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PubMedDate not supplied

Mechanisms of paraneoplastic syndromes in mice bearing a spontaneous lung adenocarcinoma.

Paraneoplastic syndromes are rarely described in animal models. It may be useful to have a suitable experimental model to study the mechanisms by which they are produced. In this study, we describe a murine lung adenocarcinoma, P07, which presents hypercalcemia, leukocytosis and cachexia. We determined the presence of PTHrP in plasma as well as GM-CSF produced by P07 cells. TNF-alpha, which is responsible for cachexia, could neither be detected in serum nor in P07 cell supernatants. We conclude that this model, which shows paraneoplastic syndromes similar to those of lung tumor patients, should be useful to study the pathways and significance of these signs.

Adenocarcinoma↗
PubMed2001

Anti-cachectic effect of clarithromycin for patients with unresectable non-small cell lung cancer.

We have previously reported that long-term treatment with clarithromycin (CAM) increased the median survival of patients with non-small cell lung cancer, and improved various clinical parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer, who had received chemotherapy, radiotherapy or both (basic cancer therapy). Patients with clinical backgrounds matched to the CAM group, who did not receive CAM treatment, were included into this study as a control group (non-CAM group). CAM treatment was initiated 4 weeks after the basic cancer therapy. The non-CAM group did not receive a placebo. Before and after the 3-month treatment with CAM, body weight, serum levels of interleukin-6 (IL-6, a cytokine which, together with TNF-alpha, plays a crucial role in the development of cancer cachexia), total protein, albumin, cholinesterase and hemoglobin were measured for the evaluation of the patients' clinical status. There were no statistically significant differences in serum levels of IL-6 between the CAM group before the treatment and the non-CAM group. After 3 months of CAM treatment, serum levels of IL-6 significantly decreased. In contrast, body weight, cholinesterase, and hemoglobin increased to a significant extent. Among these four parameters, however, the decrease in serum IL-6 levels was only statistically correlated with the increase in body weight, but not with that in other parameters. Furthermore, CAM-treated patients whose serum IL-6 levels were decreased after 3 months of treatment survived longer: there was a statistically significant correlation between the decrease in serum IL-6 and survival time. In contrast, in the non-CAM group, these parameters did not change significantly during the study. These results suggest that CAM may reduce the progression of cancer-associated cachexia.

Aged↗
PubMed1994

Tumor necrosis factor involvement in the toxicity of TCDD: the role of endotoxin in the response.

We have previously demonstrated that tumor necrosis factor is involved in the acute toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), since therapies designed to attenuate the effects of tumor necrosis factor resulted in reduced mortality and toxicity in mice exposed to an LD75 dose of TCDD. The current study addresses whether endotoxin may be a contributing factor in the cachexia and mortality resulting from TCDD exposure. Endotoxin-nonresponsive C3H/HeJ mice and endotoxin-responsive C57BL/6 mice were treated with 350 micrograms/kg TCDD and body weight and mortality were recorded. C3H/HeJ mice showed no trend in body weight loss (p = 0.554), while C57BL/6 mice demonstrated a statistically significant (p < 0.01) linear decline in body weight of -0.23 g/day, resulting in a net loss of 3.5 g over 15 days preceding mortality. Mortality was observed in the C57BL/6 mice beginning on day 16 with 100% of the mice dying by the 23rd day while no mortality was observed in C3H/HeJ mice until the 24th day of the study with only 22% mortality observed. These data further demonstrate that endotoxin is a contributing factor to the cachexia and lethality of TCDD.

Animals↗
PubMed2006

Guidelines for the use of orexigenic drugs in long-term care.

Undernutrition is defined as a state induced by nutrient deficiency that may be improved solely by administration of nutrients. By this definition, provision of adequate protein and energy sources should reverse the clinical presentation and correct the problem. However, a large number of patients who seem to be undernourished fail to respond to refeeding. A developing understanding of the acute-phase inflammatory response to illness and the role of cytokines in the pathophysiology of chronic illness has challenged the current diagnostic paradigm of undernutrition. In the presence of adequate food, weight loss is most often due to cytokine-associated cachexia and anorexia. Failure of appetite, or anorexia, may play a role in involuntary weight loss. Intervention for involuntary weight loss should aim first at the provision of adequate calories and protein, often in the form of high-density nutrition supplements. However, cytokine-mediated cachexia is remarkably resistant to hypercaloric feeding. With continued weight loss, the use of an orexigenic drug should be considered. Orexigenic drugs have been demonstrated to improve appetite and produce weight gain. The mechanism is unknown but may relate to suppression of proinflammatory cytokines. General guidelines for the use of orexigenic agents are presented. Although much work remains to be done, anticytokine drugs seem to be a promising avenue for the treatment of involuntary weight loss.

