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PubMed1989

Clinical applications of tumour necrosis factor.

Tumour necrosis factor (TNF) is a polypeptide hormone produced in vivo by activated macrophages and lymphocytes. TNF has diverse effects in vivo and has a physiological role as an immune modulator, as a mediator of the immune response, both through activation of neutrophils and eosinophils, and also affects the vascular endothelium. TNF also has antiviral activity and causes alterations in lipid metabolism. In disease states excessive production of TNF may have adverse affects. TNF has been implicated as a mediator of endotoxic shock, inflammatory joint disease, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. When used in pharmacological doses, TNF is cytotoxic to many malignant cells in vitro and in vivo. The mechanisms underlying cytotoxicity are not fully elucidated but involve both a direct toxic effect to the cell and an indirect effect on tumour vasculature. Cytotoxicity is not universal and TNF may act as a differentiating agent or growth factor for some haematological cell types. So far the clinical application of TNF has been as a treatment for cancer in Phase I and II trials in patients with advanced disease and its efficacy here is still unproven. TNF may have potential for clinical application in combination therapy for cancer. There is experimental evidence for its interaction with other biological agents and cytotoxic drugs. The use of specific antibodies to inhibit production of TNF, or other agents to antagonise the toxic effects of TNF may have clinical relevance in counteracting septic shock and the clinical manifestations of TNF in inflammatory and neoplastic disease.

Animals↗
PubMedDate not supplied

Effect of plasma from cancer patients on rat skeletal muscle protein degradation and PGE2 release in vitro.

Cachexia in tumour-bearing patients involves loss of skeletal muscle proteins. In order to elucidate the mechanisms underlying this phenomenon, we tested the hypothesis of the presence of a circulating proteolytic factor (possibly interleukin-1, acting through an increased PGE2 release) in the plasma of cancer patients, because such a mechanism has been demonstrated in patients with sepsis or trauma and in animals with bacteraemia or viraemia. The effect of plasma from 13 malnourished cancer patients and 14 controls on PGE2 release and protein degradation (assessed as Tyr release) in rat diaphragm in vitro was evaluated; human recombinant interleukin-1 alpha (IL-1) was used for comparison. IL-1 increased PGE2 release (+44% at 5 U/ml), but did not greatly affect proteolysis. On the contrary, human plasma (125 microliters/ml) from both control and tumour-bearing individuals did not affect PGE2 release significantly, but greatly reduced Tyr release. The decrease in Tyr release by plasma was dose-dependent. In conclusion, our data indicate that, at variance with what was demonstrated in patients with trauma or sepsis, loss of skeletal muscle proteins in cancer patients is not mediated by a circulating factor. In addition, evidence is provided of dissociation between PGE2 and Tyr release and of lack of proteolytic activity for IL-1.

Animals↗
PubMed2004

Wasting and the substrate-to-energy controlled pathway: a role for insulin resistance and amino acids.

Amino acids contained in proteins can be transformed either in glucose precursors or in acetate, the end product of free fatty acid (FFA) oxidation. The dynamics of glucose, FFA, and amino acid competition for entry into the citric acid cycle (tricarboxylic acid [TCA] cycle) are very complex and not fully understood. Conditions where glucose is insufficiently driven to full oxidation are characterized by lowest efficiency in energy production per mole of oxygen consumed. Moreover, acetate provided by oxidation of FFA increases consumption of amino acids as precursors of the oxaloacetate required for condensation with acetate and for maintenance of citrate synthesis. Increased consumption of amino acids in the TCA cycle, if not matched by adequate intake, leads to muscular wasting and cachexia. Therefore, amino acid needs are very complex, and their intake must provide a balanced ratio of glucogenic and ketogenic precursors suitable to trigger entry of glucose to full oxidation and blunt the level of FFA utilization. Optimization of substrate entry into energy production must also be coupled with sufficient availability of amino acids in ratios suitable for maintaining protein synthesis, inhibiting the catabolic drive, and promoting integrity of cellular proteic structures. Alimentary proteins have a content of amino acids that is far from the stoichiometric ratios of essential amino acids required by humans. An amino acid formulation suitable to match energy needs, control carbohydrate and lipid flow into the TCA cycle, and promote protein synthesis in contracting cells is detailed in this article.

