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1.
Beta-hydroxy beta-methylbutyrate/arginine/glutamine (HMB/Arg/Gln) supplementation to improve the management of cachexia in patients with advanced lung cancer: an open-label, multicentre, randomised, controlled phase II trial (NOURISH).
Pascoe, J, Jackson, A, Gaskell, C, Gaunt, C, Thompson, J, Billingham, L, Steven, N
BMC cancer. 2021;(1):800
Abstract
BACKGROUND Cancer cachexia causes significant morbidity and mortality in advanced lung cancer patients. Clinical benefit of β-hydroxy-β-methylbutyrate, arginine, and glutamine (HMB/Arg/Gln) was assessed in newly diagnosed patients. METHODS NOURISH, a prospective, two-arm, open-label, multi-centre, randomised controlled phase II trial compared cachexia in patients who received HMB/Arg/Gln with those who did not. All patients received structured nutritional, exercise and symptom control via a Macmillan Durham Cachexia Pack. Conducted in five UK centres, patients aged > 18 years, with newly diagnosed advanced small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), who were able to take oral nutrition, with a performance status of 0-to-2 and a life expectancy > 4 months were eligible for trial entry. Patients suitable for treatment with curative intent were ineligible. The trial was designed as a signal-seeking pilot study with target recruitment of 96 patients. One-to-one randomisation was stratified by diagnosis (SCLC or NSCLC), stage of disease (locally advanced or metastatic) and performance status. The primary outcome measure was treatment success defined as a patient being alive without significant loss of lean body mass (not > 5%) by 12 weeks. Secondary outcome measures included quality of life. RESULTS Between February-2012 and February-2013, 38 patients were recruited, 19 to each arm. Baseline characteristics were balanced. The trial was halted due to slow accrual and partial adherence. Trial data demonstrated no evidence of treatment benefit. No serious adverse events were reported during the trial. CONCLUSIONS Further evaluation of HMB/Arg/Gln in this setting could not be recommended on the basis of this trial. CLINICAL TRIAL REGISTRATION ISRCTN registry: 39911673; 14-Apr-2011 https://doi.org/10.1186/ISRCTN39911673 .
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2.
Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives.
Cortez, NE, Mackenzie, GG
Nutrients. 2021;(9)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs' potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.
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3.
Role of Cachexia and Fragility in the Patient Candidate for Cardiac Surgery.
Pisano, C, Polisano, D, Balistreri, CR, Altieri, C, Nardi, P, Bertoldo, F, Trombetti, D, Asta, L, Ferrante, MS, Buioni, D, et al
Nutrients. 2021;(2)
Abstract
Frailty is the major expression of accelerated aging and describes a decreased resistance to stressors, and consequently an increased vulnerability to additional diseases in elderly people. The vascular aging related to frail phenotype reflects the high susceptibility for cardiovascular diseases and negative postoperative outcomes after cardiac surgery. Sarcopenia can be considered a biological substrate of physical frailty. Malnutrition and physical inactivity play a key role in the pathogenesis of sarcopenia. We searched on Medline (PubMed) and Scopus for relevant literature published over the last 10 years and analyzed the strong correlation between frailty, sarcopenia and cardiovascular diseases in elderly patient. In our opinion, a right food intake and moderate intensity resistance exercise are mandatory in order to better prepare patients undergoing cardiac operation.
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4.
Nutrition and gastroenterological support in end of life care.
Schütte, K, Middelberg-Bisping, K, Schulz, C
Best practice & research. Clinical gastroenterology. 2020;:101692
Abstract
Malnutrition and the broad spectrum of cancer cachexia frequently occur in patients with malignant disease of all tumour stages and impact on survival and quality of life of patients. Structured screening for the risk of malnutrition with validated tools and nutritional assessment are the prerequisite for adequate nutritional support in cancer patients. In patients receiving tumour directed therapy, the patients diet should meet the requirements to give optimal support, while later on comfort feeding is part of symptom focused palliation. The basis of nutritional support in a malnourished patient is nutritional counselling, and nutritional support can be offered within a step-up approach meeting the patient's needs. A combination of nutritional support with interventions targeting metabolic changes and physical exercise is suggested to treat cancer cachexia.
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5.
Effects of Protein-Energy Wasting (PEW) and hyperphosphatemia on the prognosis in Japanese maintenance hemodialysis patients: A five-year follow-up observational study.
