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PubMed1996

Report on management of renale failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry.

The proportion of centres returning the ERA-EDTA Registry questionnaires has decreased considerably in recent years. Demographic information, based on the response rate of centres in 1994 (44%), does not allow reasonable projections for management of renal failure in Europe. To encourage the participation of non-responding centres, the timing was right to show the powerful impact of the ERA-EDTA Registry as a supra-national registry, by studying patients in renal replacement therapy (RRT) suffering from rare diseases. Four such diseases, Fabry's disease, nephropathy due to cyclosporin (CsA), nephropathy due to cisplatin and scleroderma, were studied using the records of 440665 patients on file up to 31 December 1993. There were 83 patients with Fabry's disease (0.0188%), 85 patients with CsA nephropathy (0.0193%), 120 patients with cisplatin nephropathy (0.0272%) and 625 patients with scleroderma (0.142%). Scleroderma was introduced as a primary renal disease (PRD) in the ERA-EDTA Registry in 1977. Seven patients were accepted for RRT in that year, whereas the number increased to over 50 new patients per year after 1986. More than half of the patients were aged over 55 years, and 68% of them were women. Survival rate of dialysis patients suffering from scleroderma was 22% at 5 years, compared to 51% in patients with standard primary renal diseases. The main causes of death were cardiovascular complications (41%), cachexia (15%) and infection (10%). Survival of first graft in a small number of 28 patients was 44% at 3 years, compared to 60% in standard PRD. Patient survival after first transplant, however, was higher by 32% at 3 years compared to that of dialysis patients. Cisplatin nephropathy was introduced as a PRD in the ERA-EDTA Registry in 1985, and since then six to 19 new patients have been accepted for RRT each year. The main reason for undergoing cisplatin treatment was ovarian (32%) and testicular cancer (21%), and the mean interval from treatment to RRT was 21.5 months, ranging widely from 0.1 to 131 months. Patient survival on dialysis was 22% at 5 years, compared to 51% in patients with standard PRD. Malignancy and cachexia accounted for over 60% of the total number of deaths. CsA nephropathy was introduced as a PRD in the ERA-EDTA Registry in 1985 and, despite its rarity, is of particular interest as a new iatrogenic entity resulting from CsA administration, mainly in solid organ transplantation. In 1985, two new patients commenced RRT in Europe, and the number increased to 59 in 1991-93. The main reason for undergoing CsA treatment was heart (68%) and liver transplant (22%), and the mean interval from treatment to RRT was 50.2 months, ranging from 5 to 90 months. Patient survival on dialysis was 46% at 4 years, compared to 58% in patients with standard primary nephropathies. Cardiovascular causes (48%) and infection (17%) were the main causes of death. Fabry's disease was introduced as a PRD in the ERA-EDTA Registry in 1985, and since the four to 13 new patients per year have commenced RRT in Europe. It is a sex-linked recessive disorder primarily affecting males (87%), and the mean age at start of RRT was 38 years. Proteinuria, skin lesions and painful paresthesiae were the most common presenting symptoms, and over 70% of the patients were hypertensive and had significant cardiovascular problems at RRT. Patient survival on dialysis was 41% at 5 years, compared to 68% in patients with standard primary nephropathies. Cardiovascular complications (48%) and cachexia (17%) were the main causes of death. Graft survival at 3 years in 33 patients was not inferior to that of patients with standard nephropathies (72% vs 69%), and patient survival after transplantation was comparable to that of patients under 55 years of age with standard PRD. (ABSTRACT TRUNCATED)

Adolescent↗
PubMed2006

Cellular caspase-8-like inhibitory protein (cFLIP) prevents inhibition of muscle cell differentiation induced by cancer cells.