Amino Acids, Essential↗
PubMed2006

Office management of weight loss in older persons.

Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, decreasing immune function, decreased functional status, and death. There are 4 major causes of weight loss: anorexia, sarcopenia, cachexia, and dehydration. Many of the reasons for the development of these conditions are treatable. For example, depression is the most common cause of weight loss in the elderly. Early screening for anorexia can be undertaken in the physician's office utilizing the Simplified Nutritional Assessment Questionnaire. An algorithmic approach to the office management of weight loss is provided.

Aged↗
PubMed2005

The pivotal role of cytokines in muscle wasting during cancer.

The cachectic syndrome, characterized by a marked weight loss, anorexia, asthenia and anemia, is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated catabolic state, which promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to an increased energetic inefficiency. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. Present investigation is devoted to unrevealing the different signaling pathways (particularly transcriptional factors) involved in muscle wasting. The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators involved in cancer cachexia since they may represent targets for future promising clinical investigations.

Animals↗
PubMed2005

The pivotal role of cytokines in muscle wasting during cancer.

The cachectic syndrome, characterized by a marked weight loss, anorexia, asthenia and anemia, is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated catabolic state, which promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to an increased energetic inefficiency. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. Present investigation is devoted to unrevealing the different signaling pathways (particulary transcriptional factors) involved in muscle wasting. The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators involved in cancer cachexia since they may represent targets for future promising clinical investigations.

Animals↗
PubMed2006

Impairment of IGF-I gene splicing and MGF expression associated with muscle wasting.

The characterisation of a local tissue repair factor (mechano growth factor, MGF) that is produced by exercised and/or damaged muscle by differential splicing of the IGF-I gene provides understanding of how muscle is maintained in the young normal individual. Mechano growth factor, or MGF, is different to the systemic IGF-I as it has an insert of 49 base pairs in exon 5 that introduces a reading frame shift resulting in a C terminal peptide with unique properties. Muscle is a post-mitotic tissue and as cell replacement is not a means of tissue repair there has to be an efficient local repair mechanism otherwise the damaged cells undergo cell death. The extra nuclei for muscle repair and hypertrophy are provided by the muscle satellite (stem) cells. The pool of these stem cells is apparently replenished by the action of MGF, which is produced as a pulse following a mechanical challenge. Unfortunately, the production of MGF is deficient in certain diseases such as in the muscular dystrophies in which the mechanotransduction mechanism, which may involve the dystrophin complex, is defective. In elderly muscles, decreased levels of growth hormone apparently mean that there is less primary RNA transcript of the IGF-I gene to be spliced towards MGF. Consequently, there is an increasing inability to maintain muscle mass during ageing. Delivery of MGF and cDNA or peptide produces marked increases in the strength of normal as well as diseased muscle and, therefore, MGF has considerable potential as a generic means of treating muscle cachexia.

Aging↗
PubMed2005

Liver protein synthesis stays elevated after chemotherapy in tumour-bearing mice.

We studied the effect of chemotherapy on liver protein synthesis in mice bearing colon 26 adenocarcinoma (C26). Liver protein mass decreased (-32%; P<0.05) in cachectic mice, but protein synthesis increased (20-35%; P<0.05) in cachectic mice, which is consistent with increased export protein synthesis. Increased protein synthesis in tumour-bearing mice was primarily mediated by increasing ( approximately 15%; P<0.05) the RNA concentration, i.e. the capacity for protein synthesis (Cs; mg RNA/g protein). Cystemustine, a nitrosourea chemotherapy that cures C26 with 100% efficacy, rapidly restored liver protein mass; protein synthesis however stayed higher than in healthy mice ( approximately 15%) throughout the initial and later stages of recovery. Chemotherapy had no significant effect on liver protein mass and synthesis in healthy mice. Reduced food intake was not a factor in this model. These data suggest a high priority for liver protein synthesis during cancer cachexia and recovery.

