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PubMed2003

A chart review, pilot study of two single-item screens to detect cancer patients at risk for cachexia.

OBJECTIVE: Cachexia is a problematic wasting syndrome experienced by some cancer patients that can lead to early death in these patients. The purpose of the present study was to examine the criterion validity and sensitivity and specificity of two single items from a depression scale to rapidly screen patients in ambulatory oncology clinics for cancer-related nutritional risk and cachexia. METHODS: A chart review was conducted of 50 randomly selected patient profiles. Patients' responses to item 5 ("I eat as much as I used to") and item 7 ("I notice I am losing weight") of the Zung Self Rating Depression Scale (ZSDS) were compared against the Scored Patient-Generated Subjective Global Assessment (PG-SGA) as well as to Body Mass Index (BMI) scores and weight at two time periods. RESULTS: Item 5 of the ZSDS was significantly related to initial weight (F3,45 = 6.06, p < 0.001), weight at 6-month follow-up (F3,27 = 4.16, p < 0.05), BMI score (F3,46 = 2.89, p < 0.05), and nutritional risk on the PG-SGA (F3,45 = 5.80, p < 0.01). Item 7 of the ZSDS was only a significant predictor of nutritional risk as measured by the PG-SGA (F3,46 = 6.01, p < 0.01). When the two items were combined to form a two-item scale, it maintained the individual items' significant relationship to the PG-SGA (F1,48 = 13.99, p < 0.001). Using this as the criterion for identifying nutritionally at-risk patients, the two-item screen yields a sensitivity of 50% and specificity of 88%. SIGNIFICANCE OF THE RESEARCH: It is concluded that a single item or a combination of two items can yield a reliable initial screen for identifying patients who might be at nutritional risk for the development of cachexia. Further study is needed in prospective trials to further explore the utility of these items.

Analysis of Variance↗

PubMed1991

Suppression of lipoprotein lipase in 3T3-L1 cells by a mediator produced by SEKI melanoma, a cachexia-inducing human melanoma cell line.

Production of a cachexia-inducing factor(s) by the SEKI melanoma cell line, established from a human melanoma, has been well documented. Conditioned medium from cultures of this melanoma cell line contains a factor(s) that inhibits the activity of lipoprotein lipase (LPL) in fully differentiated 3T3-L1 adipocytes. The mode of inhibition of this enzyme by the factor, i.e. its dose-dependency and time course, is very similar to that of LPL-inhibition by a macrophage-derived cachexia-inducing factor, cachectin/tumor necrosis factor (cachectin/TNF). However, the conditioned medium of SEKI melanoma cells does not contain any immuno-reactive substances reactive in enzyme-linked immunosorbent assay (ELISA) with anti-cachectin/TNF antibody, or with anti-interleukin 1 alpha or beta antibodies. This LPL-suppression factor present in the conditioned medium seems to be a peptide because of its heat-lability and apparent molecular weight of more than 25,000. The conditioned media from cultures of four other different cell lines were found to show no significant suppression of LPL activity. These results imply that SEKI melanoma cells produce a cachexia-inducing factor(s) similar to cachectin/TNF but that the molecule involved is different.

Animals↗

PubMed1985

Insulin reversal of cancer cachexia in rats.

The anabolic effects of exogenous neutral protamine hagedorn insulin on tumor-bearing (TB) and non-tumor-bearing (NTB) rats were examined. Exogenous insulin (2 units/100 g/day) produced similar hypoglycemia in TB and NTB rats. Food intake and body weight gain were significantly increased by insulin in NTB rats. In TB rats in an early stage of cachexia, insulin increased food intake and host weight (total body weight minus tumor weight). In TB rats with severe cachexia, insulin increased food intake and stabilized host weight when untreated TB controls were not eating and were losing weight. When daily insulin administration was started at an early stage of tumor growth and continued until death, there was again significant enhancement of host weight and food intake. Heart and adrenal weights were significantly reduced in insulin-treated TB animals. Tumor growth was not stimulated by insulin treatment. Survival time was slightly reduced in TB rats treated with long-term insulin. Survival time in TB rats randomized to insulin during late cachectic decline was not different from untreated TB controls. Insulin did not have any measurable effect on energy expenditure or the motor activity compartment of energy expenditure in either TB or NTB rats. Insulin treatment can reverse experimental cancer cachexia. It is a nutritional therapy which preferentially feeds the host over the tumor. As yet, its beneficial effects have not prolonged survival of tumor-bearing animals.