Cachexia is a frequent complication of cancer or other chronic diseases. To investigate the pathophysiology of cancer cachexia and pursue treatment options, we developed an in vitro assay of the effects of cancer cell-produced cytokines on primary muscle cells derived from murine skeletal muscle. These studies led to the novel observation that factors secreted by cell lines from prostate cancer and melanoma significantly inhibit differentiation of primary mouse muscle cells. The expression of interleukin (IL) -1beta, TNF-alpha, and proteolysis-inducing factor (PIF) by cancer cells used in this study suggested their role in preventing myogenic differentiation. Both NF-kappaB binding and transcriptional activity were enhanced in muscle cells treated with conditioned media from cancer cells or with proinflammatory cytokines. Stable expression of IKBSR, a known repressor of NF-kappaB activation, and cellular caspase-8-like inhibitory protein (cFLIP) inhibited activation of NF-kappaB in cancer cell media-treated muscle cells with an accompanying enhancement of myogenic protein expression and differentiation. In contrast, overexpression of antiapoptotic protein Bcl-xL did not protect myoblast cells exposed to the same treatment. Instead, we observed enhanced activation of NF-kappaB in Bcl-xL overexpressing cells. These studies show that the in vitro system recapitulates some of the molecular events causing muscle cachexia and provides the basis for new treatment approaches.

Animals↗
PubMedDate not supplied

Results of a dose-intense phase 1 study of a combination chemotherapy regimen with cisplatin and epidoxorubicin including medroxyprogesterone acetate and recombinant interleukin-2 in patients with inoperable primary lung cancer.

Based on the role of cytokines in the pathogenesis of cancer-related anorexia-cachexia and the ability of progestins, such as medroxyprogesterone acetate, to reduce cytokine production and relieve cancer-related anorexia-cachexia symptoms, the authors designed an open, dose-finding phase I study of a combined chemotherapy regimen (cisplatin [CDDP], epidoxorubicin [EPI]), including recombinant interleukin-2 (IL-2) and medroxyprogesterone acetate for patients with stage IIIB to IV inoperable primary lung cancer. The end points were clinical response and toxicity with definition of dose-limiting toxicity and maximal tolerable dose; relief of cancer-related anorexia-cachexia symptoms; the assessment of patient serum levels of IL-1beta, IL-6, tumor-necrosing factor-alpha (TNF-alpha), and soluble IL-2 receptor (sIL-2R). From March to October 1997, 16 patients (M:F ratio, 14:2; mean age, 60.5 years; age range, 41 to 74 years) were enrolled. All patients were evaluable for toxicity and 14 of them for response. The patients were assigned to increasing dose levels of drugs according to a dose-escalation schedule. The weekly schedule consisted of a combination of CDDP given intravenously on day 1, EPI given intravenously on day 1, 1 g/day medroxyprogesterone acetate given orally on days 1 to 7, and recombinant IL-2 1.8 MIU administered subcutaneously on days 2 to 7 plus 300 microg granulocyte-colony stimulating factor support given subcutaneously on days 2 to 5. Administration of medroxyprogesterone acetate began 1 week before the first cycle. Dose escalation of the drugs was as follows: 30 mg x m2 x week(-1) CDDP and 25 mg x m2 x week(-1) EPI (first level, two patients); 30 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (second level, 2 patients); 40 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (third level, 6 patients); and 40 mg x m2 x week(-1) CDDP and 40 mg x m2 x week(-1) EPI (fourth level, 6 patients). Six cycles were planned for each patient. The actual dose intensity delivered was more than 80% of the projected dose intensity of all drugs. After six cycles, clinical response (according to World Health Organization criteria), toxicity (according to World Health Organization criteria), Eastern Cooperative Oncology Group (ECOG) performance status, body weight, appetite, and serum levels of cytokines were evaluated. After six cycles, 9 of 14 patients (64.3%) had partial response, 3 of 14 (21.4%) had stable disease, and 2 of 14 (14.3%) had progressive disease, and the objective response rate was 64.3%. ECOG performance status and body weight did not change significantly after treatment, whereas appetite showed an increase that was of borderline statistical significance. Toxicity was acceptable and only hematologic. Dose-limiting toxicity was established at the fourth dose level; consequently, maximal tolerable dose was assessed at the third dose level. Before treatment, the serum levels of IL-1beta, IL-6, and TNF-alpha were significantly greater in the patients than in healthy persons. The comparison between pretreatment and posttreatment serum values of IL-1beta, IL-6, TNF-alpha, and sIL-2R did not reveal significant differences in the patients. Similar results were obtained when the patients were considered as responders (partial response) or non-responders (stable or progressive disease) to therapy. Only IL-6 serum levels were increased (p = 0.014) after treatment.