Adenocarcinoma↗
PubMed2005

Diet energy density and energy intake in palliative care cancer patients.

BACKGROUND & AIMS: Anorexia and cachexia are frequent in advanced cancer. Energy density may be important in the control of energy intake; however, current data are derived from studies in healthy or obese populations and there is no agreed definition and methods of calculation. We studied energy density and energy intake in a group of palliative cancer patients and explored which method of energy density calculation that yielded the highest determination coefficient of energy intake. METHODS: Energy density was calculated from 259 food records using four methods, differing in the types of food and beverages included in the analysis. Association between energy density and energy intake was tested using regression analysis. RESULTS: The determination coefficient for total energy intake was: 0.181, 0.148, 0.222, and 0.211 for methods 1-4, respectively (P for all <0.001). In relation to energy per kg body weight and resting energy expenditure, methods 3 and 1 yielded the highest determination coefficient, R2 = 0.164 and 0.184, respectively. CONCLUSIONS: We found a positive association between diet energy density and energy intake. The method used when calculating energy density had limited impact on this association. When calculating energy density all food and beverages should be included in the analysis.

Adult↗
PubMed2006

ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology.

Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where normal food intake is inadequate. These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in cancer patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards, are based on all relevant publications since 1985 and were discussed and accepted in a consensus conference. Undernutrition and cachexia occur frequently in cancer patients and are indicators of poor prognosis. EN should be started if undernutrition already exists or if food intake is markedly reduced for more than 7-10 days. Standard formulae are recommended for EN. Nutritional needs generally are comparable to non-cancer subjects. In cachectic patients metabolic modulators such as progestins, steroids and possibly eicosapentaenoic acid may help to improve nutritional status. EN is indicated preoperatively for 5-7 days in cancer patients undergoing major abdominal surgery. During radiotherapy of head/neck and gastrointestinal regions dietary counselling and ONS prevent weight loss and interruption of radiotherapy. Routine EN is not indicated during (high-dose) chemotherapy.

Cachexia↗
PubMed2006

Beta-hydoxy-beta-methylbutyrate supplementation affects Walker 256 tumor-bearing rats in a time-dependent manner.

BACKGROUND & AIMS: Cancer cachexia affects intermediary metabolism with intense and general catabolism. Walker 256 tumor is a model injected either subcutaneously (Sc) or intraperitoneally (Ip), with different metabolic features. Beta-hydroxy beta-methylbutyrate (HMbeta) is a leucine metabolite with anti-catabolic properties, the aim of this study being to investigate its effects on metabolic parameters in both tumor models. METHODS: Controls (subcutaneous control group (ScC) and intraperitoneal control group (IpC)) and supplemented animals (subcutaneous supplemented group (ScS) and intraperitoneal supplemented group (IpS)) showed these results. RESULTS: Protein Sc values were (47.8%) lower than Ip groups. Sc group fat content was (65.16%) higher than Ip groups. Liver glycogen value for Sc groups was (38.4%) higher than Ip groups. Muscle glycogen value for Sc groups were (2.75 times) higher than Ip groups. Corticosterone and insulin values were lower (44.53%) and higher (45.94%), respectively, in Sc when compared with Ip groups. Glucose and lactate values for ScS were the lowest (61.7% and 41.53%) compared to other groups. ScC glutamine value was the highest (40.8%) of all groups. Glutamate Sc values were (42.65%) lower than Ip groups. Sc groups showed greater survival time compared with Ip groups. ScS group showed 100% increase in survival time when compared with ScC. CONCLUSIONS: HMbeta supplementation can increase survival time and promotes metabolic changes in cancer-bearing animals, but it seems to work in a time-dependent manner.

3-Hydroxybutyric Acid↗
PubMed2004

Hormonal and metabolic strategies to attenuate catabolism in critically ill patients.

