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Cancer-associated anorexia and cachexia. Implications for drug therapy.

Anorexia and cachexia are major problems in patients with cancer. Such measures as anti-cancer therapy, dietary counselling or hyperalimentation are not very successful in reversing this phenomenon in the vast majority of cancer patients. Thus, several drugs have been evaluated as agents to ameliorate cancer-associated anorexia/cachexia. Cyproheptadine is an antiserotonergic drug which appears to cause slight appetite stimulation in patients. A randomised clinical trial, however, was unable to demonstrate any weight gain from this agent. Corticosteroids are frequently used in clinical practice for appetite stimulation in patients with advanced malignancies. Supporting this practice, 4 randomised clinical trials showed that corticosteroid medications can stimulate the appetites of advanced cancer patients. However, these studies were not able to show any substantial nonfluid weight gain in treated patients. Megestrol acetate is a progestational agent which appears to be a relatively potent appetite stimulant. Randomised studies in advanced cancer patients have shown both substantial appetite stimulation and improvement in the nonfluid bodyweights of patients receiving this drug. Preliminary evidence also suggests that this drug has antiemetic properties. Several clinical studies are currently ongoing to determine the effect of various doses of megestrol acetate in patients with cancer. Efforts are also ongoing to evaluate both anabolic steroids and hydrazine sulfate as drugs for the treatment of patients with cancer anorexia/cachexia. The preliminary nature of these investigations, however, precludes recommendations for the use of either of these latter 2 drugs in routine clinical practice.

Anorexia

Visceral leishmaniasis: a model for infection-induced cachexia.

Parasitic infections and malnutrition coexist in many tropical and subtropical areas. Studies of Leishmania donovani and of experimentally infected Syrian hamsters have provided important insights into the complex interrelationships between malnutrition and this parasitic disease. Malnutrition, which adversely affects cell-mediated immunity, is associated with the development of visceral leishmaniasis (kala-azar) in children living in endemic areas. In turn, L. donovani can cause wasting as well as hepatosplenomegaly, fever, and anemia. Syrian hamsters infected with L. donovani develop a disease that is comparable to that of humans with kala-azar. Weight loss in infected hamsters is associated with splenic macrophage secretion of potentially catabolic cytokines as measured by the D10.G4.1 assay for interleukin-1 and the L929 cytotoxicity assay for tumor necrosis factor/cachectin. Although decreased food intake contributes to wasting in infected hamsters, studies of skeletal muscle function indicate that it is not the sole factor. Leishmania donovani-infected hamsters have also been used to study drugs with the potential to prevent or reverse cachexia.

Adipose Tissue

[Pathogenesis of cachexia in cardiac insufficiency].

In 81 patients with circulatory insufficiency of the IIB-III stage some in dices of the lipids and protein metabolism along with the blood sugar level were studied. Changes in the lipids metabolism values are more pronounced in patients with mitral defects than in those with atherosclerotic cardiosclerosis. The authors attach definite importance to these derangements in the pathogenesis of cardiac cachexia secondary to the developing circulatory insufficiency.

Adult

Nutritional support and cancer cachexia. Evolving concepts of mechanisms and adjunctive therapies.

Despite the widespread employment of intravenous feeding in patients with cancer cachexia to improve outcome, conflicting data exist regarding the efficacy of such therapy in addressing metabolic alterations secondary to immobility, malnutrition, and disease-specific processes. Persistence of distinct abnormalities of body and tissue integrity and peripheral tissue plasma inter-organ nitrogen flux imply the need for anabolic agents to enhance the therapeutic effects of parenteral nutrition. This article focuses upon potential anabolic agents such as chronic submaximal exercise, hormonal augmentation, pharmacologic intervention, and variations in substrate composition. Finally, the immunologic, metabolic, and endocrine consequences of bypassing the gastrointestinal tract are considered and related to the limited efficacy of current total parenteral nutrition regimens.

Cachexia

Megestrol acetate in cancer cachexia.