Adult↗
PubMed2001

Increased muscle ubiquitin mRNA levels in gastric cancer patients.

The intramuscular ATP-dependent ubiquitin (Ub)-proteasome proteolytic system is hyperactivated in experimental cancer cachexia. The present study aimed at verifying whether the expression of the muscle Ub mRNA is altered in patients with cancer. Total muscle RNA was extracted using the guanidinium isothiocyanate/phenol/chloroform method from rectus abdominis biopsies obtained intraoperatively from 20 gastric cancer (GC) patients and 10 subjects with benign abdominal diseases (CON) undergoing surgery. Ub mRNA levels were measured by northern blot analysis. Serum soluble tumor necrosis factor receptor (sTNFR) was measured by ELISA. Ub mRNA levels (arbitrary units, means +/- SD) were 2,345 +/- 195 in GC and 1,162 +/- 132 in CON (P = 0.0005). Ub mRNA levels directly correlated with disease stage (r = 0.608, P = 0.005), being 1,945 +/- 786 in stages I and II, 2,480 +/- 650 in stage III, and 3,799 +/- 66 in stage IV. Ub mRNA and sTNFR did not correlate with age and nutritional parameters. This study confirms experimental data indicating an overexpression of muscle Ub mRNA in cancer cachexia. Lack of correlation with nutritional status suggests that Ub activation in human cancer is an early feature that precedes any clinical sign of cachexia.

Abdominal Muscles↗
PubMed1993

Expression and regulation of tumor necrosis factor in macrophages from cystic fibrosis patients.

Cachexia and anorexia commonly occur in patients with cystic fibrosis (CF), particularly those with severe pulmonary compromise and heavy tracheobronchial colonization with Pseudomonas aeruginosa. Current understanding of the pathophysiology of cachexia attributes much of the anorexia and weight loss to the effects of the cytokine tumor necrosis factor (TNF), which is secreted by endotoxin-stimulated macrophages. It has further been suggested that TNF may play a role in the pathobiochemistry of CF cachexia, secondary to the localized inflammatory response in the lung or wider systemic activation of cells of the monocyte-macrophage series in response to endotoxin. This study investigates TNF production and gene expression by peripheral blood monocyte-derived macrophages from CF patients, compared with normals (NL). The results indicate that although both cell populations responded dose-dependently to lipopolysaccharide (LPS); CF macrophages, upon stimulation with LPS at concentrations of 1 to 1,000 ng/ml, consistently produced substantially higher amounts of TNF than NL macrophages. At the molecular level, Northern blot analysis also revealed that both macrophage populations expressed TNF mRNA in response to LPS in a dose-dependent manner. However, at the same LPS concentrations, CF macrophage TNF mRNA expression was 2- to 4-fold greater than that of NL macrophages. LPS had no effect in either macrophage population on mRNA for CHO-B, a constitutive probe. To investigate differences between NL and CF macrophage TNF regulation, nuclear run-on/half-life studies as well as studies addressing potential differences in LPS membrane interactions and signal transduction were performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway.

Tissue protein hypercatabolism (TPH) is a most important feature in cancer cachexia, particularly with regard to the skeletal muscle. The rat ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and F. M. Baccino. 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor necrosis factor-alpha associated with marked perturbations in the hormonal homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993. Br. J. Cancer. 67:15-23). The present study was directed to investigate if beta 2-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle protein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130-bearing rats by restoring protein degradative rates close to control values. This normalization of protein breakdown rates was achieved through a decrease of the hyperactivation of the ATP-ubiquitin-dependent proteolytic pathway, as previously demonstrated in our laboratory (Llovera, M., C. García-Martínez, N. Agell, M. Marzábal, F. J. López-Soriano, and J. M. Argilés. 1994. FEBS (Fed. Eur. Biochem. Soc.) Lett. 338:311-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of corticosterone and insulin, which were increased and decreased, respectively, in the tumor hosts. The present data give new insights into the mechanisms by which clenbuterol exerts its preventive effect on muscle protein waste and seem to warrant the implementation of experimental protocols involving the use of clenbuterol or alike drugs in the treatment of pathological states involving TPH, particularly in skeletal muscle and heart, such as in the present model of cancer cachexia.