Animals↗

PubMedDate not supplied

Cancer cachexia in man: a review.

There are many factors which are responsible for the high incidence of cachexia in human neoplasia. In this review, those considered to be of major importance are discussed. Nutritional disturbances, such as anorexia and malabsorption, are common and nutritional repletion may be beneficial to certain patients. Raised metabolic rate and energy expenditure are also encountered. Tumour cells may act as a nitrogen trap or energy sink, but the significance of these mechanisms in man is questionable. Ectopic hormone production by tumours is well established and a number of tumour-derived substances have been described which interfere with the intermediary metabolism of the host. The significance of these various substances also remains uncertain. Most experimental studies of cancer cachexia have utilized transplantable animal tumour models which bear a poor resemblance to the clinical condition. Development of more suitable models with human tumour xenografts might allow a quicker and better understanding of the aetiologies of human cancer-induced cachexia.

Animals↗

PubMed1969

Juvenile polyps with cachexia. Report of an infant and comparison with Cronkhite-Canada syndrome in adults.

Juvenile polyps occur in adults and infants; where multiple, they may be complicated by progressive cachexia with hypoalbuminemia and electrolyte depletion. We report a fatal case of multiple juvenile polyposis with cachexia, alopecia, and megalocephaly presenting in a 9-month-old infant, and review 2 additional cases in infancy. A similar syndrome in adults had been described by Cronkhite and Canada, with intestinal polyposis, nail dystrophy, hyperpigmentation, and alopecia. Histological examination of a polyp from one case of Cronkhite-Canada syndrome suggests a juvenile rather than adenomatous pathology. Multiple juvenile polyps can cause devastating enteropathy and cachexia.

Adenomatous Polyposis Coli↗

PubMed1997

Involvement of cytokines in cachexia induced by T-cell leukaemia in the rat.

The objective of this study was to investigate the involvement of cytokines (IL-1, IL-6 and TNF-alpha) in cachexia induced by T-cell leukaemia in the rat. Leukaemic rats exhibited a marked and significant increase in circulating IL-6 concentration from days 12-17 corresponding to the period of weight loss after induction of leukaemia. IL-6 plasma bioactivity correlated significantly with spleen weight and weight loss, implicating IL-6 in the cachectic response. In contrast, IL-1 and TNF-alpha plasma bioactivities were not increased compared to control rats, indicating that these cytokines are not circulating mediators of cachexia induced by T-cell leukaemia in the rat. These data suggest that IL-6 produced by the host may contribute to cachexia induced by T-cell leukaemia.

Animals↗

PubMed1995

Inhibition of experimental cancer cachexia by anti-cytokine and anti-cytokine-receptor therapy.

Cachexia consists of a constellation of metabolic changes that occur in cancer patients, including the reduction of muscle and fat tissue, asthenia, anorexia, hypoglycemia and hypercalcemia. These syndromes complicate therapeutic intervention and decrease the quality of life of the patient. This review discusses the involvement of cytokines in cancer cachexia and describes the contribution of IL-6 and other cytokines to the wasting of C-26-bearing mice. The neutralization of IL-6 by antibody, or IL-6 receptor antagonism by suramin, significantly reduce the severity of key parameters of cachexia. The participation of several other factors (PGE2, IL-1, IL-10 and TNF-alpha) in the cellular communication between the C-26 tumor cell and tumor-infiltrating macrophages is also described.

Animals↗

PubMed1998

Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover.

