M. Muscaritoli

Plasma and CSF tryptophan in cancer anorexia

Eighteen untreated cancer patients and ten sex- and age-matched healthy volunteers were studied. In all patients eating behavior was investigated by means of a specific questionnaire from which the presence of anorexia and anorexia-related symptoms was assessed. To investigate the role of tryptophan in cancer anorexia, fasting plasma and CSF levels of tryptophan and other neutral amino acids were assayed in patients and controls. Cancer patients showed abnormally high plasma free tryptophan levels. In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryptophan for its brain entry, was observed. This increase was correlated to a consistent rise of CSF tryptophan levels suggesting a specific role of the serotoninergic system in the pathogenesis of cancer anorexia.

Therapy of muscle wasting in cancer: what is the future?

Purpose of reviewThe aim of the present review is to provide insights into the future therapeutic approaches to cancer-related muscle wasting that flow from the progressive knowledge of mechanisms regulating muscle mass in health and disease. Recent findingsCancer cachexia is a severely debilitating and life-threatening paraneoplastic syndrome accounting for approximately 20% of cancer deaths. The prominent clinical feature of cancer cachexia is the progressive loss of muscle mass, which is substantially not reversible with any of the currently available nutritional, metabolic or pharmacological approaches. Cancer cachexia has long been considered a late event in the natural history of cancer patients, thus condemning them to merely palliative interventions. The accumulating evidence that the metabolic and molecular derangements ultimately leading to muscle wasting are operating early after tumour onset, even when weight loss is minimal or absent, is strengthening the view that cancer cachexia should be considered an early phenomenon. SummaryCurrently, despite scientific and economic efforts, the therapy of cancer-related muscle wasting has a poor success rate. Present knowledge of the intracellular mechanisms involved in muscle homeoastasis is prompting continuous research aimed at developing more effective and selective therapeutic tools for the prevention and treatment of muscle loss in cancer.

The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects.

Nineteen obese female subjects with body mass index ranging between 30 and 40 were included in a double-blind crossover study aimed at evaluating the effects of oral 5-hydroxytryptophan administration on feeding behavior, mood state and weight loss. Either 5-hydroxytryptophan (8 mg/kg/day) or placebo was administered for five weeks during which patients were not prescribed any dietary restrictions. Feeding behavior was investigated by means of a questionnaire designed to establish the onset of anorexia and related symptoms. Food intake was evaluated using a three-day diet diary. BDI, SI, STAI-T, and STAI-S were used to assess mood state. The administration of 5-hydroxytryptophan resulted in no changes in mood state but promoted typical anorexiarelated symptoms, decreased food intake and weight loss during the period of observation.

Use of branched chain amino acids for treating hepatic encephalopathy: clinical experiences.

The efficacy of branched chain amino acids in two consecutive clinical studies in patients with severe hepatic encephalopathy was tested. In the preliminary uncontrolled study 19 patients with grade 3-4 hepatic encephalopathy were given an intravenous solution containing leucine 11 g/l, isoleucine 9 g/l, and valine 8.4 g/l in 20% dextrose. A complete recovery of mental state was obtained in all patients in a mean time of 20.5 hours. In a subsequent controlled study 40 patients with grade 3-4 hepatic encephalopathy were randomly assigned to receive intravenous branched chain amino acid in 20% dextrose (group A) or oral lactulose (group B). Twelve patients (70.6%) in group A and eight (47%) in group B regained consciousness in a mean time of 27.6 and 31.5 hours, respectively. The difference in the recovery rate between the two groups, although evident, was not significant. Intravenous branched chain amino acids are thus at least as effective as lactulose in reversing hepatic coma. These data argue strongly in favour of a therapeutic effect of branched chain amino acids in the treatment of hepatic encephalopathy in patients with chronic liver failure.

Ghrelin: from discovery to cancer cachexia therapy.

