Perspectives of health care professionals on cancer cachexia: results from three global surveys.

BACKGROUND: Cachexia has a high prevalence in cancer patients and negatively impacts prognosis, quality of life (QOL), and tolerance/response to treatments. This study reports the results of three surveys designed to gain insights into cancer cachexia (CC) awareness, understanding, and treatment practices among health care professionals (HCPs). METHODS: Surveys were conducted globally among HCPs involved in CC management. Topics evaluated included definitions and synonyms of CC, diagnosis and treatment practices, and goals and desired improvements of CC treatment. RESULTS: In total, 742 HCPs from 14 different countries participated in the surveys. The majority (97%) of participants were medical oncologists or hematologists. CC was most frequently defined as weight loss (86%) and loss of appetite (46%). The terms loss of weight and decreased appetite (51% and 34%, respectively) were often provided as synonyms of CC. Almost half (46%) of the participants reported diagnosing CC and beginning treatment if a patient experienced a weight loss of 10%. However, 48% of the participants would wait until weight loss was ≥15% to diagnose CC and start treatment. HCPs also reported that 61%-77% of cancer patients do not receive any prescription medication for CC before Stage IV of disease is reached. Ability to promote weight gain was rated as the most important factor for selecting CC treatment. Key goals of treatment included ensuring that patients can cope with the cancer and treatment and have a QOL benefit. HCPs expressed desire for treatments with a more CC-specific mode of action and therapies that enhance QOL. CONCLUSIONS: These surveys underscore the need for increased awareness among HCPs of CC and its management.

Muscle myostatin signalling is enhanced in experimental cancer cachexia.

BACKGROUND/AIMS: Myostatin belongs to the transforming growth factor-beta superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH-130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor-alpha may be relevant in this regard. MATERIALS AND METHODS: Protein levels of myostatin, follistatin (myostatin endogenous inhibitor) and the activin receptor type IIB have been evaluated in the gastrocnemius of tumour-bearing rats by Western blotting. Circulating myostatin and follistatin in tumour hosts were evaluated by immunoprecipitation, while the DNA-binding activity of the SMAD transcription factors was determined by electrophoretic-mobility shift assay. RESULTS: In day 4 tumour hosts muscle myostatin levels were comparable to controls, yet follistatin was reduced, and SMAD DNA-binding activity was enhanced. At day 7, both myostatin and follistatin increased in tumour bearers, while SMAD DNA-binding activity was unchanged. To investigate whether tumour necrosis factor-alpha contributed to induce such changes, rats were administered pentoxifylline, an inhibitor of tumour necrosis factor-alpha synthesis that partially corrects muscle depletion in tumour-bearing rats. The drug reduced both myostatin expression and SMAD DNA-binding activity in day 4 tumour hosts and up-regulated follistatin at day 7. CONCLUSIONS: These observations suggest that myostatin pathway should be regarded as a potential therapeutic target in cancer cachexia.

Amino acids and hepatic encephalopathy.

The consideration of HE and its etiology has undergone a radical turn within the past decade. At present HE is seen in the context of severe metabolic derangements, which failure of the liver, the central biochemical powerhouse of the body, must bring with it. The increased awarenesses on the biochemical mechanisms involved in the pathogenesis of HE have found, step by step, their own place in a complex but consequential mosaic of events, in which amino acid and HE are tightly linked. Clinical and experimental studies are needed to further improve the knowledge in this field, nontheless a certain number of corner-stones can be identified: A profound alteration of the central nervous system neurotransmission is responsible for most, if not all, of the symptoms characterizing HE. The plasma amino acid imbalance observed in cirrhotic patients represents a 'condicio sine qua non' HE may develop. A functional impairment of the amino acid transport systems at the level of the blood-brain barrier seems to play a crucial role in causing deleterious modifications of the synaptic neurotransmission in the central nervous system. The reduction of the brain entry of the "toxic" aromatic amino acids usually obtained by parenteral administration of especially tailored amino acid mixtures is most frequently followed by awakening from HE. In conclusion, most of the results obtained have demonstrated that HE represents a research field in which progresses in the knowledge of some of the pathogenic mechanisms have brought the investigators to new therapeutic approaches which have clearly improved the prognosis of patients suffering from this severe neuropsychiatric syndrome.

Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation.