Adenosine Triphosphate↗
PubMed2006

Cockayne syndrome in adults: review with clinical and pathologic study of a new case.

Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31(1/2) years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.

Adult↗
PubMed2005

Symptom distress as rated by advanced cancer patients, caregivers and physicians in the last week of life.

OBJECTIVES: To study the symptom distress as rated by patients with advanced cancer during their last week of life, and to compare patients' ratings with those perceived by caregivers and physicians. METHOD: This was a prospective study on all patients admitted to the Hospice Unit of the Caritas Medical Centre with an estimated life expectancy of two weeks or less from May 2002 to September 2002. A questionnaire with a list of 13 symptoms, including pain, dyspnoea, nausea, vomiting, dry mouth, cough, fatigue, cachexia, anorexia, constipation, diarrhoea, insomnia and haemoptysis, was administered to assess the distress. Distress was rated by a verbal rating scale consisting of five grades (grade 0 to grade 4). Patients, caregivers and physicians completed the questionnaire weekly until the patient died. Only the questionnaires completed in the last week of life were included for analysis. RESULTS: Of 82 patients who were recruited in the study, 30 patients were able to complete the questionnaire within the last week of life. Their median age was 69 years and the gender ratio was 1:1. Lung cancer was the most common primary tumour. Fatigue, cachexia and anorexia caused distress of all grades in nearly all 30 patients and caused significant distress of grade 3 and above in two-thirds of patients. Neither the caregivers nor the physicians gave congruent distress scores for these three symptoms (kappa<0.4). Caregivers' ratings agreed well with those of patients for five symptoms (kappa>0.4, P<0.005), including dyspnoea, cough, dry mouth, constipation and insomnia. For physicians, good agreement was found for three symptoms only, including pain, dyspnoea and cough. Moreover, physicians tended to underrate the distress. CONCLUSION: Fatigue, cachexia and anorexia were the three most distressful symptoms in the last week of life in this group of patients, but caregivers and physicians failed to rate them in agreement with patients.

Adult↗
PubMed2002

Autopsy findings in a human immunodeficiency virus-infected population over 2 decades: influences of gender, ethnicity, risk factors, and time.

OBJECTIVES: To examine autopsy pathology in an urban population infected with the human immunodeficiency virus (HIV) and to determine if age at death and disease frequencies are associated with gender, HIV risk factors, ethnicity, and therapeutic era. DESIGN AND METHODS: Retrospective analysis of autopsy data from 394 HIV-infected adults. The population was divided into 3 therapeutic eras for analysis: group A, 1979-1986; group B, 1987-1995; and group C, 1996-2000. RESULTS: Women died at significantly younger ages than men (mean +/- SEM age, 38.9 +/- 1.0 years vs 42.5 +/- 0.64 years), even after adjustment for risk factors, ethnicity, and therapeutic era. This age discrepancy occurred despite a lower prevalence of arteriosclerosis, cachexia, and hepatitis B in women and no significant differences in the frequencies of other infectious diseases. Whites had a longer survival than patients of other ethnicities (mean age at death, 44.7 +/- 1.2 years for whites, 39.9 +/- 0.80 years for blacks, and 41.3 +/- 0.87 years for Hispanic individuals). Renal, cardiac, and splenic pathologies, Mycobacterium avium-intracellulare (MAI) infection, and cachexia were more common in blacks than in whites and/or Hispanic individuals, and cytomegalovirus and systemic lymphoma were more common in whites and Hispanic individuals than in blacks. Diseases associated with intravenous drug use were hepatitis C, cirrhosis, and tuberculosis; those with all sexual risk factors, cytomegalovirus infection, herpes simplex virus infection, and Pneumocystis carinii pneumonia; and those with homosexual risk, Kaposi sarcoma and MAI infection. The prevalence of many disease entities changed over time: compared with the other groups, group C had lower prevalences of many viral and fungal illnesses, MAI infection, systemic lymphoma, cachexia, and Kaposi sarcoma and higher prevalences of hepatitis, cirrhosis, arteriosclerosis, staphylococcal and streptococcal infections, and traumatic lesions. When the data were adjusted for changing demographic and risk composition, the only significant changes in disease frequency for period C were decreased prevalences of PCP and Kaposi sarcoma and increased prevalences of cirrhosis and arteriosclerosis. CONCLUSIONS: Significant gender- and ethnicity-related differences in age of death occurred in this HIV-infected population, and these differences were not explained by the frequencies of diseases. The lower prevalences of PCP and Kaposi sarcoma in group C are likely a reflection of the impact of potent therapies on causes of mortality. The higher prevalences of cirrhosis and arteriosclerosis suggest that entities not targeted by antiretroviral reconstitution of immunity will play an increasingly important role in HIV-related mortality in the future.

