Nutrition Management in Geriatric Patients with CKD.

Sarcopenia, defined as age-related decline in skeletal muscle mass and functional capacity, is a hallmark nutritional abnormality observed in patients with moderate-to-advanced CKD. Uremic state and associated medical conditions also predispose older patients with CKD to protein-energy wasting, a nutritional abnormality that could include sarcopenia. Prevention of protein and energy depletion and replenishing the already low nutritional reserves elderly patients with CKD should focus on conventional and innovative strategies. This review aims to provide an overview of the mainstay of nutritional therapy in this patient population, such as intake of adequate amounts of protein and energy along with preserving fluid, electrolyte, and mineral balance, and to discuss more innovative interventions to aid these approaches.

A dose-response meta-analysis of randomized clinical trials investigating the effects of omega-3 supplementation on body weight in patients with cancer cachexia.

BACKGROUND: Cachexia is one of the side effects of cancer diseases that can be reduced weight, and lower overall survival. Weight loss has been associated with adverse outcomes in both cancer patients and patients with benign diseases. There is no definitive treatment for fully reverse cachexia. studies showed higher levels of inflammatory markers in patient with cachectic cancer. Therefore, this study aimed to investigate the dose-response effects of omega-3 as an anti-inflammatory supplement on body weight in patients with cancer cachexia. METHODS: Online databases including PubMed, Scopus, and Web of Science were systematically searched by relevant keywords up to January 2022. Random effect analysis was applied to perform meta-analysis. Subgroup analyses were performed to find heterogeneity sources. Quality assessment was conducted using Revised Cochrane Collaboration's tool II. Trim and fill analysis were also carried out in case of the presence of publication bias. The certainty in the evaluations was assessed by the GRADE approach. RESULTS: Omega-3 supplementation resulted in a significant increase of body weight in patients with cancer cachexia when the age of study participants was ≥67 years and the baseline weight of them was ≤60 kg (WMD = 0.99; 95 % CI: 0.06, 1.92 and WMD = 1.22; 95 % CI: 0.14, 2.30, respectively). Also, there was a non-significant linear relationship between the dosage of omega-3 supplementation and body weight in patients with cancer cachexia. CONCLUSION: Omega-3 supplementation may be a promising agent to increase body weight in patients with cancer cachexia. Also, a non-significant linear relationship between the dosage of omega-3 supplementation and body weight was found in these patients.

Clinical usefulness of the Patient-Generated Subjective Global Assessment and modified Glasgow Prognostic Score in decision making concerning the indication of enteral nutritional therapy in patients with incurable cancer receiving palliative care.

OBJECTIVES: This study aimed to identify the clinical usefulness of assessing nutritional status using validated tools for the indication of enteral nutrition for patients with incurable cancer in palliative care. METHODS: In this prospective cohort study, patients were assessed for nutritional risk using the Patient-Generated Subjective Global Assessment and for cancer cachexia (CC) using the modified Glasgow Prognostic Score upon enrollment and after ∼30 d. The outcome was stable or improved Karnofsky Performance Status. Logistic regression models were used, providing the odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 180 patients participated. The only nutritional status parameter that was associated with function was CC. The less severe the CC, the more likely Karnofsky Performance Status was to remain stable or improve over 30 d (non-cachectic: OR = 1.95; 95% CI, 1.01-3.47; malnourished: OR = 1.06; 95% CI, 1.01-1.42). Furthermore, white skin color (OR = 1.79; 95% CI, 1.04-2.47), higher educational level (OR = 1.39; 95% CI, 1.13-2.78), and inadequate calorie intake (OR = 1.96; 95% CI, 1.02-2.81) were also associated with the outcome. CONCLUSIONS: Using the modified Glasgow Prognostic Score to identify the existence and severity of CC, which is associated with function, has the potential to help clinical decision making concerning the indication of enteral nutrition in patients with incurable cancer receiving palliative care.

[Nutrition and dietary supplements]. / Ernährung und Nahrungsergänzungsmittel.