Cachexia is a syndrome characterized by profound skeletal muscle wasting that frequently complicates malignancies. A number of studies indicate that protein hypercatabolism, largely mediated by classical hormones and cytokines, is the major component of muscle depletion. Impaired regeneration has been suggested to contribute to the reduction of muscle size. In particular, it has been shown that the expression of MyoD, a muscle-specific transcription factor, is down-regulated by cytokines such as TNFalpha and IFNgamma in a NF-kappaB-dependent posttranscriptional manner. The present study investigated whether modulations of the transcription factor MyoD are associated with the onset of muscle wasting in a well established model of cancer cachexia. Rats bearing the Yoshida AH-130 hepatoma develop a condition of muscle protein hypercatabolism, largely dependent on TNFalpha bioactivity. In the gastrocnemius of these animals the expression of MyoD was markedly reduced, paralleling the decrease of muscle weight. This pattern is associated with increased nuclear translocation of AP-1, while DNA-binding assays did not detect any change in NF-kappaB activity. This is the first observation demonstrating that muscle depletion in tumor-bearing rats is associated with a down-regulation of MyoD levels. Although the underlying mechanisms remain to be clarified, this change is compatible with the hypothesis that a reduced expression of molecules involved in the regulation of the regenerative response may concur to muscle wasting in cancer cachexia.

Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan.

Previous observations have shown that oral administration of 5-hydroxytryptophan (5-HTP) without dietary prescriptions causes anorexia, decreased food intake, and weight loss in obese subjects. To confirm these data over a longer period of observation and to verify whether adherence to dietary restriction could be improved by 5-HTP, 20 obese patients were randomly assigned to receive either 5-HTP (900 mg/d) or a placebo. The study was double-blinded and was for two consecutive 6-wk periods. No diet was prescribed during the first period, a 5040-kJ/d diet was recommended for the second. Significant weight loss was observed in 5-HTP-treated patients during both periods. A reduction in carbohydrate intake and a consistent presence of early satiety were also found. These findings together with the good tolerance observed suggest that 5-HTP may be safely used to treat obesity.

Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation.

BACKGROUND: Nutrients may interfere with physiological and pathophysiologic mechanisms. The present study was aimed at evaluating whether the differences in the quality of energy substrates administered with total parenteral nutrition (TPN) after cytoreductive therapy may influence the clinical outcome of patients undergoing bone marrow transplantation (BMT). METHODS: Sixty-six consecutive allogeneic BMT patients with hematologic malignancies were randomized to receive either a glucose-based (100% glucose) or a lipid-based (80% lipid, using an omega-6 long-chain triacylglycerol emulsion + 20% glucose) TPN, providing 146.3 kJ/kg body weight, 1.4 g of protein/kg of body weight, administered from day +1 to day +15 after BMT. Time to engraftment (EGT), incidence of sepsis and metabolic complications (hyperglycemia and hypertriglyceridemia), incidence of acute graft-versus-host-disease (A-GVHD) and relapse, survival at 18 months, incidence of deaths for A-GVHD and relapse were evaluated. RESULTS: Six patients dropped out before completing the study period. Thirty-one patients in the glucose-based TPN group and 29 patients in the lipid-based TPN group were evaluated. The incidence of hyperglycemia was significantly lower in the lipid-based TPN group than in the glucose-based TPN group (3.4% vs. 32%, respectively; P=0.004). Five patients in the glucose group and none in the lipid group died for A-GVHD (P<0.05). Survival at 18 months tended to be higher in the lipid group than in the glucose group (62% vs. 42%, P=NS). Rate of bone-marrow EGT, time to EGT, incidence of sepsis and fungal infections during TPN, incidence of A-GVHD, and rate of relapse at 18 months were not different in the two groups. CONCLUSIONS: The results obtained suggest that the use of lipid-based TPN after allogeneic BMT is associated with lower incidence of lethal A-GVHD and hyperglycemia, without negatively affecting the EGT of infused cells. Intravenously administered lipids might have influenced the severity of A-GVHD likely via modulation of immune response and synthesis of cytokines, prostaglandins, and leukotrienes that participate in the pathogenesis of graft-versus-host disease.

VMN hypothalamic dopamine and serotonin in anorectic septic rats.