This randomized, controlled trial assessed the activity, tolerance, and degree of weight gain and anorexia of two doses of megestrol acetate in patients with advanced cancer and cachexia. Patients received either 480 mg/d or 960 mg/d megestrol acetate or placebo for 8 weeks. As of June 1990, 55 patients had been randomized; 16 died during the 8-week study, and it was too early to evaluate another 5 patients. The remaining 34 patients were included in analyses. The median initial weight loss ranged from 15% to 22% of usual body weight, which shows the severe degree of malnutrition. Further weight loss was seen in 6 of 8 patients in the placebo group compared with only 5 of 15 and 3 of 11 patients in the low-dose and high-dose megestrol acetate groups, respectively. The median further weight loss was comparable in all groups. Six of 15 and 6 of 11 patients in the low-dose and high-dose groups, respectively, gained weight with a median of 3 kg and 4 kg, respectively. A trend showed beneficial effects of megestrol acetate. Appetite improvement was similar in all groups. Due to the small sample size, however, there were no statistically significant differences among the three groups. Side effects of megestrol acetate were mild. In a subgroup of 15 patients, measurement of body water content indicated a decrease of body fat after 8 weeks in the placebo and low-dose groups. Only the high-dose megestrol acetate group showed an increase in both fat and lean body mass, suggesting a positive effect.

Adult

Nutritional assessment in cancer cachexia.

Cancer cachexia causes nutritional depletion due to the tumor burden and the patient's inability to eat. A nutritional assessment is valuable in assisting the medical team in nutritionally repleting malnourished patients. Using readily available information, the practitioner can determine nutritional assessment and plan interventions that help the child to successfully withstand cancer and its treatment.

Adolescent

Contribution of elevated protein turnover and anorexia to cachexia in patients with hepatocellular carcinoma.

Severe cachexia of extremely rapid onset typifies the young Black African patient with hepatocellular carcinoma (HCC). In order to assess whether this is a consequence of tumor-associated increases in protein metabolism or simply due to inadequate dietary intake, the following study was undertaken. The technique of constant i.v. infusion of 14C-labeled leucine was used to measure whole body protein flux, breakdown, synthesis, and oxidation rates in 8 adults with HCC, 4 patients with massive hepatomegaly due to metastatic adenocarcinoma from bowel, 6 patients with chronic liver disease, and 10 controls. Endogenous protein breakdown and oxidation were similar between patients with chronic liver disease (breakdown, 4.4 +/- 1.2 g/kg/day; oxidation, 0.8 +/- 0.4 g/kg/day) and controls but were significantly (P less than 0.002) higher in patients with liver tumors, the highest rates being observed in those with HCC (breakdown, 8.5 +/- 4.3 g/kg/day; oxidation, 1.4 +/- 0.5 g/kg/day). Protein turnover was generally higher in the HCC group, with increased rates of reincorporation of amino acids into protein synthesis (P less than 0.05). In one HCC patient a synchronized diagnostic liver biopsy demonstrated high fractional synthesis of rates of HCC proteins of 86%/day. In addition, the incorporation rates of labeled amino acid into fibrinogen, immunoglobulin G, and transferrin were also highest (P less than 0.03) in HCC patients. In order to assess the relative importance of diet in weight loss, dietary intake levels were assessed from hospital records of HCC patients and by dietary recall during the week prior to study. Intakes ranged from 30 to 70% of calculated requirement levels. In conclusion, our results suggest that the rapid wasting seen in patients with HCC is due to an imbalance between the metabolic demands, which can be elevated in some patients, and inadequate dietary replenishment.

Adolescent

Alleviation of cancer anorexia and cachexia: studies of the Mayo Clinic and the North Central Cancer Treatment Group.

Anorexia and cachexia are common clinical problems of many patients with advanced cancer. Approximately 20 years ago, a controlled, clinical study demonstrated that dexamethasone could stimulate appetites of patients with advanced gastrointestinal cancer without causing any apparent effect on patient weight or survival. More recently, two double-blind, placebo-controlled trials investigated cyproheptadine and megestrol acetate in patients with cancer anorexia/cachexia. The first of these studies suggested that cyproheptadine could mildly stimulate appetite without causing any discernible effect on patient weight. Megestrol acetate, on the other hand, can clearly cause an increase in patient-perceived appetite and food intake and can also lead to substantial nonfluid weight gain in a proportion of patients with cancer anorexia/cachexia. Ongoing studies have been designed to better study the appetite-enhancing effects of megestrol acetate. In addition, current studies are evaluating the effect of the drug hydrazine sulfate on the appetite and weight status of patients with advanced lung or colon cancer.