BACKGROUND: Data available in the literature regarding whole body protein (WBP) kinetics in patients with cachexia due to cancer are conflicting. Some authors have reported an increase of WBP synthesis and breakdown, whereas others have not found any significant changes; only a few researchers have investigated more compartments simultaneously. The main purpose of this study was to investigate WBP and skeletal muscle protein (SMP) turnover simultaneously in cachectic patients to understand better the mechanisms underlying the general wasting of the host present in cancer cachexia. METHODS: WBP and SMP synthesis and breakdown were studied in malnourished patients with advanced gastric carcinoma and in healthy volunteers. Protein turnover was evaluated in a postabsorptive state, using a model based on a primed constant infusion of L-[(2)H5] phenylalanine and L-[(2)H4]tyrosine, and by determining the isotopic enrichment and concentration in plasma during a plateau phase by gas chromatography and mass spectrometry. RESULTS: Rates of WBP synthesis and breakdown did not differ significantly between the two groups (whole body synthesis [WBS] of 4.35 +/- 0.2 g/kg/day and whole body breakdown [WBB] of 4.77 +/- 0.2 g/kg/day in the control group and WBS of 3.34 +/- 0.7 g/kg/day and WBB of 4.5 +/- 0.4 g/kg/day in the patient group). The skeletal muscle compartment of the patients showed a significantly lower synthesis compared with controls (patients, 9.6 +/- 1.8 nmol/100 mL/minute and control, 25.9 +/- 7.6 nmol/100 mL/minute; P < 0.05), whereas the breakdown was similar in the two groups. Such reduction in SMP synthesis in the gastric carcinoma patients resulted in a more negative net balance. CONCLUSIONS: Conflicting data in the literature may be accounted for by the different selection of patients and controls. Furthermore, WBP kinetics is the result of the metabolism of at least two compartments, the muscle and the nonmuscle compartments (including the tumor), which can change in opposite ways. In patients with cachexia due to cancer, the skeletal compartment appears to be the more compromised, with a significant decrease in SMP synthesis.

Adult↗

PubMed1998

Anticytokine approaches to the treatment of anorexia and cachexia.

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) have a prominent role in the pathogenesis of anorexia and cachexia of chronic disease. Pentoxyfylline and thalidomide are inhibitors of TNF-alpha that have been tried as rational therapeutic interventions in cachexia. Preliminary studies with pentoxyfylline have not shown efficacy in reversing weight loss, despite evidence of TNF-alpha inhibition. In contrast, the administration of thalidomide to patients with human immunodeficiency virus- and/or tuberculosis-associated weight loss has consistently resulted in weight gain. However, the relationship of the metabolic benefits of thalidomide treatment to its complex effects on the immune system is imperfectly understood. Studies of thalidomide, either alone or in combination with other therapies for the treatment of cancer cachexia, are warranted.

Anorexia↗

PubMed1991

Energy expenditure and protein synthesis rates in an animal model of cancer cachexia.

Food intake and energy expenditure of cachectic tumour bearing mice were measured during the course of weight loss. Four weeks after implantation of the MAC-16 tumour the body weight was reduced by 20%, there was no significant reduction in food intake, and body composition analysis revealed that both body fat and protein mass were decreased. Oxygen consumption and carbon dioxide production were measured over a 24h period both before and at weekly intervals after tumour implantation. There was a gradual increase in the rates of both oxygen consumption and carbon dioxide production per gram body weight. Similarly, energy expenditure per gram body weight was increased during the 3rd (11%) and 4th (23%) weeks. In contrast, the food intake per gram body weight was unchanged during the first three weeks and increased by only 8% during the 4th week. Despite the development of cachexia, rates of protein synthesis in the liver, heart, kidney and skeletal muscle were the same four weeks after tumour implantation as those in non-tumour bearing mice. Thus, in this murine model of cancer cachexia a negative energy balance resulted from failure of food intake to compensate for increased energy demands. These findings point to the unique pattern of metabolic alterations which occur in different models of cancer cachexia.

Journal Article↗

PubMed2002

The pathophysiology and treatment of cancer cachexia.

Cachexia in cancer patients is a major cause of morbidity and mortality. The syndrome of cachexia seems to be a facet of the inflammatory response to injury. This proinflammatory state is driven by an interdependent web of mediators such as cytokines, neurotransmitters, prostaglandins, neuroendocrine hormones, and tumor-derived catabolic factors. The resulting metabolic response to cancer prevents the effective use of calories provided and therefore blocks anabolism. The most promising interventions in cancer cachexia seem to depend on modulation of the inflammatory state (including nonsteroidal anti-inflammatory drugs and fish oil-based preparations). Suppression of the inflammatory milieu seems to allow nutrition to have an anabolic effect, resulting in gains in lean tissue with the potential to improve patient survival and quality of life.