During the prolonged phase of critical illness, the ongoing hypermetabolic response leads to loss of lean tissue mass. Although the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, most endocrine interventions attempting to correct the hormone balance have shown to be ineffective and their indiscriminate use is even harmful. Thus, a detailed understanding of the neuroendocrinology of the stress response is warranted, especially as the acute and chronic phases show remarkable differences. In the acute stress response, low circulating peripheral anabolic hormone levels, despite an actively secreting pituitary, are indicative of peripheral resistance to the anterior pituitary hormones. By contrast, the pulsatile secretion of anterior pituitary hormones is uniformly decreased in the prolonged phase of the disease, leading to proportionally reduced concentrations of peripheral anabolic hormones. As hypothalamic secretagogues can restore the pulsatile secretion of the anterior pituitary and increase peripheral target hormones, tissues are at least partially sensitive to the anterior pituitary hormones in this phase of illness. Therefore, a combination of hypothalamic secretagogues that reactivates the anterior pituitary to a greater extent could be a more physiological and effective strategy to induce anabolism in patients with prolonged critical illness.

Animals↗
PubMed2005

Melanocortin-4 receptor in sheep: a potential site for therapeutic intervention in disease models.

Reduced appetite combined with increased metabolic rate and decreased lean body mass is a major consequence of disease and other stressors. Studies in rodent species suggest that an understanding of appetite regulation may provide methodologies for intervention to prevent the deterioration of body mass such as observed with cancer or infectious diseases. For example, melanocortin-4 receptor (MC4-R) antagonists have shown a remarkable ability to reverse or prevent cachexia in rodents with sarcoma or treated with endotoxin. Studies in sheep have indicated that a number of peptide neurotransmitters may have a role in regulating appetite in this species. For example, agouti related protein mRNA and protein levels are dramatically altered with fasting in sheep. Moreover, agouti related protein, neuropeptide Y, melanin concentrating hormone and orexin are potent stimuli to increase feed intake in sheep. Recent studies have indicated that one of these neurotransmitters, NPY, can work in principal to improve appetite in endotoxin-treated sheep. Current studies are examining the role that MC4-R antagonists may have in the prevention or correction of body mass wasting diseases as well as practical applications in animal production.

Agouti-Related Protein↗
PubMed2005

The causes and consequences of cancer-associated malnutrition.

Cancer-associated malnutrition can result from local effects of a tumour, the host response to the tumour and anticancer therapies. Although cancer patients often have reduced food intake (due to systemic effects of the disease, local tumour effects, psychological effects or adverse effects of treatment), alterations in nutrient metabolism and resting energy expenditure (REE) may also contribute to nutritional status. Several agents produced by the tumour directly, or systemically in response to the tumour, such as pro-inflammatory cytokines and hormones, have been implicated in the pathogenesis of malnutrition and cachexia. The consequences of malnutrition include impairment of immune functions, performance status, muscle function, and quality of life. In addition, responses to chemotherapy are decreased, chemotherapy-induced toxicity and complications are more frequent and severe, and survival times are shortened. Depression, fatigue and malaise also significantly impact on patient well-being. In addition, cancer-related malnutrition is associated with significant healthcare-related costs. Nutritional support, addressing the specific needs of this patient group, is required to help improve prognosis, and reduce the consequences of cancer-associated nutritional decline.

Anorexia↗
PubMed2004

Interleukin-15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour-bearing rats.