Purpose of reviewDespite the high prevalence of cancer cachexia, a condition that negatively impacts patients’ prognosis and quality of life, effective therapies are still lacking. Ghrelin is a peptide hormone involved in anabolic and homeostatic functions, whose mechanisms of action are still only partially clarified, but with promising positive effects in cancer cachexia. Recently, the therapeutic administration of ghrelin in cancer has been shown to counteract loss of body mass and function, including muscle, and we specifically focus on this novel evidence. Recent findingsRecent research aimed at developing new pharmacological therapies to prevent muscle wasting has used ghrelin and molecules acting as synthetic ghrelin receptor agonists with different modalities of administration and with high selectivity for specific targeted tissues. Positive effects of these therapies were described in cancer cachexia and chemotherapy-induced muscle wasting. New insights into the mechanisms of action of ghrelin revealed how its pleiotropic effects should be ascribed both to systemic anti-inflammation effect and to muscle-specific action through the activation of the antiatrophic molecular cascade. SummaryGrowing interest arises from the identification of ghrelin as a valid and well tolerated therapeutic option to counteract structural and functional wasting derived from tumour growth.

Plasma Amino Acid Concentrations in Patients With Acute Myelogenous Leukemia

Changes in plasma-free amino acid (PFAA) concentrations in the presence of solid tumors have been widely described. Conversely, the PFAA profile in patients with acute leukemias is less well defined. The aim of the present study was to clarify whether the PFAA profile is altered in patients with acute myeloid leukemia (AML), whether the profile differs from the PFAA profile of solid tumors, and whether it may predict outcome of AML. Fasting PFAA were measured in 40 untreated, normally nourished patients with AML (17 males, 23 females), ages 22-78 y, with white blood cell (WBC) counts ranging from 1.08 to 276.5 x 10(3)/cm2, and in 24 healthy volunteers. Plasma concentrations (mu mol/L, mean +/- SE) of glutamic acid (GLU), free tryptophan (FTRP), ornithine (ORN), and glycine (GLY) were significantly higher in AML (GLU: 90.2 +/- 6.1 versus 37 +/- 8; FTRP: 7.0 +/- 0.6 versus 4.8 +/- 0.3, P < 0.005; ORN: 108.7 +/- 5.8 versus 78 +/- 6, P < 0.001; GLY: 295.0 +/- 14.8 versus 239 +/- 9, P < 0.01), whereas serine (SER), methionine (MET), and taurine (TAU) were significantly lower in AML than in controls (SER: 109.0 +/- 5.8 versus 130 +/- 4, P < 0.03; MET: 25.5 +/- 1.3 versus 33 +/- 3, P < 0.03; TAU: 46.5 +/- 3.5 versus 81 +/- 2, P < 0.001), and tended to be even lower in patients who had not responded to chemotherapy or had relapsed within 18 mo of enrollment. Such changes were unrelated to age, sex, and WBC count. Changes in PFAA that occur in AML are only in part similar to those observed in solid tumors. The reduction of TAU appears to be a typical feature of AML and might be secondary to the deficiency of its precursors SER and MET. Further studies are under way aimed at clarifying whether PFAA might predict prognosis in AML, whether PFAA is normalized by remission induction, and if its correction may be of any benefit for patients with hematologic malignancies.

Effects of 5-Hydroxytryptophan on Eating Behavior and Adherence to Dietary Prescriptions in Obese Adult Subjects

Changes in plasma amino acid levels by affecting the availability of neurotransmitter amino acid precursors within the brain may influence eating behavior (Wurtman et al., 1981; Fernstrom, 1983). Among the different neuro-transmitter systems, a number of theoretical and experimental data support the role played by serotonin in the regulation of eating habits (Lytle, 1977; Li et al., 1983). Rather recently, R.J. Wurtman et al. (1981) have shown that the serotonergic system plays an important role also in the selection of macronutrients, especially in obese people consuming preferentially carbohydrate-rich foods. Moreover, a “normalization” of such aberrant behavior was obtained by pharmacologically enhancing brain serotonin synthesis (J.J. Wurtman et al., 1981). A significant reduction in food intake has been reported by Blundell and Leshem (1975) in hyperphagic obese rats by administration of tion of 5-hydroxytryptophan (5-HTP). Previous experiences from this laboratory in a group of obese adult female subjects have shown that the oral administration of 5-HTP caused the onset of typical anorexia-related symptoms, decreased food intake and promoted weight loss in the absence of any dietary restriction (Ceci et al., 1989). The aim of the present study was to confirm these data in a longer study period and to verify whether the adherence to dietary prescriptions could be improved by oral administration of 5-HTP.