Nutritional problems occur very frequently in patients with cancer and different problems are associated with separate phases of the disease. Therefore, it is principally recommended to regularly screen all patients with cancer for nutritional disorders and in the case of conspicuous results meticulous diagnostics should be carried to clarify the underlying causes. The focus is on food intake and possible disturbing complaints, the physical performance index, nutritional status including weight change and body composition, the metabolic pattern and the presence of a systemic inflammatory reaction. As anti-cancer treatments frequently induce gastrointestinal derangements which endanger adequate food intake, individualized nutritional care should be offered routinely. After successful curative treatment patients are at risk of developing a metabolic syndrome; therefore, a balanced diet and regular physically activity are recommended. During palliative treatment special attention should be paid to the development of malnutrition. Patients are particularly endangered by cachexia with the combination of inadequate food intake, inactivity and prevailing catabolism. The treatment of cachexia requires a multiprofessional approach to ensure adequate food intake, guiding and supporting physical activity and interventions for normalization of the metabolic situation. In addition, the need for psychological and social support should be discussed. Dietary supplements are of minor relevance; however, deficits in micronutrients, such as vitamins and trace elements need to be balanced. At the end of life, care should primarily be focused on alleviating debilitating symptoms. To reliably support all patients affected by nutritional disorders, clear structures need to be established, responsibilities assigned and standardized procedures codified.

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia.

Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 µg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

Safety and Tolerability of Targeted Medical Nutrition for Cachexia in Non-Small-Cell Lung Cancer: A Randomized, Double-Blind, Controlled Pilot Trial.

Background: This pilot, double-blind, comparator-controlled trial evaluated the safety and tolerability of an oral targeted medical nutrition (TMN) supplement for the management of cachexia in patients with non-small-cell lung cancer (NSCLC).Methods: Patients receiving first-line chemotherapy for NSCLC with weight loss or low BMI were randomized 1:1 to receive juice-based TMN (∼200 kcal; 10 g whey protein; ≥2.0 g eicosapentaenoic acid/docosahexaenoic acid in fish oil; and 10 µg 25-hydroxy-vitamin D3) or a milk-based isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov: NCT02515032). Primary endpoints included number/type of adverse events and changes in vital signs/laboratory parameters. Secondary endpoints included measures of clinical relevance. Survival was an exploratory endpoint.Results: The TMN group (n = 26; mean 64.4 years) experienced fewer adverse events (64 vs. 87) than the comparator group (n = 29; mean 66.0 years), including fewer cases of neutropenia (0 vs. 4). Compliance was slightly lower in the TMN (58.5%) vs. comparator group (73.6%). There were no statistically significant between-group differences in efficacy endpoints. Fewer (4 vs. 10) patients who received TMN than comparator had died by 1-year post baseline.Conclusions: TMN was well tolerated. Trends for improved clinical outcomes with TMN identified in this study warrant further investigation.

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis-associated cachexia.

BACKGROUND: Ctns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns-/- mice are 25(OH)D3 and 1,25(OH)2 D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns-/- mice. METHODS: Twelve-month-old Ctns-/- mice and wild-type controls were treated with 25(OH)D3 and 1,25(OH)2 D3 (75 µg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns-/- mice using RNAseq. RESULTS: Supplementation of 25(OH)D3 and 1,25(OH)2 D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2 D3 in Ctns-/- mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns-/- mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF-κB pathway) in inguinal white adipose tissue in Ctns-/- mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns-/- mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL-1ß, IL-6, and TNF-α as well as an increased gene expression of Murf-2, atrogin-1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns-/- mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns-/- mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2 D3 normalized the top 20 differentially expressed genes in Ctns-/- mice. CONCLUSIONS: We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2 D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns-/- mice via multiple cellular and molecular mechanisms.

Maternal Leucine-Rich Diet Minimises Muscle Mass Loss in Tumour-bearing Adult Rat Offspring by Improving the Balance of Muscle Protein Synthesis and Degradation.

