An online survey and two focus groups were conducted. Descriptive statistics and inductive thematic analysis were used to explore current knowledge and practices in renal cachexia. RESULTS A total of 93 participants from 30 countries completed the online survey. Twelve Health Care Professionals agreed to participate in the focus groups. Reduced appetite, weight loss and muscle loss in relation to cachexia were accurately described, but the percentage of weight loss was unknown. The importance of multi-professional collaboration was recognised, however, the current management of cachexia was wide-ranging. Quality of life, patient-clinician communication and specialist support for carers were regarded as vital. CONCLUSION Timely identification and management of cachexia are needed to improve the quality of life for patients and appropriately support families. In order for these goals to be achieved, there is a need to increase awareness and understanding of cachexia amongst renal nurses.
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Affiliation(s)
- Clare Mckeaveney
- School of Nursing and Midwifery, Queens University Belfast, Belfast, UK
| | - Helen Noble
- School of Nursing and Midwifery, Queens University Belfast, Belfast, UK
| | - Ilaria de Barbieri
- Healthcare Profession Department, Padua University Hospital, Padova, Italy
| | - Veronica Strini
- Clinical Research Unit, Padua University Hospital, Padova, Italy
| | - Alexander P Maxwell
- Regional Nephrology Unit, Belfast City Hospital, Belfast, UK.,Centre for Public Health, Queens University Belfast, Belfast, UK
| | - Joanne Reid
- School of Nursing and Midwifery, Queens University Belfast, Belfast, UK
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Bieliuniene E, Brøndum Frøkjær J, Pockevicius A, Kemesiene J, Lukosevicius S, Basevicius A, Atstupenaite V, Barauskas G, Ignatavicius P, Gulbinas A, Dambrauskas Z. CT- and MRI-Based Assessment of Body Composition and Pancreatic Fibrosis Reveals High Incidence of Clinically Significant Metabolic Changes That Affect the Quality of Life and Treatment Outcomes of Patients with Chronic Pancreatitis and Pancreatic Cancer. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:649. [PMID: 31569661 PMCID: PMC6843405 DOI: 10.3390/medicina55100649] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 12/16/2022]
Abstract
Background and Objectives: Both chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) may lead to cachexia, sarcopenia, and osteoporosis due to different mechanisms. Neither patient gender, age, nor body weight are good predictors of these metabolic changes having a significant negative impact on the quality of life (QOL) and treatment outcomes. The aim of this study was to evaluate radiological changes in body composition and to compare them with manifestations of exocrine and endocrine pancreatic insufficiency, body mass, and QOL among patients with CP and PDAC. Materials and Methods: Prospectively collected data of 100 patients with diagnosed CP or PDAC were used for analysis. All patients underwent dual-energy X-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging (MRI). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) was used to assess QOL. Diabetes and changes in fecal elastase-1 were also assessed. Results: There was no significant difference in skeletal muscle mass (SMM) among patients with CP and PDAC (p = 0.85). Significantly more underweight patients had low SMM (p = 0.002). Patients with CP had more pronounced pancreatic fibrosis (PF) (p < 0.001). Data showed a significant relationship between a high degree of PF and occurrence of diabetes (p = 0.006) and low fecal elastase-1 levels (p = 0.013). A statistically significant lower QOL was determined in patients with PF ≥ 50% and in the CP group. Conclusions: Sarcopenia and osteoporosis/osteopenia are highly prevalent among patients with chronic pancreatitis and pancreatic cancer, and CT- and MRI-based assessment of body composition and pancreatic fibrosis could be a potentially useful tool for routine detection of these significant metabolic changes.
