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Biomedical subjects

K C Fearon

Publications and source records attributed to K C Fearon.

At least 91 records · Page 5Linked to original sources
PubMed1992

Regulation of tumor necrosis factor production in healthy humans and in patients with cancer.

To study the factors that influence cytokine release, the effect of endotoxin on in vitro tumor necrosis factor production by monocytes from debilitated patients with cancer (n = 6) was compared with that from healthy controls (n = 5). Spontaneous and endotoxin-stimulated monocyte tumor necrosis factor production was similar in patients with cancer and controls. However, with total peripheral blood mononuclear cells, enhancement of tumor necrosis factor production by endotoxin in patients with cancer (46 +/- 12, mean +/- SEM) was greater than in controls (0% +/- 7%). This enhanced response correlated with reduced peripheral blood mononuclear cell blastogenesis in response to phytohemagglutinin (r = .66) and could be partially reversed in vitro by addition of exogenous interleukin 2. Thus, a component of total peripheral blood mononuclear cells (probably T cells) seems to influence monocyte cytokine production in response to endotoxin. Moreover, this regulatory component is decreased in patients with cancer, correlates with decreased peripheral blood mononuclear cell blastogenesis, and can stimulated with interleukin 2.

Adult↗
PubMed1992

Bioelectrical impedance analysis in the measurement of the body composition of surgical patients.

The evaluation of nutritional status in surgical patients remains a difficult problem. Bioelectrical impedance analysis (BIA) is a new method of body composition analysis which is easily performed at the bedside. This study determined the accuracy of BIA in the measurement of total body water (TBW) and potassium (TBK) in a heterogeneous group of surgical patients. The resistance and reactance components of impedance were measured with a whole body impedance analyser. Tritiated water dilution and whole body monitoring were the reference methods for TBW and TBK analysis. With the BIA technique the coefficient of variation for the estimation of TBW was 8.1 per cent and for TBK was 6.4 per cent. Allowing for the errors of the reference methods these results show that BIA is of limited value in the estimation of TBW but may provide a useful index of TBK.

Adult↗
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↗
PubMed1991

Elevated circulating interleukin-6 is associated with an acute-phase response but reduced fixed hepatic protein synthesis in patients with cancer.

It has been suggested that, as part of the inflammatory response to the presence of a tumor, various cytokines are produced and these induce hepatic synthesis of acute-phase proteins (APP). Under these circumstances it is not known what changes occur in the fixed component of hepatic protein synthesis. The aim of this study was to compare circulating interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) concentrations and fixed hepatic protein synthesis rates in a group of healthy controls (n = 6) with a group of patients with an established APP response secondary to hepatic metastasis from colorectal cancer (n = 6). Fixed hepatic protein synthesis rates were measured following a primed, constant 20-hour infusion of 15N-glycine. The liver was biopsied at laparotomy. The APP response was assessed by serum C-reactive protein concentration and cytokines were assayed by a combination of immunoassay and bioassay. The patients with advanced cancer and an on-going APP response had elevated circulating IL-6 concentrations (p less than 0.01). Rates of fixed hepatic protein synthesis were 30% lower than those observed in controls (p less than 0.01). These findings demonstrate that in patients with hepatic metastasis, although the synthesis of certain acute-phase export proteins can be increased, fixed protein synthesis is reduced. Whether these changes in the distribution of hepatic protein synthesis are mediated by IL-6 will require further investigation.

Acute-Phase Reaction↗
PubMed1988

Influence of whole body protein turnover rate on resting energy expenditure in patients with cancer.

Whole body protein turnover and resting energy expenditure are measured simultaneously in weight stable and weight losing patients with lung (n = 22) or colorectal cancer (n = 38). These results were compared with those from weight stable and weight losing non-cancer controls (n = 22). Rates of whole body protein turnover were calculated from the plateau isotopic enrichment of urinary ammonia and urea following a primed, continuous, 24-h infusion of [15N]glycine. Resting energy expenditure was measured by indirect calorimetry. All groups of cancer patients had significantly elevated rates of whole body protein turnover (P less than 0.05) and synthesized, on average, 1.9 g/kg/day more protein compared with weight stable non-cancer controls. In contrast, the resting energy expenditure of cancer patients and controls was similar. Moreover, there was no correlation between individual rates of whole body protein turnover. Thus, although cancer patients had rates of whole body protein turnover which were 50-70% greater than controls, this did not result in a measurable increase in resting energy expenditure. The assumption that elevation of whole body protein turnover or resting energy expenditure causes weight loss in cancer patients must be an oversimplification. An acute phase protein response was observed in the majority of cancer patients. Although the presence of such an inflammatory response did not correlate with the rate of whole body protein turnover, the role of inflammatory mediators in the pathogenesis of disturbed protein metabolism in cancer patients merits further investigation.