Adult↗
PubMed2001

Effect of cyclic plasma perfusion on apoptosis regulatory proteins in primary tumors of VX2-carcinoma-bearing rabbits.

Although the mechanism of cancer cachexia is unknown, in previous studies we reported that cyclic plasma perfusion through non-coated charcoal was effective in preventing cancer cachexia. In the present study we investigated the effect of cyclic plasma perfusion on VX2 carcinoma. Sixteen tumor-bearing rabbits were divided into two groups: i) a group subjected to cyclic plasma perfusion (n=8, group PP) and ii) a group subjected to sham-perfusion (n=8, group SP), and changes in body weight, tumor size, and morphological findings were investigated. Body weight loss and tumor growth were significantly suppressed in group PP. The tumor cells in group PP showed apoptosis and a high Bax/Bcl-2 ratio, and the survival rate was significantly higher than in group SP. These results suggest that cyclic plasma perfusion is effective not only in preventing cancer cachexia but in suppressing tumor growth and improving outcome.

Animals↗
PubMed2002

NSAID zaltoprofen improves the decrease in body weight in rodent sickness behavior models: proposed new applications of NSAIDs (Review).

In infectious diseases and during inflammation, anorexia, loss of body weight, malaise, fatigue and depression are induced. These symptoms are correctively called 'sickness behaviors', and the central actions of cytokines play a role in their induction. The loss of body weight in cancer cachexia is also a result of development of sickness behaviors. It has been reported that the administration of NSAID ibuprofen to patients with cancer cachexia improves the loss in body weight. We studied the effect of NSAID on the loss of body weight by using rodent sickness behavior models. We have reported that sickness behaviors such as anorexia, decrease in body weight, and loss of locomotor activity are induced in concanavalin A (Con A)-induced mouse hepatitis and carbon tetrachloride-induced rat hepatitis. Zaltoprofen is a non-steroidal anti-inflammatory drug (NSAID) causes potent inhibition of cyclooxygenase-2 with fewer side effects on the gastrointestinal tract. Zaltoprofen improves the loss in body weight in both Con A-treated mice and carbon tetrachloride-treated rats. These results suggest the possible application of zaltoprofen for the treatment of sickness behaviors including loss of body weight occurring in cancer cachexia.

Animals↗
PubMed1999

Wasting in gastrointestinal tract cancers: clinical and etiologic aspects.

One of the major complications found in patients affected by malignancy of the gastrointestinal tract is represented by an alteration of nutritional status, up to real cachexia. The factors responsible for the severe nutritional deficiencies are: metabolic alterations, which involve carbohydrate, lipid and protein metabolism; the reduced availability of nutritional substrates, due to neoplastic growth that, by expanding locally or destroying the affected organ, determines alterations of deglutition, digestion and food absorption; the effects of surgical therapy, radiotherapy and chemotherapy, which are able to cause temporary or permanent nutritional deficiencies; the effects of immunological mediators, and above all of tumor necrosis factor-alpha (TNF-alpha). In fact, TNF-alpha is considered the main mediator of cancer cachexia as it is responsible for different metabolic alterations, both directly and by the activation of other mediators, such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF). In addition, a negative energy balance in cancer patients could occur as a consequence of increased energy requirements. In this connection, patients with different neoplasia localisation, show high or within the normal range energy expenditure values. These data indicate that the increase in energy metabolism is not likely to represent the main determining factor in neoplastic cachexia. In conclusion, since patients affected by malignancy of the gastrointestinal tract showed a reduction in body weight, fat and fat-free mass, accurate evaluation of nutritional status should be useful in the management and follow-up of these patients.

Journal Article↗
PubMed1997

[Energy metabolism in cancer patients].