During sepsis, catabolism of proteins and associated changes in plasma amino acids occur. Tryptophan and tyrosine, and their derivatives serotonin (5-HT) and dopamine (DA), influence hypothalamic feeding-related areas and are associated with the onset of anorexia. We hypothesized that anorexia of sepsis is associated with changes in serotonin and dopamine in the ventromedial nucleus (VMN) of the hypothalamus. The aim of this study was to test our hypothesis by measuring intra-VMN changes of these two neurotransmitters at the onset of anorexia during sepsis. Fischer 344 male rats had an intracerebral guide cannula stereotaxically implanted into the VMN. Ten days later, in awake, overnight-food-deprived rats, a microdialysis probe was inserted through the in situ VMN cannula. Two hours thereafter, serial baseline serotonin and dopamine concentrations were measured. Then cecal ligation and puncture to induce sepsis or a control laparotomy was performed under isoflurane anesthesia. VMN microdialysis samples were serially collected every 30 min for 8 h after the surgical procedure to determine 5-HT and DA changes in response to sepsis. During the hypermetabolic response to sepsis, a strong association occurred between anorexia and a significant reduction of VMN dopamine concentration (P < 0.05; constant rate of dopamine decrease in the Study group of 0.99 pg per 2 h); no changes occurred in 5-HT in association with anorexia of sepsis. Six hours after operation, a single meal was offered for 20 min to assess the response of neurotransmitters to food ingestion. Food intake was minimal in anorectic septic rats (mean size of the after food-deprived meal in the Septic group was 0.03+/-0.01 g, that of the Control group was 1.27+/-0.14 g; P = 0.0001), while Control rats demonstrated anticipated changes in neurotransmitters in response to eating. We conclude that the onset of anorexia in septic rats is associated with a reduction in VMN dopamine.

Idiopathic AL amyloidosis and biclonal paraproteinemia: a case report and review of the literature.

A case of 79 year-old man suffering from nephrotic syndrome, infiltrative cardiomyopathy and sensitive neuropathy of the lower limbs, associated with biclonal gammopathy (IgG K and IgA A), is described. There was a history of non-insulin dependent diabetes mellitus and of two lung nodules considered as benign lesions on the basis of cytologic, hematologic and instrumental examination. A rectal biopsy positive for amyloid deposition (Congo red histology and immunofluorescence study) led to the diagnosis of AL amyloidosis. Considering that the patient did not fulfill diagnostic criteria for lymphoproliferative diaseases (myeloma, lymphoma or Waldenström's macroglubulinemia), nor for secondary malignant paraproteinemia, a diagnosis of idiopathic AL amyloidosis with biclonal gammopathy was made. Very few cases of idiopathic AL amyloidosis with double component are reported in the literature. Our review suggests that idiopathic AL amyloidosis with biclonal gammopathy is similar to idiopathic AL amyloidosis with monoclonal paraproteinemia in terms of clinical features, response to therapy and prognosis. Further studies, however, are necessary to clarify the true incidence and the clinical features of idopathic AL amyloidosis associated with biclonal gammopathy.

Total and individual free fatty acid concentrations in liver cirrhosis.

The finding of high plasma free fatty acid (FFA) levels in cirrhotic patients has been attributed either to decreased hepatic clearance or to enhanced fat mobilization. To better clarify these hypotheses, total and individual FFA and glycerol levels were determined in 21 cirrhotic patients with different degrees of hepatocellular damage (evaluated by liver function tests), portal hypertension (evaluated by endoscopy and clinical signs), and nutritional status (evaluated by anthropometric and biohumoral parameters) and in 10 age- and sex-matched healthy subjects. Glucose tolerance and insulin and glucagon levels were determined in all individuals. Well-nourished and malnourished patients were identified within the cirrhotic group. Plasma FFA and glycerol concentrations were well correlated (r = 0.47, P less than 0.05), levels being significantly higher in cirrhotic individuals than in controls (746.6 +/- 46.29 SE v 359.22 +/- 40.82 mumol/L, P less than 0.001 for plasma FFA; 150.1 +/- 3.12 v 82.5 +/- 9.2 mumol/L, P less than 0.01 for glycerol). Plasma FFA and glycerol showed no correlation with the liver function test results or portal hypertension parameters. Interestingly, plasma levels of FFA and glycerol were influenced by the nutritional status, significantly higher FFA levels being observed in the well-nourished than in the malnourished patients (842.5 +/- 47.5 v 563.4 +/- 78 mumol/L, P less than 0.005). Furthermore, a positive correlation was found between plasma glycerol level and percentage of triceps skinfold (r = 0.45, P less than 0.05). No correlation was found between plasma levels of FFA or glycerol and glucose tolerance, insulin and glucagon.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous radioenzymatic determination of phenylethylamine, phenylethanolamine, tyramine and octopamine in plasma of patients with hepatic encephalopathy.