Anorexia↗
PubMedDate not supplied

Whole-body protein metabolism in chronic heart failure: relationship to anabolic and catabolic hormones.

BACKGROUND: Patients with chronic heart failure frequently experience profound wasting during the course of the disease, a condition termed cardiac cachexia. Although protein is the primary structural and functional component of most tissues, few studies have examined the effect of heart failure on protein metabolism. Moreover, no study has assessed the relationship of protein turnover to hormonal alterations thought to promote cachexia. Thus, our goal was to determine if whole-body protein metabolism is altered in heart failure patients and to assess the relationship of protein kinetics to circulating levels of anabolic and catabolic hormones. METHODS: We measured whole-body protein metabolism using 13C-leucine, body composition, and circulating anabolic and catabolic hormone levels in 10 patients with chronic heart failure and 11 elderly controls. RESULTS: No differences in leucine rate of appearance, oxidation, or nonoxidative disposal were noted between heart failure patients and controls. However, in a subgroup of patients characterized by increased resting energy expenditure for their metabolic body size (n = 4; > or = 20% above that predicted from fat-free mass), leucine rate of appearance (mean +/- SE; 146 +/- 6 micromol/min), an index of protein breakdown, tended to be higher compared with patients with normal resting energy expenditure (n = 5; 120 +/- 8 micromol/min) and controls (127 +/- 4 micromol/min; p = .06). Alterations in anabolic/catabolic hormone balance did not explain increased protein breakdown in this subgroup, and no correlations were found between hormone levels and protein breakdown in the heart failure group as a whole. In contrast, increased circulating interleukin-6 soluble receptor (r = 0.829; p < .01) and reduced insulin-like growth factor-I (r =-.751; p < .05) levels were related to greater rates of leucine oxidation in heart failure patients. CONCLUSION: Our results demonstrate that, although increased protein turnover is not a generalized feature of heart failure, there is a subgroup of patients characterized by resting hypermetabolism and increased protein breakdown. Moreover, hormonal alterations related to the heart failure syndrome were related to increased protein oxidation.

Aged↗
PubMed2006

Toward a core nutraceutical program for cancer management.

As previously suggested, it may be feasible to impede tumorevoked angiogenesis with a nutraceutical program composed of glycine, fish oil, epigallocatechin-3-gallate, selenium, and silymarin, complemented by a low-fat vegan diet, exercise training, and, if feasible, a salicylate and the drug tetrathiomolybdate. It is now proposed that the scope of this program be expanded to address additional common needs of cancer patients: blocking the process of metastasis; boosting the cytotoxic capacity of innate immune defenses (natural killer [NK] cells); preventing cachexia, thromboembolism, and tumor-induced osteolysis; and maintaining optimal micronutrient status. Modified citrus pectin, a galectin-3 antagonist, has impressive antimetastatic potential. Mushroombeta-glucans and probiotic lactobacilli can amplify NK activity via stimulatory effects on macrophages. Selenium, beta-carotene, and glutamine can also increase the number and/or cytotoxic activity of NK cells. Cachectic loss of muscle mass can be opposed by fish oil, glutamine, and beta-hydroxy-beta-methylbutyrate. Fish oil, policosanol, and vitamin D may have potential for control of osteolysis. High-dose aspirin or salicylates, by preventing NF-B activation, can be expected to aid prevention of metastasis and cachexia while down-regulating osteolysis, but their impacts on innate immune defenses will not be entirely favorable. A nutritional insurance formula crafted for the special needs of cancer patients can be included in this regimen. To minimize patient inconvenience, this complex core nutraceutical program could be configured as an oil product, a powder, and a capsule product, with the nutritional insurance formula provided in tablets. It would be of interest to test this program in nude mouse xenograft models.

Animals↗
PubMed2003

Nutritional and metabolic modulation in chronic obstructive pulmonary disease management.

In this paper the perspective for nutritional modulation of systemic impairment in patients with chronic obstructive pulmonary disease (COPD) is discussed. Progressive weight loss is characterised by disease-specific elevated energy requirements unbalanced by dietary intake. Weight gain per se can be achieved by caloric supplementation while future studies may prove efficacy of amino acid modulation to stimulate protein synthesis and enhance muscle anabolism. Disproportionate muscle wasting resembles the cachexia syndrome as described in other chronic wasting diseases (cancer, chronic heart failure, acquired immunodeficiency syndrome (AIDS)). There is yet no adequate nutritional strategy available to treat cachexia in COPD. Muscle substrate metabolism has hardly been investigated, but the few data available point towards a decreased fat oxidative capacity that may show similarities with the "metabolic syndrome" as described in type II diabetes and obesity and could theoretically benefit from polyunsaturated fatty acid modulation. To adequately target the different therapeutic options, clearly more clinical (intervention) studies are needed in chronic obstructive pulmonary disease patients that are adequately characterised by local and systemic impairment and in which molecular and metabolic markers are linked to functional outcome.