Aged↗
PubMed1988

Nutritional pharmacology in the treatment of neoplastic disease.

The altered energy metabolism and substrate requirements of tumour cells can provide a target for selective antineoplastic therapy. The supply of substrates for tumour energy metabolism can be reduced by dietary manipulation (e.g. ketogenic diet) or by pharmacological means at the cellular level (e.g. inhibitors of glycolysis or oxidative phosphorylation). Both these approaches are examined with a view to the development of selective and therefore non-toxic methods of controlling tumour growth in vivo.

Antineoplastic Agents↗
PubMed1988

Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism.

The aim of this study was to determine whether a ketogenic diet could decrease nitrogen losses in cachectic cancer patients and at the same time reduce the supply of glucose for tumor energy metabolism. Five patients with malignant disease and severe weight loss (mean 32%) were fed via a fine bore nasogastric tube. A normal diet was given for 6 d and this was followed by 7 d of an isonitrogenous, isocaloric, ketogenic diet. Both diets were well tolerated. At 7 d the mean ketone body concentration in the blood of patients fed the ketogenic diet was 1.21 +/- 0.33 mM. This ketosis was associated with a significant reduction of the concentration in blood of glucose, lactate, and pyruvate (p less than 0.05). There was, however, no significant alteration in host N balance or whole-body protein synthesis, degradation, or turnover rates. Whether the change from glucose- to fat-derived energy substrates might reduce tumor growth rates in the long term remains to be determined.

Acidosis↗
PubMed1988

Cancer cachexia.

Despite recent advances in the delivery of nutritional support, cachexia continues to contribute to the morbidity and mortality of cancer patients. This impasse has called for a review of the many factors that are believed to be associated with weight loss in the cancer host. This article reviews the topic with a view to past problems and areas for investigation in the future.

Cachexia↗
PubMed1987

Reduction of the growth rate of the Walker 256 tumor in rats by rhodamine 6G together with hypoglycemia.

Previous attempts to use tumor energy metabolism as a target for antineoplastic therapy have used single agents aimed at inhibiting either glycolysis or oxidative phosphorylation. Since most tumor cells use both pathways for energy production, this approach is unlikely to succeed. The aim of this study was to simultaneously manipulate both sources of intracellular ATP to achieve more selective control of tumor growth. Rhodamine 6G (R6G) is a fluorochrome mitochondrial dye which inhibits oxidative phosphorylation. 3-Mercaptopicolinic acid inhibits gluconeogenesis and is a potent hypoglycemic agent in the fasting state. Dose-response relationships were established for R6G and 3-mercaptopicolinic acid, and a nontoxic dose of the compounds was selected for subsequent experiments. Thereafter, groups of rats (n = 7 per group) underwent s.c. implantation of Walker 256 carcinosarcoma. Following a 24-h fast each group received either saline, R6G (0.8 mg/kg), 3-mercaptopicolinic acid (40 mg/kg), or the combination given i.p. Seven days after tumor implantation animals were sacrificed, and tumors were exercised and weighed. Administration of R6G during a period of hypoglycemia significantly reduced the tumor growth rate when compared to control experiments (3.6 +/- 0.3 g cf. 7.1 +/- 0.7 g, mean +/- SE; P less than 0.05). In contrast, neither R6G nor the period of hypoglycemia alone significantly affected tumor growth. These results suggest that simultaneous manipulation of oxidative phosphorylation and glycolysis may be used to selectively inhibit tumor growth in vivo.

Adenosine Triphosphate↗
PubMed1987

Reduction of weight loss and tumour size in a cachexia model by a high fat diet.

An attempt has been made to reverse cachexia and to selectively deprive the tumour of metabolic substrates for energy production by feeding a ketogenic regime, since ketone bodies are considered important in maintaining homeostasis during starvation. As a model we have used a transplantable mouse adenocarcinoma of the colon (MAC 16) which produces extensive weight loss without a reduction in food intake. When mice bearing the MAC16 tumour were fed on diets in which up to 80% of the energy was supplied as medium chain triglycerides (MCT) with or without arginine 3-hydroxybutyrate host weight loss was reduced in proportion to the fat content of the diet, and there was also a reduction in the percentage contribution of the tumour to the final body weight. The increase in carcass weight in tumour-bearing mice fed high levels of MCT was attributable to an increase in both the fat and the non-fat carcass mass. Blood levels of free fatty acids (FFA) were significantly reduced by MCT addition. The levels of both acetoacetate and 3-hydroxybutyrate were elevated in mice fed the high fat diets, and tumour-bearing mice fed the normal diet did not show increased plasma levels of ketone bodies over the non-tumour-bearing group despite the loss of carcass lipids. Both blood glucose and plasma insulin levels were reduced in mice bearing the MAC16 tumour and this was not significantly altered by feeding the high fat diets. The elevation in ketone bodies may account for the retention of both the fat and the non-fat carcass mass. This is the first example of an attempt to reverse cachexia by a diet based on metabolic differences between tumour and host tissues, which aims to selectively feed the host at the expense of the tumour.