A sensitive radioenzymatic assay for the simultaneous determination of phenylethylamine, phenylethanolamine, tyramine and octopamine in plasma samples is reported. After extraction with ethanol, the amines are subjected to enzymatic N-methylation with labelled S-adenosylmethionine, preceded in the case of phenylethylamine and of tyramine, by an enzyme-catalyzed beta-hydroxylation step. The procedure is completed by extraction with toluene containing different amounts of isoamylalcohol, followed by controlled evaporation of the solvent. A generalized and highly significant increase in the concentration of all the four amines was found in plasma samples from patients suffering from hepatic encephalopathy.

Octopamine and ammonia plasma levels in hepatic encephalopathy.

It has been recently proposed that hepatic encephalopathy could be due to the accumulation of octopamine acting as a false neurotransmitter, and the increase of ammonia might reflect this accumulation. The simultaneous determination of octopamine and ammonia was performed in 88 cases with or without encephalopathy. The correlation between the two substances appeared to be good (P less than 0.01; r = 0.5), except in shunted patients. All the cases with low octopamine and high ammonia were patients who had been submitted to surgical portal-systemic anastomosis. This finding does not seem to be coincidental; in this type of patients, the mechanism of hepatic encephalopathy could involve other beta-hydroxyphenylethanolamines in addition to octopamine. The presence of the inhibition of the reaction of transmethylation constantly observed during octopamine plasma assay is in favour of this hypothesis.

Influence of phenylethanolamine on octopamine plasma determination in hepatic encephalopathy.

Octopamine and phenylethanolamine levels were measured by a radioenzymatic procedure in 30 cirrhotic patients with and without hepatic coma and in 15 normal controls. Octopamine data were obtained either by direct extraction with 40% isoamyl alcohol in toluene according to Molinoff et al. (Molinoff, P.B., Landsberg, L. and Axelrod, J. (1969) J. Pharm. Exp. Ther. 170, 253), or after pre-extraction of phenylethanolamine with 3% isoamyl alcohol in toluene. Phenylethanolamine was statistically correlated with the grade of hepatic encephalopathy. Octopamine levels also appeared to parallel the grade of coma, although the values obtained after pre-extraction were lower and less significant than those obtained with 40% isoamyl alcohol in toluene extraction. The higher values of directly extracted octopamine are due to contamination of other beta-hydroxylated phenylethylamines, among which is phenylethanolamine.

Octopamine plasma levels and hepatic encephalopathy: a re-appraisal of the problem.

An investigation on the blood levels of octopamine was carried out on 70 adult individuals. There was a statistically significant correlation between the levels of octopamine and hepatic encephalopathy. Normal subjects had values below 1 ng/ml, while patients with grade 3 or grade 4 encephalopathy constantly showed values above 3.2 ng/ml. In these two groups the distribution was fairly homogeneous. Through the differences between cirrhotics without neurologic involvement and those with grade 1 or 2 hepatic encephalopathy displayed statistical significance, distribution of values in these groups was rather non-homogeneous. Octopamine levels paralleled variations in mental state in 3 out 4 cases. No difference was found between venous and arterial values. The reaction of transmethylation used in the assay of octopamine was constantly found to be inhibited by the presence of plasma. This inhibition is probably due to the presence of one or more beta-hydroxyphenylethanolamines other than octopamine.

Involvement of plasma leptin, insulin and free tryptophan in cytokine-induced anorexia.

BACKGROUND: Hypothalamic serotonin, the synthesis of which parallels plasma free tryptophan, contributes to satiety. Plasma free tryptophan, insulin and leptin, all of which can also decrease food intake partly via the hypothalamic serotonergic system, are modulated by cytokines, which decrease food intake. The mechanisms of anorexia induced by cytokines, as related to plasma tryptophan, leptin and insulin, have not been fully determined. OBJECTIVE: We determined the plasma concentrations of free as well as total tryptophan, leptin and insulin, and correlations to those of food intake and body weight change after cytokines or tryptophan injection. DESIGN: Interleukin-1alpha and/or tumor necrosis factor-alpha, or tryptophan was injected subcutaneously into male rats for 2 days. Daily food intake, body weight, carcass adiposity, plasma total as well as free tryptophan, plasma leptin and insulin were measured. RESULTS: Interleukin-1alpha injection decreased food intake, body weight, carcass adiposity and plasma leptin, but increased plasma free tryptophan and insulin. Tryptophan injection increased both free and total tryptophan, but did not change food intake, body weight, carcass adiposity or leptin. Plasma free tryptophan, but not total tryptophan, was significantly negatively correlated with food intake. There was a negative correlation between plasma insulin and food intake. CONCLUSIONS: Increased plasma free tryptophan may contribute to synthesis of brain serotonin but anorexia may be due to stimulation of its release induced by interleukin-1alpha. Plasma insulin, but not leptin, may partly contribute to anorexia of cytokines.