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Affiliation(s)
- Edita Bieliuniene
- Department of Radiology, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (J.K.), (S.L.), (A.B.), (V.A.)
| | - Jens Brøndum Frøkjær
- Department of Radiology, Aalborg University Hospital, Aalborg 9000, Denmark;
- Department of Clinical Medicine, Aalborg University, Aalborg 9000, Denmark
| | - Alius Pockevicius
- Department of Veterinary Pathobiology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania;
| | - Jurate Kemesiene
- Department of Radiology, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (J.K.), (S.L.), (A.B.), (V.A.)
| | - Saulius Lukosevicius
- Department of Radiology, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (J.K.), (S.L.), (A.B.), (V.A.)
| | - Algidas Basevicius
- Department of Radiology, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (J.K.), (S.L.), (A.B.), (V.A.)
| | - Vaida Atstupenaite
- Department of Radiology, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (J.K.), (S.L.), (A.B.), (V.A.)
| | - Giedrius Barauskas
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (G.B.); (P.I.)
| | - Povilas Ignatavicius
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania; (G.B.); (P.I.)
| | - Antanas Gulbinas
- School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
| | - Zilvinas Dambrauskas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania;
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A leucine-rich diet modulates the mTOR cell signalling pathway in the gastrocnemius muscle under different Walker-256 tumour growth conditions. BMC Cancer 2019; 19:349. [PMID: 30975087 PMCID: PMC6458732 DOI: 10.1186/s12885-019-5448-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 03/07/2019] [Indexed: 12/13/2022] Open
Abstract
Background The exact signalling mechanism of the mTOR complex remains a subject of constant debate, even with some evidence that amino acids participate in the same pathway as used for insulin signalling during protein synthesis. Therefore, this work conducted further study of the actions of amino acids, especially leucine, in vivo, in an experimental model of cachexia. We analysed the effects of a leucine-rich diet on the signalling pathway of protein synthesis in muscle during a tumour growth time-course. Methods Wistar rats were distributed into groups based on Walker-256 tumour implant and subjected to a leucine-rich diet and euthanised at three different time points following tumour development (the 7th, 14th and 21st day). We assessed the mTOR pathway key-proteins in gastrocnemius muscle, such as RAG-A-GTPase, ERK/MAP4K3, PKB/Akt, mTOR, p70S6K1, Jnk, IRS-1, STAT3, and STAT6 comparing among the experimental groups. Serum WF (proteolysis-induced factor like from Walker-256 tumour) and muscle protein synthesis and degradation were assessed. Results The tumour-bearing group had increased serum WF content, and the skeletal-muscle showed a reduction in IRS-1 and RAG activation, increased PKB/Akt and Erk/MAP4K3 on the 21st day, and maintenance of p70S6K1, associated with increases in muscle STAT-3 and STAT-6 levels in these tumour-bearing rats. Conclusion Meanwhile, the leucine-rich diet modulated key steps of the mTOR pathway by triggering the increased activation of RAG and mTOR and maintaining JNK, STAT-3 and STAT-6 levels in muscle, leading to an increased muscle protein synthesis, reducing the degradation during tumour evolution in a host, minimising the cancer-induced damages in the cachectic state.
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Trantham L, Sikirica MV, Candrilli SD, Benson VS, Mohan D, Neil D, Joshi AV. Healthcare costs and utilization associated with muscle weakness diagnosis codes in patients with chronic obstructive pulmonary disease: a United States claims analysis. J Med Econ 2019; 22:319-327. [PMID: 30580639 DOI: 10.1080/13696998.2018.1563414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
AIMS Muscle weakness (MW)-attributable healthcare resource utilization (HCRU) and costs in patients with chronic obstructive pulmonary disease (COPD) have not been well-characterized in US insurance claims databases. The primary objective of this study was to estimate HCRU in patients with evidence of COPD with and without MW diagnosis codes. MATERIALS AND METHODS This retrospective analysis used the MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. Between January 2007 and March 2016, we identified patients aged ≥40 years with diagnosis codes for COPD (≥1 emergency department or inpatient claim or ≥2 outpatient claims within 1 year). The cohort was divided into patients with and without ≥1 MW diagnosis code. Propensity score matching was used to generate pairs of patients with and without MW (1:1). Multivariable regression analyses were used to estimate adjusted incremental costs and utilization attributable to the presence of MW diagnosis codes among patients with COPD. RESULTS Of 427,131 patients who met the study inclusion criteria, 14% had evidence of MW. After matching, 107,420 unique patients remained equally distributed across MW status. Patients with MW diagnosis codes had greater predicted annual HCRU, $2,465 greater total predicted annual COPD-related costs, and $15,179 greater total all-cause costs than those without MW diagnosis codes. Overall, <1% of patients received COPD-related pulmonary rehabilitation services. LIMITATIONS Study limitations include the potential for undercoding of MW and lack of information on severity of MW in claims data. CONCLUSION The presence of MW diagnosis codes yielded higher HCRU in this COPD population and suggests that the burden of MW affects both all-cause and COPD-related care. However, utilization of pulmonary rehabilitation, a known effective treatment for MW, remains low. Future research should expand on our results by assessing data sources that allow for clinical confirmation of MW among patients with COPD.
