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Background Evidence regarding the efficacy of nutritional supplementation to enhance exercise training responses in COPD patients with low muscle mass is limited. The objective was to study if nutritional supplementation targeting muscle derangements enhances outcome of exercise training in COPD patients with low muscle mass. Methods Eighty‐one COPD patients with low muscle mass, admitted to out‐patient pulmonary rehabilitation, randomly received oral nutritional supplementation, enriched with leucine, vitamin D, and omega‐3 fatty acids (NUTRITION) or PLACEBO as adjunct to 4 months supervised high intensity exercise training. Results The study population (51% males, aged 43–80) showed moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. Intention‐to‐treat analysis revealed significant differences after 4 months favouring NUTRITION for body mass (mean difference ± SEM) (+1.5 ± 0.6 kg, P = 0.01), plasma vitamin D (+24%, P = 0.004), eicosapentaenoic acid (+91%,P < 0.001), docosahexaenoic acid (+31%, P < 0.001), and steps/day (+24%, P = 0.048). After 4 months, both groups improved skeletal muscle mass (+0.4 ± 0.1 kg, P < 0.001), quadriceps muscle strength (+12.3 ± 2.3 Nm,P < 0.001), and cycle endurance time (+191.4 ± 34.3 s, P < 0.001). Inspiratory muscle strength only improved in NUTRITION (+0.5 ± 0.1 kPa, P = 0.001) and steps/day declined in PLACEBO (−18%,P = 0.005). Conclusions High intensity exercise training is effective in improving lower limb muscle strength and exercise performance in COPD patients with low muscle mass and moderate airflow obstruction. Specific nutritional supplementation had additional effects on nutritional status, inspiratory muscle strength, and physical activity compared with placebo.

Background Assessment of handgrip strength and fat‐free mass provides quick and objective information on muscle performance and mass that might complement subjective World Health Organization Performance Status (WHO PS). We investigated to what extent the presence of pre‐treatment handgrip weakness and low fat‐free mass index (FFMI) provides additional prognostic information on top of well‐established prognostic factors (including WHO PS) in non‐small cell lung cancer (NSCLC) patients selected for curative‐intent (chemo)radiation. Methods Prospectively, patients with early and locally advanced NSCLC (stages I‐III) treated with (chemo)radiation were enrolled. Handgrip weakness and low FFMI, derived from bioelectrical impedance analysis, were defined using normative values and were correlated with overall survival (OS). Results We included 936 patients (age 68 ± 10 years; 64% male; 19% stage I, 9% stage II, and 72% stage III disease; 26% handgrip weakness; 27% low FFMI). In patients with good performance status (WHO PS 0 or 1), handgrip weakness and low FFMI were significant prognostic factors for OS, after adjustment for age, gender, disease stage, and co‐morbidities. The combined presence of handgrip weakness and low FFMI was a strong prognostic factor for OS when compared with patients with normal handgrip strength and FFMI (hazard ratio: 1.79, 95% confidence interval: 1.34–2.40, P < 0.0001). In patients with impaired performance status (WHO PS ≥ 2, 19% of sample), handgrip weakness and low FFMI were not related to OS. Conclusions In early and locally advanced NSCLC patients treated with curative‐intent (chemo)radiation who have good WHO PS, patients with combined handgrip weakness and low FFMI have the worst prognosis.

Cachexia is a syndrome characterized by involuntary weight loss and wasting of skeletal muscle mass. It is associated with worse overall survival and quality of life. The cancer‐induced systemic inflammation and the consequent host derived catabolic stimuli, trigger cachexia by inhibiting muscle protein synthesis and enhancing muscle catabolism. The muscle itself may further promote chronic inflammation, introducing a vicious catabolic circle. Nutritional support alone plays a limited role in the treatment of cancer cachexia and should be combined with other interventions. Physical exercise lowers systemic inflammation and promotes muscle anabolism. It also attenuates the age‐related physical decline in elderly and it might counteract the muscle wasting induced by the cancer cachexia syndrome. This review describes how cancer‐induced systemic inflammation promotes muscle wasting and whether physical exercise may represent a suitable treatment for cancer‐induced cachexia, particularly in patients with non‐small cell lung cancer. We summarized pre‐clinical and clinical studies investigating whether physical exercise would improve muscle performance and whether this improvement would translate in a clinically meaningful benefit for patients with cancer, in terms of survival and quality of life. Moreover, this review describes the results of studies investigating the interplay between physical exercise and the immune system, including the role of the intestinal microbiota.