Anorexia

Tentative identification of the toxohormones of cancer cachexia: roles of vasopressin, prostaglandin E2 and cachectin-TNF.

A proposed role for the hypothesized toxohormone/s (Vasopressin, Prostaglandin E2 and TNF-Cachectin) in the development and maintenance of cancer cachexia was investigated in rats bearing the Walker 256 carcinosarcoma. Elevated levels of arginine vasopressin and prostaglandin E2 in the plasma and urine were associated with reduced hepatic ketogenesis, fatty acid oxidation and increased fatty acid esterification. The oxidation of branched chain amino acids by the muscle tissue of tumour bearing rats was increased and attributed to the enhanced activity of muscle branched chain keto-acid dehydrogenase. Concerted actions by the triology of factors (AVP, PGE2, Cachectin-TNF) are proposed to instigate a sequence of reactivities that lead to the clinical symptoms of muscle and adipose tissue wasting, together with the negative nitrogen balance characteristic of the cachectic state.

Amino Acids, Branched-Chain

Psychosocial issues in the diagnosis and management of cancer cachexia and anorexia.

Anorexia with its associated decreased food intake and weight loss is a common and profoundly important symptom in cancer, and one which has at times a psychological as well as physical component. When it is physical in origin it may be caused directly or indirectly by the disease process or treatment. Most poorly understood is the anorexia-cachexia syndrome of advanced disease. Psychological causes often reflect anxiety about cancer, its possible progression, depression, anticipatory phenomena, and learned food adversions. Pre-existing psychiatric disorders, especially anorexia nervosa or paranoid states, can substantially complicate cancer treatment. Learned food aversions, which can further restrict limited intake, have been demonstrated in children receiving chemotherapy and may also contribute to aversions of specific foods seen among adult patients after chemotherapy or radiation. Regardless of etiology, psychological management of the anorexia is often helpful. Optimal management often involves use of a combination of modalities: psychotherapeutic, behavioral and/or pharmacologic supplemented by education, counseling and support. Behavioral techniques such as relaxation exercises are useful tools to alter this response as well as to relieve the anxiety precipitated by the patient's concerns about anorexia and weight loss. Environmental interventions and nutritional advice can also be of considerable value in reversing the negative effects of this distressing symptom in cancer.

Anorexia

Multi-organ damage (MOD) induced by cancer cachexia and its pathogenesis.

The intraperitoneal implantation of the ascitic hepatoma cells, AH-130 to rats induced marked atrophy of the systemic organs within 2 weeks, resulting in the animal death. By the method of Feulgen hydrolysis curve analysis, the amount of single-stranded DNA and the degree of DNA instability were shown to be increased in these atrophic organs. In keeping pace with the progression of the cachectic multi-organ damage (MOD), the amount of lipidperoxide and the activity of superoxide dismutase (SOD) as measured by electron spin resonance (ESR) were increased in the ascites toward the end stage of chachexia. The increased lipidperoxide and SOD induction reflect the increased production of active oxygens, especially superoxide. The marked systemic organ damage induced in cancer cachexia seems to be due to DNA damage by active oxygens.

Animals

Thyroid hormones and experimental cancer cachexia.

The relationship between circulating thyroid hormones and nutritional status was studied in sarcoma-bearing inbred C57BL/6J mice and control mice. Supplementation with exogenous thyroxine (T4) was also evaluated. Tumor-bearing animals had depressed levels of circulating thyroid hormones. This was also found in food-restricted (pair-fed and pair-weighed) controls. Plasma levels of thyroid hormones decreased with increased tumor burden. Thyrotropin-releasing hormone caused an increased response of thyroid-stimulating hormone in tumor-bearing animals. Low levels of thyroid hormones in sarcoma-bearing mice were due to depressed hormone production by the thyroid gland rather than to increased clearance rate of hormones. Plasma levels of triiodothyronine (T3) correlated to the amount of whole-body nitrogen among sarcoma-bearing mice and food-restricted controls. Exogenous T4 increased food intake by 20% in sarcoma-bearing mice. The benefit of this was probably counteracted by an increased metabolic rate, since reversal of plasma levels of T3 and free T4 had no net effect on body composition of freely eating sarcoma-bearing mice, although it had a negative effect on body and muscle composition in food-restricted controls. Exogenous T4 did not stimulate tumor growth. The results indicate that low circulating levels of thyroid hormones in experimental cancer cachexia are probably caused by the reduced food intake (anorexia), which is in agreement with findings in clinical cancer. Depression of thyroid hormones is probably a physiological means to reduce energy expenditure and to preserve substrates in progressive cancer disease.