Comparative effects of arginine and other amino acid deprivation on in vitro expression of lymphocyte activation markers.

Enteral or parenteral arginine supplementation enhances lymphocyte activation after mitogenic stimulation, in rats and humans. Arginine deprivation in culture media is associated with a reduction of lymphocyte activation; this effect, however, has not yet been proven to be specific for arginine. This study was designed to evaluate the specificity of arginine deprivation from culture media on the reduction of in vitro lymphocyte activation. Peripheral blood mononuclear cells, obtained from 11 healthy volunteers, were cultured in RPMI 1640, selectively deprived of single amino acids (i.e. arginine, phenylalanine, leucine, methionine, and threonine) and supplemented with phytohemagglutinin (PHA). The expression of interleukin-2 receptor and transferrin receptor was evaluated by cytometric analysis; the levels of soluble IL-2 receptor were determined by immuno-enzymatic assay. Results were compared with those obtained by culturing cells in non-deprived, RPMI 1640 medium. The expression of transferrin and IL-2 receptor, as well as the levels of IL-2 soluble receptor, were significantly reduced in all deprived media irrespective of the lacking amino acid. These results suggest that the reduction of in vitro lymphocyte activation is not an arginine specific effect. Therefore, the known enhancement of immune response, following arginine supplementation in vivo, is likely to involve a more complex series of events.

Effect of energy substrate manipulation on tumour cell proliferation in parenterally fed cancer patients.

The effects of isocaloric carbohydrate-based vs. fat-based total parenteral nutrition (TPN) regimens on cancer cell proliferation and host nutritional status were evaluated in 27 patients with tumours of the gastro intestinal tract consecutively assigned to receive for 14 days: a glucose-based (A) or a lipid-based (B) TPN formula, or an oral diet (C) isocaloric and isonitrogenous to A and B. Cancer cell replication rate was evaluated by thymidine labelling index (LI) on tumour samples before and at the end of each nutritional regimen. The number of replicating cells increased by 32.2% in patients receiving regimen A. LI decreased by 24.3% in patients given regimen B. LI values were slightly increased (+15%) in patients maintained on regimen C. Nutritional status remained within normal limits. None of the LI changes observed between and within the three arms of the trial were found to be statistically significant. Thus we failed to prove that glucose consistently stimulates or lipids inhibit tumour proliferation despite a trend in this sense.

Alternating intravenous courses of melphalan and peptichemio in high-risk multiple myeloma (preliminary results).

Six patients with high-risk multiple myeloma and one patient with primary amyloidosis were treated with a melphalan-peptichemio-prednisone association (PMP). The response trend seems promising, also in view of the low regimen bone marrow toxicity, but further studies could better evaluate the optimal PMP scheduling and peptichemio side effects.

Increased plasma free tryptophan levels in human cancer: a tumor related effect?

High free tryptophan (F-TRP) plasma levels are found in cancer patients (CP). F-TRP plasma concentrations are affected by the levels of its carrier, albumin (ALB), and free fatty acids (FFA) competing with TRP for ALB binding sites. The lack of correlation between F-TRP, ALB and FFA in CP suggests a tumor-dependent effect on the rise in F-TRP. To verify this hypothesis, F-TRP, ALB and FFA levels were assayed in 12 lung and 16 breast CP susceptible to radical surgery, before and 15 days after surgical removal of the tumor. F-TRP levels significantly decreased after tumor ablation. Since no correlation was found between F-TRP, ALB and FFA variations, it is conceivable that the tumor itself may be responsible for the high F-TRP levels in CP.

Plasma amino acid imbalance in patients with lung and breast cancer.

In order to evaluate whether different solid tumors may specifically influence plasma free amino acid (PFAA) profile, PFAA were analysed in seventy-four patients with lung (41 patients) and breast cancer (33 patients) and 28 healthy subjects. In lung cancer patients a significant reduction of gluconeogenic amino acids, threonine, serine, glycine and a significant increase of free tryptophan and glutamic acid was found. In breast cancer patients a significant increase of ornithine, glutamic acid and free tryptophan was found. The comparison of PFAA profiles between lung and breast cancer suggests that different tumors have a different influence on the host's PFAA pattern.