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Affiliation(s)
- Laurel Trantham
- a Health Economics, RTI Health Solutions , Research Triangle Park , NC , USA
| | - Mirko V Sikirica
- b Value Evidence and Outcomes , GlaxoSmithKline , Collegeville , PA , USA
| | - Sean D Candrilli
- a Health Economics, RTI Health Solutions , Research Triangle Park , NC , USA
| | - Victoria S Benson
- c Real World Evidence and Epidemiology, GlaxoSmithKline , West Drayton , Uxbridge , UK
| | - Divya Mohan
- d Research and Development, GlaxoSmithKline , Collegeville , PA , USA
| | - David Neil
- b Value Evidence and Outcomes , GlaxoSmithKline , Collegeville , PA , USA
| | - Ashish V Joshi
- b Value Evidence and Outcomes , GlaxoSmithKline , Collegeville , PA , USA
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40
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Impact of preoperative cachexia on postoperative length of stay in elderly patients with gastrointestinal cancer. Nutrition 2019; 58:65-68. [DOI: 10.1016/j.nut.2018.06.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 05/22/2018] [Accepted: 06/08/2018] [Indexed: 12/24/2022]
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Affiliation(s)
- Mitja Lainscak
- Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Giuseppe M C Rosano
- IRCCS San Raffaele Roma, St George's Hospital Medical School, University of London, UK
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42
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Anker MS, Holcomb R, Muscaritoli M, von Haehling S, Haverkamp W, Jatoi A, Morley JE, Strasser F, Landmesser U, Coats AJS, Anker SD. Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review. J Cachexia Sarcopenia Muscle 2019; 10:22-34. [PMID: 30920776 PMCID: PMC6438416 DOI: 10.1002/jcsm.12402] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/09/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Cachexia has significant impact on the patients' quality of life and prognosis. It is frequently observed in patients with cancer, especially in advanced stages, but prevalence data for the overall population are lacking. Good quality estimates of cancer cachexia in general and for each of the major cancer types would be highly relevant for potential treatment development efforts in this field. Both the USA and European Union (EU) have implemented special clinical development rules for such rare disorders what are called 'orphan diseases'. The cut-off level for a disease to be considered an orphan disease in the USA is 200 000 people (0.06% of the population) and EU is 5 per 10 000 people (0.05% of the population). METHODS For this systematic review, we searched at PubMed (from inception to 31 January 2018) to identify clinical studies that assessed the prevalence of cachexia in cancer patients at risk. Studies reporting the prevalence of either cancer cachexia or wasting disease in the top-10 cancer types and 4 other selected cancer types known to be particularly commonly complicated by cachexia were included in this analysis (i.e. prostate cancer, breast cancer, colorectal cancer, melanoma, endometrial cancer, thyroid cancer, urinary bladder cancer, non-hodgkin lymphoma, lung cancer, kidney and renal pelvis cancer, head and neck cancer, gastric cancer, liver cancer, and pancreatic cancer). We calculated the current burden of cancer cachexia, disease by disease, in the USA and in the EU and compared them to the current guidelines for the definition of orphan disease status. RESULTS We estimate that in 2014 in the USA, a total of 527 100 patients (16.5 subjects per 10 000 people of the total population), and in 2013 in the EU, a total of 800 300 patients (15.8 subjects per 10 000 people of the total population) suffered from cancer cachexia (of any kind). In the 14 separately analysed cancer types, the prevalence of cancer cachexia in the USA ranged between 11 300 (0.4/10 000, gastric cancer) and 92 000 patients (2.9/10 000, lung cancer) and in the EU between 14 300 (0.3/10 000, melanoma of the skin) and 150 100 (3.0/10 000, colorectal cancer). CONCLUSIONS The absolute number of patients affected by cancer cachexia in each cancer group is lower than the defined thresholds for orphan diseases in the USA and EU. Cancer cachexia in each subgroup separately should be considered an orphan disease.