Adenocarcinoma↗
PubMed1987

Characterization of a transplantable adenocarcinoma of the mouse colon producing cachexia in recipient animals.

MAC16 is a chemically induced, transplantable adenocarcinoma of the colon passaged in inbred NMRI mice. At small tumor burdens (less than 1% of the host weight), weight loss was observed without a reduction in food intake. As the tumor mass increased, weight loss also increased and reached 33% of host body weight in females and 20% in males when compared with the weight of age-matched controls. The reduction in host body weight was directly proportional to the tumor size and was reversible when the tumor was excised. There was a preferential loss of body fat in tumor-bearing animals with an increase in the plasma level of free fatty acids, although there was a minimal elevation of ketone bodies. Tumor growth was accompanied by progressive hypoglycemia and a reduction in the plasma insulin levels. The decrease in plasma insulin may have contributed to the catabolic effects of progressive tumor growth.

Adenocarcinoma↗
PubMed1985

Failure of systemic ketosis to control cachexia and the growth rate of the Walker 256 carcinosarcoma in rats.

The Walker 256 carcinosarcoma was shown to lack the enzyme 3-ketoacid CoA transferase. This suggests that ketone bodies cannot be used as a major substrate for the energy metabolism of this tumour. Systemic ketosis (1-2 mM acetoacetate plus 3-hydroxybutyrate) was induced both in tumour-bearing and in non-tumour-bearing rats with a diet containing 70% medium chain triglyceride. However, in rats bearing the Walker 256 tumour, this dietary ketosis did not reduce the tumour growth rate nor did it prevent the subsequent decrease in host body weight. Host body nitrogen losses were similarly unaffected. The ketosis induced in tumour bearing rats was shown to be abnormal since the blood glucose concentration of ketotic, tumour-bearing rats was significantly higher compared with that of ketotic non-tumour bearing rats (5.2 +/- 0.4 mM cf 3.4 +/- 0.6 mM, P less than 0.01). These results may partly explain why systemic ketosis failed to alter the growth and cachexia induced by the Walker 256 carcinosarcoma.

Acetyl-CoA C-Acetyltransferase↗
PubMed1983

Prediction of risk in biliary surgery.

To identify individual risk factors and to establish an index of risk in biliary tract surgery, data on 16 potential predictive factors were compiled from a series of 186 biliary tract operations excluding simple cholecystectomy. Eight factors had a significant association with postoperative mortality. Linear discriminant analysis showed that serum creatinine, serum albumin and serum bilirubin levels in the week before surgery had independent significance in predicting postoperative mortality. The discriminant function derived identified a high risk group of patients and the predictive value was confirmed in an independent series of 54 biliary tract operations carried out in another surgical unit. The discriminant function derived for patients jaundiced before surgery also defined a high and low risk group and was similarly validated. Identification of high risk patients undergoing surgery for obstructive jaundice may be useful in defining a group of patients to be considered for trials of preliminary biliary drainage.

Biliary Tract Diseases↗
PubMedDate not supplied

Effect of glutamine on immune function in the surgical patient.

The beneficial effects of glutamine on immune function in vitro have been well described. Severely ill surgical patients undergo glutamine depletion and this has been implicated as a cause of immune dysfunction in vivo. With the introduction of the stable dipeptides of glutamine into total parenteral nutrition (TPN) regimens, the clinical effects of glutamine on the immune system have taken on an increased relevance and importance. In a randomized clinical trial, we have shown that glutamine-supplemented TPN increased the T cell mitogenic response in patients undergoing colorectal resection. This was not associated with an altered production of the pro-inflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor (TNF). In a subsequent clinical trial comparing glutamine-supplemented TPN with control TPN in patients with severe acute pancreatitis there was a similar modest enhancement of the T cell response in the glutamine-supplemented group. Although Il-6 and TNF production were again unchanged, there was a significant reduction in IL-8 production in the glutamine-supplemented group. Glutamine may exert its immunological effects by a direct action on the cells of the immune system. Possible indirect mechanisms by which glutamine may influence the immune system include the maintenance of gut barrier function, or the preservation of action of the antioxidant glutathione.

Glutamine↗
PubMedDate not supplied

Proximal and distal measurements of extracellular and total body water by multi-frequency bio-impedance analysis in surgical patients.

Measurements of extracellular water (ECW) and total body water (TBW) can be useful when assessing the nutritional status of surgical patients. The simple and non-invasive nature of bio-impedance techniques may allow repeat measurements to assess clinically significant changes in ECW and TBW. We have evaluated bio-impedance spectroscopy (BIS) and multi-frequency bio-impedance analysis (MFBIA) using radioisotope dilution as the independent method.

Body Composition↗