Administration of interleukin-15 (IL-15) to rats bearing the Yoshida AH-130 ascites hepatoma (a tumour that induces an important cachectic response) resulted in a significant reduction of muscle wasting, both measured as muscle weight and as protein content of different types of skeletal muscle. In addition, the administration of the cytokine completely reversed the increased DNA fragmentation observed in skeletal muscle of tumour-bearing animals. Concerning the mechanism(s) involved in the anti-apoptotic effects of IL-15 on skeletal muscle, the administration of the cytokine resulted in a considerable decrease in both R1 (43%) and R2 (64%) TNF-alpha receptors (TNFRs), and therefore it may be suggested that IL-15 decreases apoptosis by affecting TNF-alpha signalling. Formation of NO could be the signalling event associated with the activation of apoptosis in muscle of tumour-bearing rats; indeed, administration of IL-15 decreased the inducible nitric oxide synthase protein levels by 73%, suggesting that NO formation and muscle apoptosis during tumour growth are related. In conclusion, IL-15 seems to be able to reduce/suppress protein loss and apoptosis related to muscle wasting during cancer cachexia in experimental animals.

Animals↗
PubMed2004

Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study.

Systemic syndromes characterized by a persistent activity of circulating mediators (cytokines) are frequently present with advanced cancer. We grouped under the general heading of "Systemic Immune-Metabolic Syndrome (SIMS)" a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis, with overlapping clinical manifestations. SIMS may include cachexia, anorexia, nausea, early satiety, fatigue, tumor fever, cognitive changes and superinfection. The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy. Fifteen patients with evidence of SIMS were studied. SIMS was defined as the presence of weight loss, anorexia, fatigue performance status>/=2 and acute-phase protein response. Patients received medroxyprogesterone (MPA) (500 mg twice daily), celecoxib (200 mg twice daily), plus oral food supplementation for 6 weeks. After treatment, 13 patients either had stable weight (+/- 1%) or had gained weight. There were significant differences in improvement of body-weight-change rate, nausea, early satiety, fatigue, appetite and performance status. Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients (P=0.039). Our results suggest that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and dietary intervention, might have considerable improvement in certain SIMS outcomes. This multitargeted symptomatic approach deserves further study.

Adenocarcinoma↗
PubMed2005

"Starve a fever and feed a cold": feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance.

Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut. Emerging evidence suggests that the vagal and neurohormonal output of the gut during feeding promotes Th1 function, which is desirable in fighting viral infections. Since fever may be an adaptation to fight bacteria and "colds" are generally viral in origin, the adage "starve a fever and feed a cold" may reflect a sensible behavioral strategy to tilt autonomic and Th balance in directions that are optimal for fighting the particular type of infection. The ability to modulate T helper balance through the neurohormonal and autonomic axis by adjusting food intake may be the mechanism behind other unexplained clinical observations such as the improved outcomes of ICU patients after enteric versus parenteric feedings. Compared to the prehistoric period when bacterial infection was commonplace, the anorexic response may be less adaptive today when viruses and cancers have become common triggers of anorexia. By promoting host anorexia, cachexia, and insomnia, cancers and viruses can deter behaviors such as digestion and sleep that would raise vagal and Th1 activity against tumors and viruses. Hydration and sleep, unexplained but widely accepted recommendations for flu patients, may also work by promoting vagal and Th1 functions. Modulating feeding, hydration, and sleep may prove beneficial in treating other conditions associated with abnormal autonomic and Th balance.

Adaptation, Physiological↗
PubMed2005

Central administration of peptide and small molecule MC4 receptor antagonists induce hyperphagia in mice and attenuate cytokine-induced anorexia.

We investigated the effect of melanocortin 4 receptor (MC4) antagonists on food intake in mice. Food intake during the light phase was significantly increased by ICV administration of mixed MC3/MC4 antagonists (AgRP and SHU9119) or MC4 selective antagonist peptide [(Cyclo (1-5)[Suc-D-Nal-Arg-Trp-Lys]NH2] (MBP10) and the small molecule antagonists THP and NBI-30. Both mixed and selective antagonists significantly reversed anorexia induced by ICV administration of the MC4 agonist (c (1-6) HfRWK-NH2) and the cytokine IL-1beta. These findings provide pharmacological evidence that the MC4 receptor mediates the effects of melanocortin agonists and antagonists on food intake in mice, and support the idea that selective small molecule MC4 antagonists may be useful as therapeutics for cachexia.

Animals↗