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Affiliation(s)
- Markus S Anker
- Division of Cardiology and Metabolism, Department of Cardiology & Berlin-Brandenburg Center for Regenerative Therapies (BCRT), DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Charité-Universitätsmedizin Berlin (CVK), Berlin, Germany.,Department of Cardiology, Charité Campus Benjamin Franklin, Berlin, Germany
| | | | | | - Stephan von Haehling
- Department of Cardiology and Pneumology, DZHK (German Center for Cardiovascular Research), University of Göttingen Medical Center (UMG), Göttingen, Germany
| | - Wilhelm Haverkamp
- Department of Internal Medicine and Cardiology, Charité University Medicine, Berlin, Germany
| | | | - John E Morley
- Division of Geriatric Medicine, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Florian Strasser
- Oncological Palliative Medicine, Clinic Medical Oncology and Haematology, Department of Internal Medicine, Cantonal Hospital, St Gallen and Integrated Cancer Rehabilitation, Klinik Gais, Switzerland
| | - Ulf Landmesser
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin Institute of Health (BIH), Berlin, Germany.,Department of Cardiology Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Stefan D Anker
- Division of Cardiology and Metabolism, Department of Cardiology & Berlin-Brandenburg Center for Regenerative Therapies (BCRT), DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Charité-Universitätsmedizin Berlin (CVK), Berlin, Germany
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Counts BR, Fix DK, Hetzler KL, Carson JA. The Effect of Estradiol Administration on Muscle Mass Loss and Cachexia Progression in Female Apc Min/+ Mice. Front Endocrinol (Lausanne) 2019; 10:720. [PMID: 31736871 PMCID: PMC6838005 DOI: 10.3389/fendo.2019.00720] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 10/07/2019] [Indexed: 12/12/2022] Open
Abstract
Cancer cachexia is a multifactorial muscle wasting condition characterized by severe body weight and muscle mass loss which is secondary to chronic disease. The mechanistic examination of cachexia has predominately focused on the male phenotype and created significant gaps in understanding cachexia progression in the female. Female hypogonadism can accompany cancer cachexia and is characterized by reduced circulating 17ß-estradiol and uterine atrophy. Estrogen has known functions in skeletal muscle homeostasis involving the regulation of muscle protein turnover, cellular stressors, and oxidative metabolism. However, 17ß-estradiol's ability to regulate cachexia progression in the female is not known. The purpose of this study was to determine the effect of gonadal function and estradiol administration on muscle mass loss and cachexia progression in female Apc Min/+ mice. Methods: Female C57BL/6 (B6; N = 82) and Apc Min/+ (MIN; N = 88) mice were used in two separate experiments. In experiment 1, mice were sacrificed at either 12 (N = 20) or 20 (N = 41) weeks of age. Body weight and estrous cycle presence was determined weekly. In experiment 2, B6 and MIN mice were randomly allocated to: Control (N = 17), received E2 pellet (E2, N = 18), ovariectomy surgery (OVX; N = 19) or ovariectomy surgery with E2 pellet (OVX + E2; N = 21). 17ß-estradiol was administered through an implanted slow-releasing pellet (0.1 mg). In estrogen and ovariectomy experiments, food intake, and functional outcomes were recorded 1 week prior to sacrifice. Results: We report that E2 administration prevented body weight loss, muscle mass loss, cage inactivity, and grip strength loss associated with cachexia. In skeletal muscle, E2 reduced skeletal muscle AMPK phosphorylation, improved mTORC1 signaling, and prevented mitochondrial dysfunction. Conclusion: Our results demonstrate a role for 17ß-estradiol for the prevention of skeletal muscle mass loss in female tumor bearing mice. Furthermore, 17ß-estradiol prevented cachexia's disruption in skeletal muscle signaling involving AMPK and mTORC1, in addition to improving mitochondrial function in female tumor bearing mice.
