Efficacy of Anamorelin, a novel non-peptide ghrelin analogue, in patients with advanced non-small cell lung cancer (NSCLC) and Cachexia—Review and expert opinion

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Cancer cachexia is a multilayered syndrome consisting of the interaction between tumor cells and the host, at times modulated by the pharmacologic treatments used for tumor control. Key cellular and soluble mediators, activated because of this interaction, induce metabolic and nutritional alterations. This results in mass and functional changes systemically, and can lead to increased morbidity and reduced length and quality of life. For most solid malignancies, a cure remains an unrealistic goal, and targeting the key mediators is ineffective because of their heterogeneity/redundancy. The most beneficial approach is to target underlying systemic mechanisms, an approach where the novel non-peptide ghrelin analogue anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain. In the ROMANA studies, compared with placebo, anamorelin significantly increased lean body mass in non-small cell lung cancer (NSCLC) patients. Body composition analysis suggested that anamorelin is an active anabolic agent in patients with NSCLC, without the side effects of other anabolic drugs. Anamorelin also induced a significant and meaningful improvement of anorexia/cachexia symptoms. The ROMANA trials have provided unprecedented knowledge, highlighting the therapeutic effects of anamorelin as an initial, but significant, step toward directly managing cancer cachexia

Metabolic reprogramming promotes myogenesis during aging

Sarcopenia is the age-related progressive loss of skeletal muscle mass and strength finally leading to poor physical performance. Impaired myogenesis contributes to the pathogenesis of sarcopenia, while mitochondrial dysfunctions are thought to play a primary role in skeletal muscle loss during aging. Here we studied the link between myogenesis and metabolism. In particular, we analyzed the effect of the metabolic modulator trimetazidine (TMZ) on myogenesis in aging. We show that reprogramming the metabolism by TMZ treatment for 12 consecutive days stimulates myogenic gene expression in skeletal muscle of 22-month-old mice. Our data also reveal that TMZ increases the levels of mitochondrial proteins and stimulates the oxidative metabolism in aged muscles, this finding being in line with our previous observations in cachectic mice. Moreover, we show that, besides TMZ also other types of metabolic modulators (i.e., 5-Aminoimidazole-4-Carboxamide Ribofuranoside-AICAR) can stimulate differentiation of skeletal muscle progenitors in vitro. Overall, our results reveal that reprogramming the metabolism stimulates myogenesis while triggering mitochondrial proteins synthesis in vivo during aging. Together with the previously reported ability of TMZ to increase muscle strength in aged mice, these new data suggest an interesting non-invasive therapeutic strategy which could contribute to improving muscle quality and neuromuscular communication in the elderly, and counteracting sarcopenia

What are the risk factors for malnutrition in older-aged institutionalized adults?

Malnutrition is common in older adults and is associated with functional impairment, reduced quality of life, and increased morbidity and mortality. The aim of this study was to explore the association between health (including depression), physical functioning, disability and cognitive decline, and risk of malnutrition. Participants were recruited from nursing homes in Italy and completed a detailed multidimensional geriatric evaluation. All the data analyses were completed using Stata Version 15.1. The study included 246 participants with an age range of 50 to 102 (80.4 ± 10.5). The sample was characterised by a high degree of cognitive and functional impairment, disability, and poor health and nutritional status (according to Mini Nutritional Assessment (MNA), 38.2% were at risk for malnutrition and 19.5% were malnourished). Using a stepwise linear regression model, age (B = −0.043, SE = 0.016, p = 0.010), depression (B = −0.133, SE = 0.052, p = 0.011), disability (B = 0.517, SE = 0.068, p < 0.001), and physical performance (B = −0.191, SE = 0.095, p = 0.045) remained significantly associated with the malnutrition risk in the final model (adjusted R-squared = 0.298). The logistic regression model incorporating age, depression, disability, and physical performance was found to have high discriminative accuracy (AUC = 0.747; 95%CI: 0.686 to 0.808) for predicting the risk of malnutrition. The results of the study confirm the need to assess nutritional status and to investigate the presence of risk factors associated with malnutrition in order to achieve effective prevention and plan a better intervention strategy

Effect of the specific proteasome inhibitor Bortezomib on cancer-related muscle wasting