Animals

Production of lipolytic and proteolytic factors by a murine tumor-producing cachexia in the host.

Animals given transplants of the MAC16 colon adenocarcinoma show a progressive decrease in carcass weight as the tumor size increases without a reduction in either fluid or caloric intake when compared with non-tumor-bearing controls. There is a decrease in both carcass fat and muscle mass which is directly proportional to the weight of the tumor. In male animals weight loss occurs when the tumor mass comprises more than 0.3% of the body weight and reaches 30% when the tumor represents 3% of the body weight. There is evidence for the production by the tumor of both lipolytic and proteolytic factors, which may be responsible for the cachexia, since two related mouse adenocarcinomas, which do not produce weight loss, have little lipolytic or proteolytic activity. The lipolytic factor is nondialyzable and is destroyed by both heat and acid. Both insulin and 3-hydroxybutyrate suppress the lipolytic activity of the tumor extract. The MAC16 tumor also contains a serine protease, the activity of which is also completely abolished by insulin and 3-hydroxybutyrate. Animals bearing the MAC16 tumor have an elevated plasma lipolytic and proteolytic activity when compared with non-tumor-bearing controls, suggesting a peripheral effect of the tumor products. The catabolic factors elaborated by the MAC16 adenocarcinoma may be responsible for the loss of both the fat and nonfat carcass mass, but they do respond to normal metabolic controls.

Adenocarcinoma

High-dose megestrol acetate. A possible treatment for cachexia.

Weight loss and anorexia are significant complications of a variety of disorders and add morbidity to the underlying process. We observed marked weight gain (median, 5.1 kg; range, 0.9 to 20.1 kg) and appetite enhancement in 27 of the 28 patients with breast cancer receiving treatment consisting of high doses of oral megestrol acetate (480 to 1600 mg/d). Weight gain occurred regardless of pretreatment weight, extent of metastases, or response to therapy. Our results suggest a possible role for megestrol acetate in reversing anorexia and weight loss, thereby improving the quality of life of patients with cachexia. Further research is needed to establish the mechanism of weight gain and potential clinical applications.

Body Weight

The cachexia of cancer.

This review examines the contributions made by anorexia, loss of taste, malabsorption and disturbances of intermediary metabolism to the cachexia of cancer. Methods of nutritional assessment are outlined and mention is made of the usefulness of nutritional support as an adjunct to anti-cancer therapies.

Animals

Nutritional support in cardiac cachexia.

A nutritional survey of 350 hospital patients reveals 50 with cardiac disease who had clinically significant protein-calorie malnutrition. Assessment criteria of malnutrition (per cent normal) included triceps skin fold (52 per cent), arm muscle circumference (88 per cent), and impaired delayed hypersensitivity skin testing (i.e., deficiency in cell-mediated immunity), the latter frequently observed in patients with concurrent weight loss. The functional category of cardiac status was not precise in predictin the morbidity and mortality of 14 patients undergoing cardiac valvuloplasty. By contrast, a nutritional/metabolic profile using weight loss, triceps skin fold (35 per cent), arm muscle circumference (27 per cent), and cell-mediated immunity (29 per cent) did identify high-risk patients who could be expected to benefit by concurrent nutritional support (4/4). Further studies are indicated to determine if nutritional support for cardiac cachexia can reduce the levels of morbidity and mortality during mitral and tricuspid valve surgery.

Adult

[Enteral resorption and tumor cachexia].

The rapid loss of the body weight of oncological patients in the advanced stage of the carcinomatous disease is caused by numerous pathophysiological mechanisms. With the help of the modified D-xylose absorption test was investigated which value have disturbances of the enteral absorption in the complex of causes for the development of a tumour cachexia. For the patients in the stage of generalisation of the carcinomatous disease clear disturbances in the enteral food intake could be proved in contrast to patients with carcinoma without general tumour symptomatology and healthy persons. The influence of chemo- and radio-therapy on the enteral absorption of patients with carcinoma was discussed. The forced alimentation of oncological patients with unspezific tumour symptoms must be regarded as a firm constituent in the treatment of patients with carcinoma.

Cachexia