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Affiliation(s)
- Brittany R. Counts
- Integrative Muscle Biology Laboratory, Division of Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Dennis K. Fix
- Department of Exercise Science, University of South Carolina, Columbia, SC, United States
| | - Kimbell L. Hetzler
- Department of Exercise Science, University of South Carolina, Columbia, SC, United States
| | - James A. Carson
- Integrative Muscle Biology Laboratory, Division of Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN, United States
- *Correspondence: James A. Carson
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Khan S, Shahzadi A. Clinical pharmacokinetics of drugs in cardiopulmonary associated cachexia without hepatorenal pathology: a systematic review. Drug Metab Rev 2018; 51:1-11. [PMID: 30449195 DOI: 10.1080/03602532.2018.1508226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Cachexia not only has a dramatically harmful impact on a patient's life, but also a poor response to therapeutic agents. The purpose of the present review is to provide updated information concerning the pharmacokinetic aspects of drugs used to treat cardiopulmonary cachexia in patients with no signs of hepatic or renal pathology. A systematic search of PubMed, the Cochrane Central Register of Control Trials, Science Direct, and Clinical Trials Registry (ClinicalTrials.gov), encompassing the period between 2000 and 2017, was conducted in accordance to PRISMA guidelines. Seven studies were identified. Collectively, these studies included a total of 196 individuals (19 healthy subjects and 177 diseased patients). This data review found no differences in bisoprolol and prothionamide absorption in cachectic patients with chronic heart failure and tuberculosis, but higher absorption of oflaxocin in the same set of patients was observed. The distribution of bisoprolol, prothionmaide, ceftazidime, and cefipirome was reduced in cardiopulmonary cachexia patients. Hepatic clearance of rifampin was equivalent in cachectic and non-cachectic patients that had normal hepatic function. Similarly in cardiopulmonary cachexia patients, renal clearance of ceftazidime was reduced by 19% but no significant differences in bisorpolol and prothionamide clearance were observed. In the case of cefipirome, both renal clearance and creatinine clearance were higher in cachectic patients with cystic fibrosis. From the limited evidence available, the main drug pharmacokinetic changes seen in cardiopulmonary cachexia patients were a reduction in the volume of distribution and impairment of clearance.
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Affiliation(s)
- Safeer Khan
- a Al-Taaluf National Group of Polyclinics , Alqunfdha , Makkah , Kingdom of Saudi Arabia
| | - Anum Shahzadi
- b Department of Pharmacy , COMSATS Institute of Information Technology (CIIT) , Khyber Pakhtun Khwa , Abbottabad , Pakistan
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45
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Emerging role of extracellular vesicles in mediating cancer cachexia. Biochem Soc Trans 2018; 46:1129-1136. [PMID: 30242118 DOI: 10.1042/bst20180213] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/23/2018] [Accepted: 08/23/2018] [Indexed: 12/19/2022]
Abstract
Cancer cachexia is a multifactorial metabolic syndrome characterized by the rapid loss of skeletal muscle mass with or without the loss of fat mass. Nearly 50-80% of all cancer patients' experience rapid weight loss results in ∼20% of cancer-related deaths. The levels of pro-inflammatory and pro-cachectic factors were significantly up-regulated in cachexia patients when compared with the patients who were without cachexia. It is becoming evident that these factors work synergistically to induce cancer cachexia. Extracellular vesicles (EVs) including exosomes and microvesicles are implicated in cell-cell communication, immune response, tissue repair, epigenetic regulation, and in various diseases including cancer. It has been reported that these EVs regulate cancer progression, metastasis, organotropism and chemoresistance. In recent times, the role of EVs in regulating cancer cachexia is beginning to unravel. The aim of this mini article is to review the recent knowledge gained in the field of EVs and cancer cachexia. Specifically, the role of tumour cell-derived EVs in promoting catabolism in distally located skeletal muscles and adipose tissue will be discussed.