The presence of cachexia as defined by a series of clinical symptoms, such as anorexia, weight loss, muscular atrophy, tissue wasting, altered organ function, is frequently observed in cancer and makes a decisive contribution to morbidity and mortality. The onset of neoplastic cachexia is characterized by two events: the presence of primary or secondary anorexia and alterations of the host's intermediate metabolism. Among the most frequent metabolic alterations described in cancer patients is an absolute or relative increase in basal energy consumption with lack of adaptation to fasting. The causes of increased energy consumption in cancer patients are still not clear. Numerous studies on glucose, fat and protein metabolism induced by cancer have significantly contributed to our understanding of the phenomenon. The main alterations of the glucose metabolism are increased glucose turnover and reduced peripheral utilization, both of which probably depend on the presence of the tumour, as shown by their normalization after treatment. Increased gluconeogenesis, from lactate and from gluconeogenetic AA, is the main factor responsible for increased glucose turnover. The main alterations of the fat metabolism are increased mobilization of lipids from adipose tissues, reduced use of exogenous triglycerides and increased oxidation of free fatty acids that cannot be suppressed by glucose. The main alterations of protein metabolism are increased protein turnover with reduced synthesis and increased degradation of muscular proteins and increased hepatic protein synthesis. Knowledge of the pathogenesis of neoplastic cachexia represents a valuable aid for its effective prevention and treatment.

English Abstract↗
PubMed1997

Alterations in carbohydrate metabolism in dogs with nonhematopoietic malignancies.

OBJECTIVE: To determine whether alterations in carbohydrate metabolism exist in dogs with nonhematopoietic malignancies but without evidence of weight loss or cachexia. ANIMALS: 90 dogs with nonhematopoietic malignancies and 18 control dogs. PROCEDURE: An intravenous glucose tolerance test was done in 90 dogs with previously untreated nonhematopoietic malignancies and in 18 clinically normal dogs. These dogs also had no evidence of unrelated diseases that would affect glucose metabolism. None of the dogs had evidence of cachexia. Samples were assayed for glucose, lactate, and insulin concentrations. This procedure was repeated for 45 of the tumor-bearing dogs from which all gross evidence of tumor was completely excised and evidence of diseases that would alter carbohydrate metabolism did not exist. RESULTS: The mean of all time points during the intravenous glucose tolerance test (ie, 0, 5, 15, 30, 45, and 60 minutes) for lactate (12.9 +/- 6.7 mg/dl) and insulin (69.1 +/- 44.9 microU/ml) concentrations in untreated dogs with nonhematopoietic malignancies were significantly higher than values for controls (lactate, 9.7 +/- 4.3 mg/dl; and insulin, 31.7 +/- 11.5 microU/ml). This increase in lactate and insulin values did not return to normal when the dogs were rendered free of all observable evidence of cancer after surgery. CONCLUSIONS: Carbohydrate metabolism is altered in dogs with a variety of nonhematopoietic malignancies and these abnormalities do not abate when dogs are rendered free of gross evidence of malignant disease after surgery. CLINICAL RELEVANCE: Alterations in carbohydrate metabolism may result in decreased quality of life and may be associated with the paraneoplastic syndrome, cancer cachexia.

Animals↗
PubMed2000

Tumor necrosis factor-alpha regulates secretion of the adipocyte-derived cytokine, leptin.

The seminal observation that secretion of the adipocyte-derived hormone leptin was induced by inflammatory challenge has been expanded upon to demonstrate the importance of the pro-inflammatory cytokines, especially tumor necrosis factor (TNF)-alpha, in inflammatory hyperleptinemia. Initially, it was thought that cytokine-induced hyperleptinemia might somehow be involved in the anorexia and cachexia that often accompany chronic infectious, neoplastic, and autoimmune disease. While the role of leptin in disease-associated anorexia and cachexia appears tenuous in light of recent findings, there is evidence that the hyperleptinemia induced by cytokines is an integral part of the acute phase response and necessary for comprehensive immunocompetence. This hints at the existence of an integrated communication network, wherein the energy status of the animal impacts its ability to fight pathogens.

Animals↗
PubMed1991

Insulin action and metabolism in patients with head and neck cancer.