Inoue, A, Ishikawa, E, Shirai, Y, Murata, T, Miki, C, Hamada, Y
Clinical nutrition ESPEN. 2020;:134-138
Abstract
BACKGROUND & AIMS In dialysis patients, malnutrition is a poor prognostic factor. In patients with chronic kidney disease (CKD), malnutrition is qualitatively different from general malnutrition, which is defined as "Protein-Energy Wasting (PEW)." Dietary therapy for the enhancement of PEW requires the aggressive intake of protein. Conversely, as protein intake and phosphorus intake correlate positively, increasing the protein intake increases the phosphorus intake, which is a poor prognostic factor in dialysis patients. One of the treatments for hyperphosphatemia in dialysis patients is the intake restriction of phosphorus by dietary counseling. However, protein uptake to maintain and augment the nutritional status and the protein intake restriction to correct hyperphosphatemia are contradictory treatments. Hence, this study aims to investigate the effects of PEW and hyperphosphatemia on the prognosis in hemodialysis patients. METHODS We enrolled 60 outpatients who underwent maintenance hemodialysis for 6 months (May-November 2012) at Iga City General Hospital (Mie, Japan). In November 2012, we assessed the presence or absence of PEW and hyperphosphatemia in patients and evaluated the survival rate over the next 5 years. RESULTS Overall, 10 patients (17%) were diagnosed as PEW. While 17 patients (28%) exhibited average phosphorus level >6.0 mg/dL (hyperphosphatemia). The 5-year survival rate was 30% in the PEW group, 66% in the non-PEW group, 57% in the hyperphosphatemia group, and 61% in the non-hyperphosphatemia group. A statistically significant difference existed between the PEW and non-PEW groups (P = 0.021). However, we observed no significant difference between the hyperphosphatemia and non-hyperphosphatemia groups. CONCLUSIONS This study suggests that PEW affects the prognosis more than hyperphosphatemia in maintenance hemodialysis patients. The normalization of the serum phosphorus level by the protein intake restriction could prevent secondary hyperparathyroidism and vascular calcification. Conversely, restricting the protein intake poses a risk of malnutrition. In fact, early death occurred in patients with PEW in this study. Perhaps, patients with PEW should prioritize improving their nutritional status rather than controlling the serum phosphorus level.
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6.
Cancer Cachexia and Related Metabolic Dysfunction.
Fonseca, GWPD, Farkas, J, Dora, E, von Haehling, S, Lainscak, M
International journal of molecular sciences. 2020;(7)
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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7.
Differences and Effects of Metabolic Fate of Individual Amino Acid Loss in High-Efficiency Hemodialysis and Hemodiafiltration.
Murtas, S, Aquilani, R, Iadarola, P, Deiana, ML, Secci, R, Cadeddu, M, Bolasco, P
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2020;(5):440-451
Abstract
OBJECTIVE The objective of the study was to quantify the loss and arterial blood concentration of the three main classes of amino acids (AAs)-nonessential amino acids (NEAAs), essential amino acids (EAAs), and branched-chain amino acids-as resulting from high-efficiency hemodialysis (HED) and hemodiafiltration (HDF). We moreover aimed to identify the different fates and metabolic effects manifested in patients undergoing hemodialysis and the consequences on body composition and influence of nutritional decline into protein energy wasting. DESIGN AND METHODS Identical dialysis monitors, membranes, and dialysate/infusate were used to ensure consistency. Ten patients were recruited and randomized to receive treatment with on-line modern HED and HDF. Arterial plasma concentrations of individual AAs were compared in healthy volunteers and patients undergoing hemodialysis, and AA levels outflowing from the dialyzer were evaluated. Baseline AA plasma levels of patients undergoing hemodialysis were compared with findings obtained 1 year later. RESULTS A severe loss of AA with HED/HDF was confirmed: a marked loss of total AAs (5 g/session) was detected, corresponding to more than 65% of all AAs. With regard to individual AAs, glutamine displayed a consistent increase (+150%), whereas all other AAs decreased after 12 months of HD/HDF. Only a few AAs, such as proline, cysteine, and histidine maintained normal levels. The most severe metabolic consequences may result from losses of EAAs such as valine, leucine, and histidine and from NEAAs including proline, cysteine, and glutamic acid eliciting the onset of hypercatabolism threatening muscle mass loss. CONCLUSION Dialysis losses, together with the effect of chronic uremia, resulted in a reduction of fundamental EAAs and NEAAs, which progressively led our patients after 12 months to a deterioration of lean mass toward sarcopenia. Therefore, the reintroduction of a correctly balanced AA supplementation in patients undergoing HD to prevent or halt decline of hypercatabolism into cachexia is recommended.
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8.
Dietary Amino Acids and Immunonutrition Supplementation in Cancer-Induced Skeletal Muscle Mass Depletion: A Mini-Review.