Early changes of muscle IGF-1 and myostatin gene expression in gastric cancer patients

Cachexia increases morbidity and mortality of cancer patients. The progressive loss of muscle mass negatively affects physical function and quality of life. We previously showed reduced muscle insulin‐like growth factor‐1 (IGF‐1) expression and enhanced myostatin signaling in tumor‐bearing animals. This study was aimed at investigating whether similar perturbations occur in gastric cancer patients.

Protein Kinases in the Pathogenesis of Muscle Wasting

The skeletal muscle is a very heterogeneous tissue, that is in charge of a broad range of functions such as movement, stability, heat production and cold tolerance. It represents approximately 50% of total body protein, and plays a central role in whole body metabolism (Bassel-Duby & Olson, 2006). In the last two decades, the skeletal muscle, previously considered as a mere protein reservoir, has been shown to release cytokines and other humoral factors (Pedersen & Febbraio, 2008). This tissue plays a pivotal role in the overall energy balance. Indeed, it regulates lipid flux, takes up and stores most of plasma glucose, and modulates insulin sensitivity. In this regard, the skeletal muscle likely plays a crucial role in pathological states characterized by peripheral insulin resistance such as obesity, as also suggested by recent evidence showing the occurrence of a cross-talk between muscle and the adipose tissue (reviewed in Clarke & Henry, 2010).

Anorexia and serum leptin levels in hemodialysis patients

BACKGROUND AND AIMS Hyperleptinemia is a common feature in hemodialysis (HD) patients. However, the role of increased serum leptin levels in the pathogenesis of HD-related anorexia is still controversial. The purpose of the present prospective study was to ascertain whether hyperleptinemia is causally implicated in the pathogenesis of HD-related anorexia. METHODS We measured the serum leptin levels and the serum leptin/body mass index (BMI) ratio in 24 healthy subjects and in 49 end-stage renal disease patients on maintenance HD. HD patients were subdivided into anorexic (14/49, 28.5%) and non-anorexic (35/49, 71.5%) according to a questionnaire discriminating for the presence of anorexia-related symptoms. RESULTS Calorie (kcal/kg/day) and protein (g/ kg/day) intakes were significantly lower in anorexic than in non-anorexic patients (20.1 +/- 1.1 vs. 27.9 +/- 1.3, p = 0.004, and 0.82 +/- 0.05 vs. 1.19 +/- 0.05, p = 0.001, respectively). Accordingly, serum albumin, total lymphocyte count, mid-arm muscle circumference, and the protein equivalence of nitrogen appearance (PNA) were significantly lower in anorexic patients. The serum leptin concentration (ng/ml) was significantly higher in HD patients than in controls, in males (15.33 +/- 3.4 vs. 3.7 +/- 0.3, p = 0.003) and in females (42.3 +/- 7.2 vs. 10.5 +/- 1.3, p = 0.03). Similarly, serum leptin/BMI ratio was significantly higher in HD patients than in controls, in males (0.56 +/- 0.1 vs. 0.16 +/- 0.02, p = 0.0028) and in females (1.8 +/- 0.2 vs. 0.4 +/- 0.04, p < 0.0001). However, serum leptin levels were similar in anorexic and in non-anorexic patients, in males (15.3 +/- 5.6 vs. 16.9 +/- 4.2, p = 0.85) and in females (46.6 +/- 12.9 vs. 47.4 +/- 9.4, p = 0.96). No differences were observed between the 2 groups in the serum leptin/BMI ratio, in males (0.59 +/- 0.2 vs. 0.58 +/- 0.14, p = 0.92) and in females (1.5 +/- 0.4 vs. 1.8 +/- 0.3, p = 0.94). Similarly, no statistically significant differences in terms of serum leptin levels and leptin/BMI ratio were observed between patients with dietary energy intake of <30 or > or =30 kcal/kg/day and between those with a dietary protein intake of <1.2 or > or =1.2 g/kg/day. No significant correlations were found between serum leptin levels and PNA, albumin, cholesterol, total lymphocytes number, weight change, C-reactive protein, fibrinogen, ferritin, and complement. CONCLUSION The present results indicate that mechanisms other than increases in serum leptin levels might be involved in the pathogenesis of HD-related anorexia.