Cachexia is a phenomenon commonly observed in patients with cancer, but its etiology is poorly understood. Abnormalities of insulin action and metabolism that have been hypothesized to promote cancer cachexia were investigated in this study using a computerized euglycemic clamp and modified frequently sampled intravenous glucose tolerance test (FSIGT) in a group of malnourished patients with localized head and neck cancer, and in healthy, well-nourished, age- and, sex-matched controls. Glucose disposal rates, determined by the euglycemic clamp at three different rates of insulin infusion did not differ significantly between the two groups. However, mean plasma insulin concentrations at each level of insulin infused were significantly lower in the patients with cancer than in the control subjects resulting in unexpectedly higher calculated insulin metabolic clearance rate in the patients with cancer. Peripheral insulin sensitivity calculated from the slope of glucose disposal versus plasma insulin concentration did not differ between the two groups. Results from the FSIGT demonstrated no difference in insulin sensitivity or insulin-independent glucose disappearance between the two groups. However, whole body glucose appearance was significantly elevated in the patients with cancer. Thus, increased whole body glucose utilization in the absence of insulin resistance or increased insulin-dependent glucose disposal was observed. These data are consistent with the concept of a localized tumor acting as a glucose drain in which case increased glucose appearance and increased insulin clearance would defend against hypoglycemia.

Blood Glucose↗
PubMed1985

Intravenous hyperalimentation as nutritional support for the cancer patient--an update.

Debilitating cancer cachexia is multifactorial, but many of the etiologies and most of the resulting effects are similar to those seen in malnourished patients without cancer. From the work in human beings and experimental animals, nutritional support of the tumor-bearing host can replenish lean body mass, visceral protein components, and immunocompetence. This induction of anabolism, however, depends on time, content, the method of administration of hyperalimentation solutions; the initial and continuing catabolic response of the patient, as well as the degree of initial malnutrition; the energy expenditure of the patient required during oncologic therapy; and the expertise of the physician administering nutritional support. Increased tumor stimulation resulting from intravenous hyperalimentation (IVH) has never been observed in humans; the stimulatory effects of IVH on animal tumor systems have been identified only in previously depleted animals, and then growth rates have not been out of proportion to that of the host or to that of otherwise healthy animals. Animal data suggest that tumor growth characteristics can be affected by nutritional state and the exact substrates administered, ie, amino acids, carbohydrates, or fat. Further evidence suggests that the apparent enhanced tumor growth can be used to increase responsiveness to cell cycle-specific chemotherapeutic agents during nutritional repletion. Current evidence supports the use of intravenous hyperalimentation in malnourished cancer patients who have effective oncologic therapeutic options; such patients should not be denied these options simply on the basis of severe nutritional cachexia.

Adenocarcinoma↗
PubMed1995

Cytokine-mediated alterations in host metabolism prevent nutritional repletion in cachectic cancer patients.

The clinical syndrome of cachexia is characterized by anorexia, continued losses of lean body mass, and altered carbohydrate and lipid metabolism. As early as the 1930s, this "chronic wasting" syndrome had been identified as the most frequent immediate cause of death in patients with cancer [Warren: Am J Med Sci 184:610-619, 1932]. At present, controversy remains as to the benefit of supplemental parenteral or enteral feedings in the nutritional repletion of cachectic cancer patients, since only selected patient groups have demonstrated clear benefit from their administration [Copeland et al.: Cancer 43:2108-2116, 1979; Copeland et al.: Cancer Res 37:2451-2456, 1977; Terepka and Waterhouse: Am J Med 20:225-238, 1956]. Despite having these advanced nutritional modalities firmly in our therapeutic armamentarium, the progression of cachexia in the nutritionally depleted cancer patient often continues unabated, and our ability to intervene successfully remains limited. This review proposes that host: tumor interactions lead to a nonspecific inflammatory response mediated in part by the chronic production and release of proinflammatory cytokines, including interleukin-1, tumor necrosis factor alpha, interleukin-6 and interferon-gamma, which antagonize the anabolic signals associated with enteral and parenteral nutrition support. Cytokine-mediated alterations can explain the inability of adequate dietary nitrogen and calories to result in lean tissue repletion. Based on this proposal, interrupting proinflammatory cytokine production or target organ action may be an appropriate therapeutic objective to improve nutrient utilization in patients with tumors.

Cachexia↗