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Off-Label Megestrol in Patients with Anorexia-Cachexia Syndrome Associated with Malignancy and Its Treatments. Am J Med 2018; 131:623-629.e1. [PMID: 29784194 DOI: 10.1016/j.amjmed.2017.12.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Accepted: 12/11/2017] [Indexed: 11/23/2022]
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Lee JY, Hong N, Kim HR, Lee BW, Kang ES, Cha BS, Lee YH. Effects of Serum Albumin, Calcium Levels, Cancer Stage and Performance Status on Weight Loss in Parathyroid Hormone-Related Peptide Positive or Negative Patients with Cancer. Endocrinol Metab (Seoul) 2018; 33:97-104. [PMID: 29589391 PMCID: PMC5874202 DOI: 10.3803/enm.2018.33.1.97] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/15/2018] [Accepted: 01/30/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND A recent animal study showed that parathyroid hormone-related peptide (PTHrP) is associated with cancer cachexia by promoting adipose tissue browning, and we previously demonstrated that PTHrP predicts weight loss (WL) in patients with cancer. In this study, we investigated whether prediction of WL by PTHrP is influenced by clinical factors such as serum albumin, corrected calcium levels, cancer stage, and performance status (PS). METHODS A cohort of 219 patients with cancer whose PTHrP level was measured was enrolled and followed for body weight (BW) changes. Subjects were divided into two groups by serum albumin (cutoff value, 3.7 g/dL), corrected calcium (cutoff value, 10.5 mg/dL), cancer stage (stage 1 to 3 or 4), or PS (Eastern Cooperative Oncology Group 0 to 1 or 2 to 4), respectively. Clinically significant WL was defined as either percent of BW change (% BW) <-5% or % BW <-2% plus body mass index (BMI) <20 kg/m². RESULTS After a median follow-up of 327 days, 74 patients (33.8%) experienced clinically significant WL. A positive PTHrP level was associated with a 2-fold increased risk of WL after adjusting for age, baseline BMI, serum albumin, corrected calcium level, cancer stage, and PS. The effect of PTHrP on WL remained significant in patients with low serum albumin, stage 4 cancer, and good PS. Regardless of calcium level, the effect of PTHrP on WL was maintained, although there was an additive effect of higher calcium and PTHrP levels. CONCLUSION Early recognition of patients with advanced cancer who are PTHrP positive with hypercalcemia or hypoalbuminemia is needed for their clinical management.
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Affiliation(s)
- Ji Yeon Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Namki Hong
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Ryun Kim
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Cancer Center, Seoul, Korea
| | - Byung Wan Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Bong Soo Cha
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Ho Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea.
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Kostyukevich OI, Sviridov SV, Rylova AK, Rylova NV, Korsunskaya MI, Kolesnikova EA. [Malnutrition: from pathogenesis to current methods for diagnosis and treatment]. TERAPEVT ARKH 2018; 89:216-225. [PMID: 29488484 DOI: 10.17116/terarkh20178912216-225] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Progressive weight loss is a frequent companion to somatic pathology. The risk of death is known to increase dramatically among those with a body mass index of less than 19 kg/m2. Even mild weight loss in the presence of severe diseases can have a substantial impact on the course of the disease. The paper presents current views on malnutrition, its prevalence in the presence of various somatic diseases, and clinical significance. It describes the basic pathogenetic components of weight loss and the possible ways of correcting nutritional status. Particular emphasis is placed on the methods of nutritional support that is currently regarded as one of the most important components of a comprehensive approach to treating patients with chronic diseases. The authors give recommendations for the assessment of the nutritional status of patients in clinical practice and algorithms for their malnutrition management.