Background It is not well known to what extent effectiveness of treatment with immune checkpoint inhibitors in stage IV non‐small‐cell lung cancer (NSCLC) is influenced by weight loss and changes in body composition. Therefore, the goal of this study was to evaluate body composition changes in relation to early weight change and overall survival (OS) in stage IV NSCLC patients treated with second‐line nivolumab. Methods All patients with stage IV NSCLC, who were treated with second‐line nivolumab between June 2015 and December 2018 at Maastricht University Medical Center, were evaluated. Skeletal muscle mass (SMM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were assessed at the first lumbar level on computed tomography images obtained before initiation of nivolumab and at week 6 of treatment. The contribution of changes in body weight (defined as >2% loss), SMM, VAT, and SAT to OS was analysed by Kaplan–Meier method and adjusted for clinical confounders in a Cox regression analysis. The results from the study cohort were validated in another Dutch cohort from Erasmus Medical Center, Rotterdam. Results One hundred and six patients were included in the study cohort. Loss of body weight of >2% at week 6 was an independent predictor for poor OS (hazard ratio 2.39, 95% confidence interval 1.51–3.79, P < 0.001) when adjusted for gender, >1 organ with metastasis, pretreatment hypoalbumenaemia, and pretreatment elevated C‐reactive protein. The result was confirmed in the validation cohort (N = 62). Loss of SMM as a feature of cancer cachexia did not significantly predict OS in both cohorts. Significant (>2%) weight loss during treatment was reflected by a significant loss of VAT and SAT, while loss of SMM was comparable between weight‐stable and weight‐losing patients. Conclusions Weight loss, characterized by loss of subcutaneous and visceral adipose tissues, at week 6 of treatment with nivolumab, is a significant poor prognostic factor for survival in patients with Stage IV NSCLC.

Introduction Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour‐bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle‐specific alterations associated with human lung cancer cachexia. Methods Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour‐bearing group. Syngeneic lung epithelium‐derived adenocarcinoma cells (K‐rasG12D; p53R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis. Results Two‐third of the tumour‐bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; P < 0.01), muscle mass (−13.8 ± 8.1%; P < 0.01) and muscle strength (−25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post‐surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy‐lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E‐BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin‐2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia. Conclusions We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.

Background Pulmonary rehabilitation (PR) is a cornerstone in the management of chronic obstructive pulmonary disease (COPD), targeting skeletal muscle to improve functional performance. However, there is substantial inter‐individual variability in the effect of PR on functional performance, which cannot be fully accounted for by generic phenotypic factors. We performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients and comprehensively characterized their baseline pulmonary and physical function, body composition, blood profile, comorbidities, and medication use. Methods Musculus vastus lateralis biopsies were obtained from 51 COPD patients (age 64 ± 1 years, sex 73% men, FEV1, 34 (26–41) %pred.) before and after 4 weeks high‐intensity supervised in‐patient PR. Muscle molecular markers were grouped by network‐constrained clustering, and their relative changes in expression values—assessed by qPCR and western blot—were reduced to process scores by principal component analysis. Patients were subsequently clustered based on these process scores. Pre‐PR and post‐PR functional performance was assessed by incremental cycle ergometry and 6 min walking test (6MWT). Results Eight molecular processes were discerned by network‐constrained hierarchical clustering of the skeletal muscle molecular rehabilitation responses. Based on the resulting process scores, four clusters of patients were identified by hierarchical cluster analysis. Two major patient clusters differed in PR‐induced autophagy (P < 0.001), myogenesis (P = 0.014), glucocorticoid signalling (P < 0.001), and oxidative metabolism regulation (P < 0.001), with Cluster 1 (C1; n = 29) overall displaying a more pronounced change in marker expression than Cluster 2 (C2; n = 16). General baseline characteristics did not differ between clusters. Following PR, both 6 min walking distance (+26.5 ± 8.3 m, P = 0.003) and peak load on the cycle ergometer test (+9.7 ± 1.9 W, P < 0.001) were improved. However, the functional improvement was more pronounced in C1, as a higher percentage of patients exceeded the minimal clinically important difference in peak workload (61 vs. 21%, P = 0.022) and both peak workload and 6 min walking test (52 vs. 8%, P = 0.008) upon PR. Conclusions We identified patient groups with distinct skeletal muscle molecular responses to rehabilitation, associated with differences in functional improvements upon PR.