Cachexia syndrome can affect cancer patients and new prevention strategies are required. Maternal nutritional supplementation can modify metabolic programming in the offspring, which lasts until adulthood. This could be a good approach against diseases such as cancer. A 3% leucine-rich diet treatment improved muscle protein turnover by modifying the mTOR and proteolytic pathways, thus we analysed whether maternal supplementation could ameliorate muscle protein turnover in adult offspring tumour-bearing rats. Pregnant Wistar rats received a control diet or 3% leucine-rich diet during pregnancy/lactation, and their weaned male offspring received a control diet until adulthood when they were distributed into following groups (n = 7-8 per group): C, Control; W, tumour-bearing; L, without tumour with a maternal leucine-rich diet; and WL, tumour-bearing with a maternal leucine-rich diet. Protein synthesis and degradation were assessed in the gastrocnemius muscle, focusing on the mTOR pathway, which was extensively altered in W group. However, the WL adult offspring showed no decrease in muscle weight, higher food intake, ameliorated muscle turnover, activated mTOR and p70S6K, and maintained muscle cathepsin H and calpain activities. Maternal leucine nutritional supplementation could be a positive strategy to improve muscle protein balance in cancer cachexia-induced muscle damage in adult offspring rats.

Fatty acids uptake and oxidation are increased in the liver of rats with adjuvant-induced arthritis.

Severe rheumatoid cachexia is associated with pronounced loss of muscle and fat mass in patients with advanced rheumatoid arthritis. This condition is associated with dyslipidemia and predisposition to cardiovascular diseases. Circulating levels of triglycerides (TG) and free fatty acids (FFA) have not yet been consistently defined in severe arthritis. Similarly, the metabolism of these lipids in the arthritic liver has not yet been clarified. Aiming at filling these gaps this study presents a characterization of the circulating lipid profile and of the fatty acids uptake and metabolism in perfused livers of rats with adjuvant-induced arthritis. The levels of TG and total cholesterol were reduced in both serum (10-20%) and liver (20-35%) of arthritic rats. The levels of circulating FFA were 40% higher in arthritic rats, possibly in consequence of cytokine-induced adipose tissue lipolysis. Hepatic uptake and oxidation of palmitic and oleic acids was higher in arthritic livers. The phenomenon results possibly from a more oxidized state of the arthritic liver. Indeed, NADPH/NADP+ and NADH/NAD+ ratios were 30% lower in arthritic livers, which additionally presented higher activities of the citric acid cycle driven by both endogenous and exogenous FFA. The lower levels of circulating and hepatic TG possibly are caused by an increased oxidation associated to a reduced synthesis of fatty acids in arthritic livers. These results reveal that the lipid hepatic metabolism in arthritic rats presents a strong catabolic tendency, a condition that should contribute to the marked cachexia described for arthritic rats and possibly for the severe rheumatoid arthritis.

Differential Metabolic Responses to Adipose Atrophy Associated with Cancer Cachexia and Caloric Restriction in Rats and the Effect of Rikkunshito in Cancer Cachexia.

Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose metabolic changes in a novel rat model of CC, mild CR (70% of the food intake of control rats, which is similar to the food consumption of CC rats), and severe CR (30% of the food intake of controls). We show that CC and severe CR are associated with much smaller adipocytes with significantly lower mitochondrial DNA content; but, that mild CR is not. CC and both mild and severe CR similarly upregulated proteins involved in lipolysis. CC also downregulated proteins involved in fatty acid biosynthesis, but mild CR upregulated these. These findings suggest that CC might impair de novo fatty acid biosynthesis and reduce mitochondrial biogenesis, similar to severe CR. We also found that rikkunshito, a traditional Japanese herbal medicine, does not ameliorate the enhanced lipolysis and mitochondrial impairment, but rather, rescues de novo fatty acid biosynthesis, suggesting that rikkunshito administration might have partially similar effects to mild CR.

Nutritional status and interventions in hospice: physician assessment of cancer patients.