Soares, JDP, Howell, SL, Teixeira, FJ, Pimentel, GD
Current pharmaceutical design. 2020;(9):970-978
Abstract
Cancer patients display systemic inflammation, which leads to an increase in protein catabolism, thus promoting the release of free amino acids to further support metabolism and remodelling of muscle proteins. Inflammation associated with tumor growth leads to malnutrition, a factor that increases the risk of developing cachexia. With cancer-induced cachexia, nutritional interventions have gained traction as a preventative method to manage this condition. Currently, cancer consensus recommendations suggest a protein intake above 1.0 g/kg.day-1 up to 2.0 g/k.day-1 for cancer patients, although an ideal amount for some amino acids in isolation has yet to be determined. Due to controversy in the literature regarding the benefits of the biochemical mechanisms of various muscle mass supplements, such as L-leucine (including whey protein and BCAA), β-hydroxy-beta-methyl butyrate (HMβ), arginine, glutamine and creatine, several studies have carefully examined their effects. L-leucine and its derivatives appear to regulate protein synthesis by direct or indirect activation of the mTORC1 pool of kinases, further promoting muscle protein balance. Arginine and glutamine may act by reducing inflammation and infection progression, thus promoting improvements in food intake. Creatine exerts anabolic activity, acting as an immediate energy substrate to support muscle contraction further increasing lean mass, mainly due to greater water uptake by the muscle. In this narrative review, we highlighted the main findings regarding protein consumption and amino acids to mitigate cancer-induced skeletal muscle depletion.
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9.
Health-related quality of life across cancer cachexia stages.
Kasvis, P, Vigano, M, Vigano, A
Annals of palliative medicine. 2019;(1):33-42
Abstract
Cancer cachexia (CC) is common in advanced cancer and is accompanied by negative effects on health-related quality of life (HRQOL). However, methods to identify the impact of CC on HRQOL are limited. Single questionnaire items may provide insight on the effect of CC on HRQOL. Specifically, the use of "feeling of wellbeing" (FWB) on the Edmonton Symptom Assessment System (ESAS) questionnaire and the Distress Thermometer (DT) have been explored. Assessing how these two surrogate measures of HRQOL are impacted among CC stages and what drives these negative effects may allow for focused treatments. Five-hundred and twelve patients referred to a Cancer Rehabilitation Program completed the ESAS, with the question on FWB and the DT at baseline. Patients were separated into CC stages: non-cachexia (NC), pre-cachexia (PC), cachexia (C), refractory cachexia (RC). A mixed model ANOVA with post hoc Tukey adjustment was used to compare means of FWB and distress among the CC stages. To understand what was driving the differences between CC stages, a robust regression model was created with either distress or FWB as the outcome measure, dependent on the other measures in ESAS, age and sex. Finally, the use of cannabinoids in treating appetite loss was examined, as it has a detrimental effect on FWB; 54 patients underwent cannabinoid treatment for appetite loss within a community-based, physician-lead, medical cannabis clinic. A t-test to assess changes in ESAS appetite score after 3 months of cannabinoid treatment was examined. RC patients had a significantly poorer sense of wellbeing than the other cachexia stages (RC: 6.07±0.33). Significant differences in distress were identified between RC patients and those with NC and C, but not with PC (RC: 4.87±0.38, NC: 3.35±0.26, PC: 4.11±0.30, C: 3.60±0.28). FWB was negatively affected by worsening appetite in all CC stages except NC (PC: 0.19±0.08, P=0.022; C: 0.26±0.06, P<0.001; RC: 0.23±0.08, P=0.007). ESAS score for lack of appetite significantly improved between baseline (5.07±3.21) and follow-up (3.56±3.15, P=0.003) after cannabinoid treatment, with no significant difference in weight (baseline: 70.7±14.6 kg, 3-month follow-up: 71.0±14.8 kg). Future research should validate both multidimensional and single-item tools to measure HRQOL in patients at different stages of CC. Improvement of HRQOL via appetite stimulation, may be achieved through a multidisciplinary approach, which includes cannabinoid therapy.
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10.
Vitamin D, muscle recovery, sarcopenia, cachexia, and muscle atrophy.
Garcia, M, Seelaender, M, Sotiropoulos, A, Coletti, D, Lancha, AH
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:66-69
Abstract
The relevance of vitamin D to skeletal muscle metabolism has been highlighted in recent years. The interest arises from the important findings of studies demonstrating multiple effects of vitamin D on this tissue, which can be divided into genomic (direct effects) and non-genomic effects (indirect effects). Another important aspect to be considered in the study of vitamin D and muscle fiber metabolism is related to different expression of vitamin D receptor (VDR), which varies in muscle tissue depending on age, sex, and pathology. The correlation between low circulating levels of vitamin D and muscle metabolism disorders is documented in various contexts, including muscle recovery, atrophy, sarcopenia, and cachexia. The aim of this review was to analyze recent results of both in vitro and in vivo studies to address the relationship between vitamin D and skeletal muscle biology. The words muscle atrophy, muscle hypertrophy, sarcopenia, and cachexia were crossed over with vitamin D in a Pubmed search. All original contributions, along with reviews on the topic, were included, and no publications in the past 10 y were discarded. The papers retrieved different topics such as vitamin D in skeletal muscle; vitamin D in circulation; vitamin D, sarcopenia, and muscle atrophy; vitamin D and cachexia; and vitamin D and muscle recovery.