Amino Acids↗
PubMed2006

Anorexia: a taste of things to come?

Anorexia, the loss of the desire to eat, is common in patients with cancer. Studies report a prevalence of up to 66% and clinical practice suggests that it is an almost universal experience as the cancer progresses. It generally leads to a reduction in food intake that contributes to the development of malnutrition and cachexia, impairing quality of life and increasing morbidity and mortality. Successful curative or palliative treatment of the underlying cancer is an effective approach. When this is not possible, there are limited treatment options, which generally have not been shown to be practicable, tolerable, effective or safe in the long-term management of the cachexia-anorexia syndrome. Recent increases in the understanding of the physiology of energy intake and of the pathophysiology of anorexia are helping to guide the development of rational approaches. This journal club provides an outline of the pathophysiology of anorexia and highlights a paper that may provide an exciting glimpse of the future.

Animals↗
PubMed1997

Role of androgens in testicular tumor development in inhibin-deficient mice.

To understand gonadal tumor development, we have previously created a mouse model in which mice deficient in the inhibins develop gonadal sex cord-stromal tumors with essentially 100% penetrance. These tumors develop as early as 4 weeks of age and cause cancer cachexia-like symptoms and subsequent death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice eventually develop adrenal cortical tumors with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumor suppressor protein with specificity for the gonads and adrenal glands. Sex steroids have been implicated to influence gonadal tumor development in humans and mice. To determine the role of androgens in gonadal tumorigenesis in inhibin-deficient male mice, we have used a genetic intercross strategy, breeding inhibin alpha mutant mice with tfm (testicular feminization, a naturally occurring androgen receptor mutant) carrying females to eventually generate compound mutant male mice that lack inhibins and carry the tfm mutation. These compound mutant mice, like inhibin-deficient mice, continue to develop testicular tumors and the accompanying cancer cachexia-like wasting syndrome. Consistent with these findings, elevated levels of activins A and B secreted from the gonadal tumors are seen in the adult compound mutant mice as well as the secondary pathological consequences of these high activin levels in the livers and glandular stomachs. However, in contrast to male mice lacking only inhibin, in which essentially 100% of the testicular tumors are hemorrhagic, 65% of the tumors in these compound mutant male mice are less hemorrhagic, and approximately 50% of the compound mutants live longer than 17 weeks of age (95% of the male mice lacking only inhibin die by 12 weeks). These results suggest that androgens are not required for testicular tumor development in inhibin-deficient mice, but may play a regulatory role in testicular tumor progression.

Activins↗
PubMed2001

Central melanocortins and the regulation of weight during acute and chronic disease.

Recent advances in our understanding of the regulation of body weight, appetite, and metabolic rate have highlighted the role of the adipose-derived hormone leptin and its receptor as fundamental modulators of these processes. Investigations of the neural targets for leptin action--as well as characterization of the agouti obesity syndrome--have, in turn, led to the discovery of fundamental neural pathways involved in the central regulation of energy homeostasis. In particular, the central melanocortin system has been shown to regulate appetite and metabolic rate in rodents; mutations in this system have been demonstrated to result in obesity in humans. Overall, the melanocortin system appears to function as a bidirectional rheostat in the regulation of energy intake and expenditure in rodents and potentially in humans. The first section of this chapter will focus on the development of our understanding of melanocortin physiology in the context of obesity. In particular, recent data regarding the interplay between melanocortin and neuropeptide Y (NPY) signaling at a cellular level will be discussed. The following section will discuss the hypothesis that melanocortin signaling plays a role in pathological weight loss and hypermetabolism observed in murine cachexia models. The potential role of this system in integrating a variety of anorexic and cachexic signals, as well as the potential for its pharmacological manipulation in the treatment of human cachexia, will be discussed.

Animals↗
PubMed2005

Neurohumoral activation as a link to systemic manifestations of chronic lung disease.