BACKGROUND: Cancer cachexia is a multifactorial syndrome characterised by a progressive loss of skeletal muscle mass. It adversely influences quality of life, treatment response and survival. Early identification and multimodal interventions can potentially treat cancer cachexia. However, healthcare professionals demonstrate a lack of understanding and the ability to identify cancer cachexia early. The present study aimed to evaluate the assessment by physicians of nutritional status in cancer patients admitted to hospice. METHODS: A retrospective medical record review was conducted on all cancer admissions to a specialist in-patient palliative care unit over a 4-month period between October 2016 and January 2017. Charts were reviewed for evidence of documented nutritional assessment by physicians. Data were collected from the referral letter, admission notes, drug kardex and discharge letter. The information extracted included: (i) patient demographics and characteristics; (ii) terms used by physicians to describe nutritional status; (iii) any record of nutritional impact symptoms (NIS) experienced by the patient; and (iv) nutritional interventions prescribed. RESULTS: One hundred and forty admissions were evaluated. Nutritional terminology and NIS were most commonly documented on the admission notes. Only 41% of documents recorded any nutritional term used by physicians to assess nutritional status. Furthermore, 71% of documents recorded at least one NIS experienced by the patient. Fatigue was the most frequent NIS. CONCLUSIONS: We identified an inadequate nutritional assessment of cancer patients admitted to hospice. Implementation of a nutritional symptom checklist and nutrition screening tools, along with enhanced physician education and multidisciplinary nutrition care, could improve the identification and management of cancer cachexia in the palliative care setting.

[Cachexia and sarcopenia in chronic heart failure : Change in muscle strength and muscle structure]. / Kachexie und Sarkopenie bei chronischer Herzinsuffizienz : Veränderung von Muskelkraft und Muskelaufbau.

Alterations to the body composition, i.e. the makeup of skeletal muscle, fat and bone density, are frequent in heart insufficiency. Their prevalence and clinical consequences are often underestimated. Cachexia is recognized as a complex multifactorial syndrome in chronic diseases that leads to weight loss. This point constitutes the essential differential criterion from sarcopenia. Cachexia is defined as a non-edematous weight loss of more than 5% within 12 months or less. Cachexia means weight loss, while sarcopenia means loss of muscle mass without weight loss because the functional muscle can be replaced by adipocytes. Sarcopenia is defined as a skeletal muscle mass index (SMMI) of at least 2 standard deviations below the mean value of a healthy young reference group between 20 and 30 years of the same sex and ethnic background. At the same time the walking speed is reduced to 1 m/s or the distance covered in a 6-min walk is <400m. The determination of loss of muscle mass should be carried out by whole body scanning, ideally with dual-energy x­ray absorptiometry. A reliable and simple method for measurement of performance capability is the short physical performance battery (SPPB) test. The treatment of sarcopenia and cardiac cachexia in patients with heart insufficiency is still a great challenge. Power and endurance training, nutritional supplementation and drug therapy are possible therapeutic approaches; however, the study situation is unsatisfactory.

Using polyphenol derivatives to prevent muscle wasting.

PURPOSE OF REVIEW: To highlight recent evidence for the ability of polyphenols and their derivatives to reduce muscle wasting in different pathological states. RECENT FINDINGS: From January 2016 to August 2017, four articles dealt with the effects of polyphenols on muscle wasting, which were all carried out in mice. The four studies found that polyphenols reduced muscle mass loss associated with cancer cachexia, acute inflammation or sciatic nerve section. One study even showed that muscle mass was totally preserved when rutin was added to the diet of mice undergoing cancer cachexia. The beneficial effects of polyphenols on muscle wasting were mainly due to a reduction in the activation of the nuclear factor-kappa B pathway, a lower oxidative stress level and a better mitochondrial function. In addition, urolithin B was found to have a testosterone-like effect and to favorably regulate muscle protein balance. SUMMARY: During the last 20 months, additional data have been collected about the beneficial effects of rutin, curcumin, quercetin, ellagitanins and urolithin B to limit the loss of muscle mass associated with several pathological states. However, currently, scientific evidence lacks for their use as nutraceuticals in human.

HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.

Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome.

Experimental Cancer Cachexia Changes Neuron Numbers and Peptide Levels in the Intestine: Partial Protective Effects after Dietary Supplementation with L-Glutamine.