Journal Article↗

PubMed1979

Cachexia of malignancy: potential role of insulin in nutritional management.

Patients manifesting the syndrome of cachexia of malignancy exhibit an abnormal diabetic glucose tolerance. In our patients this has been correlated with a marked resistance to administered insulin, while insulin receptors on monocytes are normal. Lipolysis remains responsive to the effects of insulin. The oxidation of FFA, as a substrate for metabolism, has been reported to be increased, and the utilization of glucose as a metabolic fuel is reduced. Increased Cori cycle activity has been demonstrated, which produces an enhanced gluconeogenesis from lactate and amino acids; there is an expenditure of 6 ATP for the synthesis of each mole of glucose. An attempt to interrupt the Cori cycle in man, using hydrazine sulfate to inhibit the enzyme phosphoenolpyruvate carboxykinase, has not resulted in reproducible clinical benefit. However, successful treatment of the underlying tumor may produce a total reversal of the cachexia syndrome, suggesting that neoplasms have the potential to elaborate an, as yet, unidentified metabolic toxin. The use of insulin to counteract the reported abnormalities should be examined as a possible supportive measure in the total nutritional management of the cancer patient.

Amino Acids↗

PubMed1991

Interaction between dactinomycin and tumor necrosis factor in mesothelioma. Cachexia without oncolysis.

There is no effective therapy for human malignant mesothelioma, and its susceptibility to recombinant cytokines has not been studied extensively. Recombinant human tumor necrosis factor alpha (rHuTNF alpha) was evaluated for its in vitro and in vivo antitumor activity using a human malignant mesothelioma cell line [DeH128(m)], both in culture and heterotransplanted in nude mice. In vitro, rHuTNF alone had no direct antimesothelioma activity assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, but in combination with the transcription inhibitor, dactinomycin (AD), mesothelioma cell metabolic activity was inhibited (80% of control). The effects of this combination of agents were studied on DeH128(m) cells heterotransplanted as subcutaneous tumors in nude mice. In vivo there was no significant inhibition of tumor growth by combined rHuTNF alpha and AD therapy, but the combination produced marked cachexia in doses at which each component (rHuTNF alone or AD alone) was well tolerated. The authors conclude that the well-described in vitro interaction between AD and rHuTNF also operates in vivo to produce cachexia and that the combination of these two agents is likely to have a low therapeutic index in malignant mesothelioma.

Animals↗

PubMed2001

Cancer cachexia: a therapeutic approach.

Cancer cachexia is a complex syndrome which occurs in more than two-thirds of patients who die with advanced cancer. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present study is to review the different therapeutic approaches that have been designed to fight and counteract cancer cachexia.

Cachexia↗

PubMed2002

Cachexia in rheumatoid arthritis is not explained by decreased growth hormone secretion.

OBJECTIVE: Patients with rheumatoid arthritis (RA) lose body cell mass (BCM) by unknown mechanisms. Since the loss of BCM in normal aging individuals parallels the characteristic age-related decline in growth hormone (GH) secretion, this study was carried out to determine whether further decreased GH secretion plays a role in the pathogenesis of this loss of BCM in RA patients, termed "rheumatoid cachexia." METHODS: GH secretory kinetics were determined by deconvolution analysis in 16 patients with RA and 17 healthy controls matched for age (mean +/- SD 45.4 +/- 13.2 years and 47.1 +/- 14.6 years, respectively), sex, race, and body mass index. Blood samples were obtained every 20 minutes for 24 hours. Body composition was ascertained using total-body potassium (TBK) as a measure of BCM and dual x-ray absorptiometry to determine fat mass. RESULTS: BCM was reduced in patients with RA compared with healthy controls (mean +/- SD gm TBK 79.5 +/- 9.5 versus 94.9 +/- 11.9; P < 0.0005), but there was no difference in fat mass. GH kinetic parameters in patients with RA did not differ from those in controls. CONCLUSION: These findings suggest that GH kinetics are unaltered in RA patients compared with healthy subjects; thus, GH deficiency does not account for rheumatoid cachexia.