COPD is a major cause of death and disability worldwide. Treatment of COPD improves lung function but is unlikely to slow the steady downhill course of the disease or reduce mortality. In COPD, numerous abnormalities can be found outside the lung. These include systemic inflammation, cachexia, and skeletal muscle dysfunction. Thus, COPD has been called a systemic disease. Convincing data demonstrate that COPD causes neurohumoral activation. By precedents derived from chronic heart failure and other diseases characterized by neurohumoral activation, we propose that the negative consequences of neurohumoral activation, namely inflammation, cachexia, effects on ventilation, and skeletal muscle dysfunction, give rise to a self-perpetuating cycle that contributes to the pathogenesis of COPD, and which may involve respiratory muscle dysfunction as well as systemic inflammation. This concept may further help explain the increased cardiovascular morbidity and mortality in COPD patients. Currently, little is known about the effect of treatments directed at neurohumoral activation and COPD. As this aspect of COPD becomes better understood, new insights may direct novel therapeutic approaches.

Aldosterone↗
PubMedDate not supplied

Serum tumor necrosis factor does not correlate with changes in muscle volume in children with malignancies.

This study examined the connection between serum tumor necrosis factor (TNF) concentration and the development of cachexia in 12 children with acute lymphoblastic leukemia (ALL). The changes in muscle thickness were used as criteria for malnutrition, estimated by an ultrasound method during the 16 weeks of chemotherapy subsequent to diagnosis. Serum TNF concentrations were elevated at diagnosis and gradually decreased toward the reference limits by week 16. There was no correlation between TNF and muscle thickness. The results were also compared to those obtained from 8 children with other malignancies in whom the mean relative weight remained below normal whereas in those with ALL it gradually increased to +15%. Thus, we found no evidence of the association between elevated serum TNF concentrations and cachexia in man.

Adolescent↗
PubMed1999

Tumour growth and nitrogen metabolism in the host (Review).

Tumour growth is frequently associated with massive loss of body weight and negative nitrogen balance leading to cachexia, one of the worst features of malignancy accounting for nearly two thirds of cancer deaths. At the metabolic level, cachexia is associated with depletion of body lipid stores as well as loss of skeletal muscle protein, which is manifested as an excessive nitrogen loss. The present study reviews the modulations of nitrogen metabolism in tumour-bearing conditions. In addition, the role of different mediators (such as cytokines) in the development of protein wasting is discussed. Particular emphasis has been given to tumour necrosis factor-alpha (TNF-alpha) which seems to have a key role in mediating changes related to nitrogen metabolism in the tumour-bearing host.

Animals↗
PubMed1983

Nutritional support of the cancer patient.

Cachexia is common in patients with advanced neoplastic disease, and beyond certain levels, is associated with decreased survival. Depletion of vitamins and minerals may co-exist with protein-calorie undernutrition. The causes of the cancer cachexia syndrome may include decreased food intake, increased fecal and urinary nutrient losses, and abnormal metabolic pathways in both the host and the tumor. The complex nature of weight loss in cancer makes restoration of lean body mass more difficult in cancer than in non-cancer undernutrition. Non-volitional feeding (hyperalimentation) frequently causes cancer patients to gain weight, but this weight may be more fat and water than lean body mass. Hyperalimentation has not yet been shown to prolong survival in cancer, but additional nutritional support studies are in progress.

Cachexia↗
PubMed2000

Pancreatic cancer and serum organochlorine levels.

Occupational exposure to p,p'-dichlorodiphenyltrichloroethane (DDT) has been associated with increased pancreatic cancer risk. We measured organochlorine levels in serum obtained at the study enrollment from 108 pancreatic cancer cases and 82 control subjects aged 32-85 years in the San Francisco Bay Area between 1996 and 1998. Cases were identified using rapid case-ascertainment methods; controls were frequency-matched to cases on age and sex via random digit dial and random sampling of Health Care Financing Administration lists. Serum organochlorine levels were adjusted for lipid content to account for variation in the lipid concentration in serum between subjects. Median concentrations of p,p'-dichlorodiphenyldichloroethylene (DDE, 1290 versus 1030 ng/g lipid; P = 0.05), polychlorinated biphenyls (PCBs; 330 versus 220 ng/g lipid; P<0.001), and transnonachlor (54 versus 28 ng/g lipid; P = 0.03) were significantly greater among cases than controls. A significant dose-response relationship was observed for total PCBs (P for trend <0.001). Subjects in the highest tertile of PCBs (> or =360 ng/g lipid) had an odds ratio (OR) of 4.2 [95% confidence interval (CI) = 1.8-9.4] compared to the lowest tertile. The OR of 2.1 for the highest level of p,p'-DDE (95% CI = 0.9-4.7) diminished (OR = 1.1; 95% CI = 0.4-2.8) when PCBs were included in the model. Because pancreatic cancer is characterized by cachexia, the impact of this on the serum organochlorine levels in cases is difficult to predict. One plausible effect of cachexia is bioconcentration of organochlorines in the diminished lipid pool, which would lead to a bias away from the null. To explore this, a sensitivity analysis was performed assuming a 10-40% bioconcentration of organochlorines in case samples. The OR associated with PCBs remained elevated under conditions of up to 25% bioconcentration.