A prematurely aged phenotype is a common characteristic of chronic kidney disease (CKD) and other chronic organ diseases, including heart failure and rheumatoid arthritis. In this opinion article, the authors suggest four major pathophysiological mechanisms that may underlie premature ageing in CKD. Chronic kidney disease (CKD) shares many phenotypic similarities with other chronic diseases, including heart failure, chronic obstructive pulmonary disease, HIV infection and rheumatoid arthritis. The most apparent similarity is premature ageing, involving accelerated vascular disease and muscle wasting. We propose that in addition to a sedentary lifestyle and psychosocial and socioeconomic determinants, four major disease-induced mechanisms underlie premature ageing in CKD: an increase in allostatic load, activation of the 'stress resistance response', activation of age-promoting mechanisms and impairment of anti-ageing pathways. The most effective current interventions to modulate premature ageing—treatment of the underlying disease, optimal nutrition, correction of the internal environment and exercise training—reduce systemic inflammation and oxidative stress and induce muscle anabolism. Deeper mechanistic insight into the phenomena of premature ageing as well as early diagnosis of CKD might improve the application and efficacy of these interventions and provide novel leads to combat muscle wasting and vascular impairment in chronic diseases.

The term sarcopenia was introduced in 1988. The original definition was a “muscle loss” of the appendicular muscle mass in the older people as measured by dual energy x‐ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC‐F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease‐related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age‐related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age‐related and disease‐related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life‐long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.

The objective of this study was to derive food-based dietary guidelines for the Dutch population. The dietary guidelines are based on 29 systematic reviews of English language meta-analyses in PubMed summarizing randomized controlled trials and prospective cohort studies on nutrients, foods and food patterns and the risk of 10 major chronic diseases: coronary heart disease, stroke, heart failure, diabetes, breast cancer, colorectal cancer, lung cancer, chronic obstructive pulmonary disease, dementia and depression. The committee also selected three causal risk factors for cardiovascular diseases or diabetes: systolic blood pressure, low-density lipoprotein cholesterol and body weight. Findings were categorized as strong or weak evidence, inconsistent effects, too little evidence or effect unlikely for experimental and observational data separately. Next, the committee selected only findings with a strong level of evidence for deriving the guidelines. Convincing evidence was based on strong evidence from the experimental data either or not in combination with strong evidence from prospective cohort studies. Plausible evidence was based on strong evidence from prospective cohort studies only. A general guideline to eat a more plant food-based dietary pattern and limit consumption of animal-based food and 15 specific guidelines have been formulated. There are 10 new guidelines on legumes, nuts, meat, dairy produce, cereal products, fats and oils, tea, coffee and sugar-containing beverages. Three guidelines on vegetables, fruits, fish and alcoholic beverages have been sharpened, and the 2006 guideline on salt stayed the same. A separate guideline has been formulated on nutrient supplements. Completely food-based dietary guidelines can be derived in a systematic and transparent way.