Background: Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia. Methods: Cancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH-130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH-130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26-bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF-κB and proteasome activation, MuRF1 and atrogin-1 mRNA expression and beclin-1 protein levels were evaluated in the gastrocnemius of controls and AH-130 hosts. Results: Bortezomib administration in the AH-130 hosts, although able to reduce proteasome and NF-κB DNA-binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF-κB DNA-binding activity in the AH-130 hosts 3 days after tumour transplantation. Beclin-1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH-130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour-bearing animals. Regarding C26-bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation. Conclusions: The results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia. © 2015 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society of Sarcopenia, Cachexia and Wasting Disorder

clinical impact of whey protein and nutritional counseling in gastrointestinal cancer patients

n/

Kidney dysfunction is associated with adverse outcomes in internal medicine COVID-19 hospitalized patients

OBJECTIVE: In this study, we aimed to evaluate the kidney involvement as-sessed by estimated glomerular filtration rate (eGFR), the associations with specific clinical disease variables and laboratory findings, and the predictive role of eGFR on clinical outcomes of patients admitted with COVID-19 in Internal Medicine ward in the first wave. PATIENTS AND METHODS: Clinical data of 162 consecutive patients hospitalized in the University Hospital Policlinico Umberto I in Rome, Italy, between December 2020 to May 2021 were collected and retrospectively analyzed. RESULTS: The median eGFR was significantly lower in patients with worse outcomes than in patients with favorable outcomes [56.64 ml/min/1.73 m2 (IQR 32.27-89.73) vs. 83.39 ml/min/1.73 m2 (IQR 69.59-97.08), p<0.001]. Patients with eGFR < 60 ml/ min/1.73 m(2) (n=38) were significantly older com-pared to patients with normal eGFR [82 years (IQR 74-90) vs. 61 years (IQR 53-74), p<0.001] and they had fever less frequently [39.5% vs. 64.2%, p<0.01]. Kaplan-Meier curves demonstrated that over-all survival was significantly shorter in patients with eGFR < 60 ml/min/1.73 m(2) (p<0.001). In mul-tivariate analysis, only eGFR < 60 ml/min/1.73 m2 [HR=2.915 (95% CI=1.110-7.659), p<0.05] and plate-let to lymphocyte ratio [HR=1.004 (95% CI=1.002-1.007), p<0.01] showed a significant predictive val-ue for death or transfer to intensive care unit (ICU). CONCLUSIONS: Kidney involvement on ad-mission was an independent predictor for death or transfer to ICU among hospitalized COVID-19 patients. The presence of chronic kidney dis-ease could be regarded as a relevant factor in risk stratification for COVID-19

MuRF-1 and p-GSK3β expression in muscle atrophy of liver cirrhosis

Background: Chronic diseases, including cirrhosis, are often accompanied by protein-energy malnutrition and muscle loss, which in turn negatively affect quality of life, morbidity and mortality. Unlike other chronic conditions, few data are available on the molecular mechanisms underlying muscle wasting in this clinical setting. Aims: To assess mechanisms of muscle atrophy in patients with cirrhosis. Methods: Nutritional [subjective global assessment (SGA) and anthropometry] and metabolic assessment was performed in 30 cirrhotic patients awaiting liver transplantation. Rectus abdominis biopsies were obtained intraoperatively in 22 cirrhotic patients and in 10 well-nourished subjects undergoing elective surgery for non-neoplastic disease, as a control group. Total RNA was extracted and mRNA for atrogenes (MuRF-1, Atrogin-1/MAFbx), myostatin (MSTN), GSK3β and IGF-1 was assayed. Results: A total of 50% of cirrhotic patients were malnourished based on SGA, while 53% were muscle-depleted according to mid-arm muscle area (MAMA<5th percentile). MuRF-1 RNA expression was significantly increased in malnourished cirrhotic patients (SGA-B/C) vs. well-nourished patients (SGA-A) (P = 0.01). The phosphorylation of GSK3β was up-regulated in cirrhotic patients with hepatocellular carcinoma (HCC) vs. patients without tumour (P < 0.05). Conclusions: Muscle loss is frequently found in end-stage liver disease patients. Molecular factors pertaining to signalling pathways known to be involved in the regulation of muscle mass are altered during cirrhosis and HCC. © 2013 John Wiley & Sons A/S