Adult↗
PubMed2001

Megacolon in pigs due to segmental colon aganglionosis.

Four pigs, each of about 8 weeks of age were submitted for pathological examination because of severe cachexia, combined with an enormous distension of the abdomen. In the herd, where these pigs originated from, these clinical signs were observed frequently for some period of time and stricture of the rectum was suspected. All pigs showed a severe cachexia, and most prominent in all pigs was a megacolon with large and distended colon and caecum and stenosis about 30 to 60 cm cranial of the anus. Tissue specimens were taken from the rectum, from the colon cranial and caudal of the stenosis and from the jejunum and examined histologically. Ganglia in the intestinal wall were examined immunohistochemically by using antibodies recognising neurofilament protein (kD 200). In all pigs submucosal and myenteric ganglia were absent in the post stenotic colon and rectum and in transverse section of the stenosis, whereas in the prestenotic colon of all pigs and also in the jejunum ganglia were present. Segmental aganglionosis of the colon is also known in humans (Hirschsprung disease) and other animal species and is considered as a congenital disorder. We also suggest a familiar background of the disease in these pigs.

Animals↗
PubMed2001

[Plasma concentration of leptin, neuropeptide Y and tumor necrosis factor alpha in patients with cancers, before and after radio- and chemotherapy].

In patients with cancers progressive reduction of body mass is frequently recent. Pathogenesis of cachexia in patients with cancer is multifactorial. Such factors as cytokines, peptides relieved by tumor mass and different forms of treatment as radio or chemotherapy may play a major role in the pathogenesis of cachexia in patients with cancer. The aim of this study was to assess the relationship between body fat and lean mass and plasma leptin, NPY and TNF concentrations in patients with cancer of oral cavity and pharynx, cancer of larynx and non-Hodgkin lymphoma (NIL). 30 patients (10 with cancer of oral cavity and pharynx, 10 with cancer of larynx and 10 with non-Hodgkin lymphoma) were enrolled into this study. Mean age of all cancer patients was 50 +/- 2.9 years (from 18 to 76 years). The control group consisted of 29 healthy subjects with a means age 48 +/- 3.5 years (from 18 to 75 years), properly chosen according to the body weight, BMI, gender and age as above mentioned groups of patients with cancer. In control and study groups body fat and not-fat mass was assessed before and after treatment using the bioelectrical impedance method. Before oncological therapy patients with cancer did not differ from healthy subject with regard to body weight and body mass index. After treatment significant: decrease of body weight, body fat mass and BMI was observed. Serum leptin, NPY and TNF concentrations were analysed in healthy subjects and patients with cancer before and after treatment. Before oncological treatment significantly lower serum leptin concentration in comparison to leptinaemia in control group was found. In contrast to serum leptin, NPY serum concentration was similar in patients with cancer and in control subjects. Serum concentration of TNF was significantly higher in patients with cancer in comparison to subjects of control group. After oncological treatment, serum leptin and NPY concentration did not change significantly. In contrast, serum TNF concentration decreased significantly after oncological therapy. From the results obtained in this study we can conclude, that in patients with cancer secretion of leptin is decreased in relation to body fat mass. However, contribution of this hormone to pathogenesis of cancer induced anorexia seems not to proven. From the other side, the role of TNF in pathogenesis of disregulation of leptin secretion seems to be very likely. After chemo or radiotherapy, serum NPY concentration did not change significantly. After this oncological treatment the relationship between serum leptin concentration and body mass is no longer significant.

Adult↗
PubMed1992

Current pharmacological management of anorexia in cancer patients.

Cancer cachexia is one of the most prevalent and devastating syndromes associated with advanced cancer. Its main clinical manifestation is profound anorexia. Progestational drugs have shown meaningful effects on appetite, food intake, and nutritional status in patients with advanced cancer and AIDS, and could be useful in managing anorexia. Corticosteroids also seem to produce increased appetite, but these effects are short-lived. Cyproheptadine, hydrazine sulfate, and cannabinoids also are being studied in the management of cancer-induced anorexia, but their role has not yet been clearly established. Future research should evaluate how the different drugs affect specific symptoms associated with cachexia.

Adrenal Cortex Hormones↗