Gastrointestinal dysmotility frequently occurs in cancer cachexia and may result from damage to enteric innervation caused by oxidative stress, especially due to glutathione depletion. We assessed the effect of dietary supplementation with 20 g/kg l-glutamine (a glutathione precursor) on the intrinsic innervation of the enteric nervous system in healthy and Walker 256 tumor-bearing Wistar rats during the development of experimental cachexia (14 days), in comparison with non-supplemented rats, by using immunohistochemical methods and Western blotting. The total neural population and cholinergic subpopulation densities in the myenteric plexus, as well as the total population and VIPergic subpopulation in the submucosal plexus of the jejunum and ileum, were reduced in cachectic rats, resulting in adaptive morphometric alterations and an increase in vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) expression, suggesting a neuroplastic response. l-glutamine supplementation prevented decrease in myenteric neuronal density in the ileum, morphometric alterations in the neurons and nerve fibers (in both the plexuses of the jejunum and ileum), and the overexpression of VIP and CGRP. Cancer cachexia severely affected the intrinsic innervation of the jejunum and ileum to various degrees and this injury seems to be associated with adaptive neural plasticity. l-glutamine supplementation presented partial protective effects on the enteric innervation against cancer cachexia, possibly by attenuating oxidative stress.

Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals.

BACKGROUND: The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart. METHODS: Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity. RESULTS: Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity. CONCLUSIONS: Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.

A phase III study evaluating oral glutamine and transforming growth factor-beta 2 on chemotherapy-induced toxicity in patients with digestive neoplasm.

BACKGROUND: Patients with gastrointestinal (GI) cancer are exposed to cachexia, which is highly correlated with chemotherapy-induced side effects. Research suggests that specific immunonutrients could prevent such toxicities. AIMS: The primary objective of this phase III study was to evaluate the efficacy of glutamine and transforming growth factor-ß2 (TGF-ß2) in the prevention of grade 3-4 non-hematological toxicities induced by chemotherapy in patients with GI cancer. PATIENTS AND METHODS: We designed a double-blind, randomized, controlled and multicenter trial stratified according to center, type of chemotherapy, presence of cachexia, and age. Patients were randomized to receive either Clinutren Protect(®) (CP) or a control isocaloric diet (without TGF-ß2 or glutamine). RESULTS: Between November 2007 and October 2011, 210 patients were enrolled in the study, of which 201 were included in the intention-to-treat analysis. Grade 3-4 non-hematological toxicities were not significantly different between the CP and control groups when evaluated by univariate and multivariate analyses. Likewise, no difference was observed regarding grade 3-4 hematological toxicities or reasons for treatment interruption. CONCLUSION: This randomized study does not support the hypothesis that oral glutamine and TGF-ß2 supplementation is effective to reduce grade 3 or 4 non-hematological toxicities induced by chemotherapy in patients with GI neoplasm.

The central role of hypothalamic inflammation in the acute illness response and cachexia.

When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes.

Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia.

Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals.

The elderly patient with cancer: a holistic view.

The elderly cancer patient (ECP) population is a heterogeneous group, ranging from competent, active, and fit individuals to those who are frail and cognitively impaired. A continuum exists from an increased vulnerability to stressors that results from the usual decreases in physiologic reserves (=aging) to the deregulation of multiple physiologic systems (=frailty). The ability or inability of carrying out activities of daily living is both a cause and an effect of frailty and may exacerbate the clinical manifestations of comorbidities. Cachexia is one of the most important comorbid conditions in ECPs, which can directly impair their quality of life, their ability to tolerate tumor-directed treatments, and their ability to respond to rehabilitation. Gait speed, handgrip strength, and cognitive tests along with simple laboratory tests to rule out the presence of increased inflammatory state and/or a particular hormonal deficiency may guide interventions and allow for monitoring of clinical outcomes over time. An organized social network, collaborative support from the team of caregivers and sufficient home care services comprise a comprehensive care approach that guarantees successful treatment outcomes for the ECP population.