Adult↗

PubMed1993

Cancer cachexia, malnutrition, and tissue protein turnover in experimental animals.

The role of malnutrition in the development of cachexia in rats bearing the Yoshida ascites hepatoma AH-130 was investigated by comparing the changes in tissue protein turnover in these animals with those observed in pair-fed controls. The tumor elicited in rats an early and conspicuous loss of body weight and tissue waste. Protein loss was particularly prominent for the gastrocnemius muscle and the heart and less pronounced for the soleus, while the diaphragm was little affected. Liver, kidneys, and spleen transiently increased in weight then regressed and eventually atrophied, while adrenals were enlarged over the whole experimental period. Protein waste was mainly due to acceleration of tissue protein breakdown, this protein hypercatabolic state being associated with increased cathepsin D activity in liver and gastrocnemius. In pair-fed animals the liver showed a marked protein loss resulting from enhanced catabolism, while the sharp decrease of heart protein content and the less prominent waste of the gastrocnemius were due to a reduction in protein synthesis. The total plasmatic concentration of free amino acids in AH-130-bearing rats was decreased at Day 4, when the tumor was actively proliferating, and returned to control values at Day 10, when the tumor had reached a stationary state. On the contrary, in pair-fed animals total plasma amino acids decreased over the whole experimental period. Plasma branched-chain amino acids were unchanged or even decreased in tumor hosts, while the Gly/Pro ratio was elevated in pair-fed rats. The intracellular concentration of free amino acids was higher in stationary than in exponentially- growing tumors, reflecting the enhanced proteolytic rates observed in stationary tumor cells. On the whole, the results suggest that reduced food uptake and metabolic competition by the tumor are not sufficient to justify the marked hypercatabolism in host tissues during the AH-130 hepatoma growth. The profound differences between tumor-bearing and pair-fed animals suggest that, if malnutrition undoubtedly played a role in this model of cancer cachexia, its effects were overwhelmed and subverted in the frame of the tumor-host interplay that dictated a distinctively peculiar syndrome.

Amino Acids↗

PubMed2000

DNA fragmentation occurs in skeletal muscle during tumor growth: A link with cancer cachexia?

In two different experimental models of cancer cachexia, the rat Yoshida AH-130 ascites hepatoma and the mouse Lewis lung carcinoma, the implantation of the tumor caused a loss of body weight which was associated with a reduction in the weight of different skeletal muscles, as well as with their protein content. The decrease in protein content was accompanied by a reduction in DNA content. Interestingly, the protein/DNA ratio was unchanged in the skeletal muscle of the tumor-bearing animals as compared with the non-tumor-bearing controls. Analysis of DNA fragmentation in skeletal muscle clearly showed enhanced laddering in the skeletal muscle of tumor-bearing animals, suggesting an apoptotic phenomenon. Interestingly, the degree of laddering (total DNA fragmented) increased with tumor burden. These results suggest that DNA fragmentation may be a primary event in cancer-associated cachexia.

Animals↗

PubMed1994

Growth failure and AIDS-like cachexia syndrome in HIV-1 transgenic mice.

The mechanisms which predispose to growth failure in infants and children infected with immunodeficiency virus type-1 (HIV-1) are not fully understood. The contributions of viral replication and CD4+ T cell depletion to growth failure in an HIV-1 transgenic mouse model were investigated. Mice homozygous for the transgene, a gag-pol deletion mutant of the HIV-1 provirus pNL4-3, exhibited marked cachexia, growth retardation, lymphoproliferation with a reduction in the percentage of CD4+ T cells but an increase in the absolute number of splenic CD4+ and CD8+ T cells, thymic hypoplasia, and early death. Despite the absence of T cells, athymic nude mice, homozygous for the HIV transgene, displayed comparable growth failure. The results indicate that AIDS-like cachexia may be produced by expression of viral envelope or accessory genes, need not be accompanied by absolute depletion of CD4+ T cells, and may occur independent of T cell function.

Acquired Immunodeficiency Syndrome↗