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Affiliation(s)
- O I Kostyukevich
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
| | - S V Sviridov
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
| | - A K Rylova
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
| | - N V Rylova
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
| | - M I Korsunskaya
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
| | - E A Kolesnikova
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
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Naito T, Okayama T, Aoyama T, Ohashi T, Masuda Y, Kimura M, Shiozaki H, Murakami H, Kenmotsu H, Taira T, Ono A, Wakuda K, Imai H, Oyakawa T, Ishii T, Omori S, Nakashima K, Endo M, Omae K, Mori K, Yamamoto N, Tanuma A, Takahashi T. Unfavorable impact of cancer cachexia on activity of daily living and need for inpatient care in elderly patients with advanced non-small-cell lung cancer in Japan: a prospective longitudinal observational study. BMC Cancer 2017; 17:800. [PMID: 29183277 PMCID: PMC5706408 DOI: 10.1186/s12885-017-3795-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 11/17/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cancer cachexia in elderly patients may substantially impact physical function and medical dependency. The aim of this study was to estimate the impact of cachexia on activity of daily living (ADL), length of hospital stay, and inpatient medical costs among elderly patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy. METHODS Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to receive first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. ADL was assessed using the Barthel index. The disability-free survival time (DFS) was calculated as the time between the date of study entry and the date of onset of a disabling event, which was defined as a 10-point decrease in the Barthel index from that at baseline. The mean cumulative function of the length of hospital stay and inpatient medical costs (¥, Japanese yen) was calculated. RESULTS The study patients comprised 11 women and 19 men, with a median age of 74 (range, 70-82) years. Cachexia was diagnosed in 19 (63%) patients. Cachectic patients had a shorter DFS (7.5 vs. 17.1 months, p < 0.05). During the first year from study entry, cachectic patients had longer cumulative lengths of hospital stay (80.7 vs. 38.5 days/person, p < 0.05), more frequent unplanned hospital visits or hospitalizations (4.2 vs. 1.7 times/person, p < 0.05), and higher inpatient medical costs (¥3.5 vs. ¥2.1 million/person, p < 0.05) than non-cachectic patients. CONCLUSIONS Elderly NSCLC patients with cachexia showed higher risks for disability, prolonged hospitalizations, and higher inpatient medical costs while receiving chemotherapy than patients without cachexia. Our results might indicate that there is a potential need for an early intervention to minimize progression to or development of cachexia, improve functional prognosis, and reduce healthcare resource burden in this population. TRIAL REGISTRATION Trial registration number: UMIN000009768 . Name of registry: UMIN (University hospital Medical Information Network). Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.
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Affiliation(s)
- Tateaki Naito
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
| | - Taro Okayama
- Division of Rehabilitation Medicine, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Takashi Aoyama
- Division of Nutrition, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Takuya Ohashi
- Division of Rehabilitation Medicine, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.,Division of Physical Medicine and Rehabilitation, Shizuoka General Hospital, 4-27-1 Kita Ando Aoi-ku, Shizuoka, 420-8527, Japan
| | - Yoshiyuki Masuda
- Division of Rehabilitation Medicine, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Madoka Kimura
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.,Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Tosei-ku, Osaka, 537-8511, Japan
| | - Hitomi Shiozaki
- Division of Nutrition, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Haruyasu Murakami
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Hirotsugu Kenmotsu
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Tetsuhiko Taira
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Akira Ono
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Kazushige Wakuda
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Hisao Imai
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.,Division of Respiratory Medicine, Gunma Prefectural Cancer Center, 617-1 Takabayashi-nishi-machi, Ohta-shi, Gunma, 373-8550, Japan
| | - Takuya Oyakawa
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.,Division of Cardiology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Takeshi Ishii
- Division of Rehabilitation Medicine, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Shota Omori
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Kazuhisa Nakashima
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Masahiro Endo
- Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Katsuhiro Omae
- Clinical Research Center, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Keita Mori
- Clinical Research Center, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Nobuyuki Yamamoto
- Third Department of Internal Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8509, Japan
| | - Akira Tanuma
- Division of Rehabilitation Medicine, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Toshiaki Takahashi
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
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50
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Garcia JM, Shamliyan TA. Omega-3 Fatty Acids in Patients with Anorexia-Cachexia Syndrome Associated with Malignancy and Its Treatments. Am J Med 2017; 130:1151-1155. [PMID: 29016347 DOI: 10.1016/j.amjmed.2017.03.066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 11/18/2022]
Affiliation(s)
- Jose M Garcia
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Wash
| | - Tatyana A Shamliyan
- Quality Assurance, Evidence-Based Medicine Center Elsevier, Philadelphia, Pa.
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