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Kenneth C H Fearon

Publications and source records attributed to Kenneth C H Fearon.

16 recordsLinked to original sources
PubMed2006

Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia.

PURPOSE: Eicosapentaenoic acid (EPA) has been proposed to have specific anticachectic effects. This trial compared EPA diethyl ester with placebo in cachectic cancer patients for effects on weight and lean body mass. PATIENTS AND METHODS: Five hundred eighteen weight-losing patients with advanced gastrointestinal or lung cancer were studied in a multicenter, double-blind, placebo controlled trial. Patients were randomly assigned to receive a novel preparation of pure EPA at a dose of 2 g or 4 g daily or placebo (2g EPA, n = 175; 4 g EPA, n = 172; placebo, n = 171). Patients were assessed at 4 weeks and 8 weeks. RESULTS: The groups were well balanced at baseline. Mean weight loss at baseline was 18% (n = 518). Over the 8-week treatment period, both intention-to-treat analysis and per protocol analysis revealed no statistically significant improvements in survival, weight, or other nutritional variables. There was, however, a trend in favor of EPA with analysis of the primary end point, weight, at 8 weeks showing a borderline, nonsignificant treatment effect (P = .066). Relative to placebo, mean weight increased by 1.2 kg with 2 g EPA (95% CI, 0 kg to 2.3 kg) and by 0.3 kg with 4 g EPA (-0.9 kg to 1.5 kg). CONCLUSION: The results indicate no statistically significant benefit from single agent EPA in the treatment of cancer cachexia. Future studies should concentrate on other agents or combination regimens.

Adult↗
PubMed2006

The adaptive response of the reticuloendothelial system to major liver resection in humans.

OBJECTIVE: To evaluate the contribution of the liver to total circulatory reticuloendothelial system (RES) phagocytosis capacity in patients undergoing liver resection and to compare it with values in end-stage chronic liver disease. SUMMARY BACKGROUND DATA: The mechanism whereby major liver resection is associated with a high incidence of infection is unknown. Significant impairment of RES phagocytosis has been described in liver failure, rendering such patients susceptible to infection; and we hypothesized that similar impairment might occur following major liver resection. METHODS: A prospective study was conducted in which Tc-albumin microspheres blood clearance served as a parameter for RES phagocytosis and was studied together with indocyanine green blood clearance, actual liver volume measured by three-dimensional image analysis, and a clinical score of hepatic dysfunction in 17 patients undergoing liver resection and in 8 patients with end-stage chronic liver disease assessed for liver transplantation. RESULTS: When expressed relative to volume unit of residual liver, microspheres clearance increased significantly in the immediate postoperative period (day 1) following major (0.009% versus 0.022% min(-1) mL(-1), P < 0.001), but not minor liver resection. In contrast, the absolute rate of microsphere clearance decreased following major resection (15% min(-1) versus 10% min(-1), P < 0.001) and was comparable with the rate observed in end-stage chronic liver disease (9% min(-1)). This decrease in circulatory microspheres clearance after resection paralleled a decrease in indocyanine green clearance (R2 = 0.511, P = 0.006), and there was a trend for those with moderate liver dysfunction to have lower microspheres clearance rates (P = 0.068). CONCLUSION: Preservation of a minimum volume of functioning liver is a prerequisite for adequate RES phagocytosis capacity, and failure of this system may predispose patients undergoing major liver resection to infection as observed in clinical studies.

Adaptation, Physiological↗
PubMed2005

Febrile-range temperature but not heat shock augments the acute phase response to interleukin-6 in human hepatoma cells.

The relationship between the stress protein response and the acute phase response (APPR) was studied in human hepatoma cells to investigate the hierarchy of regulation of these survival responses. Huh-7 cells were subjected to heat treatment (febrile-range temperature 40 degrees C or heat shock 43 degrees C) followed by recovery at 37 degrees C in the presence or absence of IL-6 given either before or after heat treatment. The effects on total, fractional, and acute phase protein synthesis were then analyzed by metabolic labeling, ELISA, real-time PCR, Northern blot analysis, and activation of an alpha(1)-antitrypsin reporter plasmid. Cell energetics were studied under the same conditions using an index of mitochondrial activity and measurement of cellular ATP levels. Febrile-range temperature (40 degrees C) augmented acute phase protein production when cells had been pretreated with IL-6. Pretreatment of cells with IL-6 also prevented heat shock-induced suppression of alpha(1)-antichymotrypsin (ACT) but not transferrin. mRNA expression of ACT and alpha(1)-antitrypsin reporter activation studies was consistent with transcriptional regulation of these proteins. Expression of mRNA transcripts for transferrin was increased despite protein expression being reduced by heat shock. The effects of heat shock on acute phase protein synthesis can be modified by preincubation with IL-6, whereas addition of this ligand after heat treatment has no effect on the suppressive effect of heat on the APPR. The mechanism of this action appears to be transcriptionally regulated in the case of ACT, but in the case of transferrin, it may be mediated by another process such as posttranslational modification.

Acute-Phase Proteins↗
PubMed2005

Serum parathyroid hormone-related peptide is associated with systemic inflammation and adverse prognosis in gastroesophageal carcinoma.

BACKGROUND: Parathyroid hormone-related peptide (PTHrP) is a tumor-derived circulating factor that has been associated with hypercalcemia of malignancy. The role of PTHrP as a prognostic indicator remains unclear. Studies suggest that it may function as a growth factor; and, recently, the ability of PTHrP to induce cytokine expression has been described. PTHrP also has been proposed as a procachectic factor. In this study, the authors investigated the prognostic value of PTHrP in patients who had gastroesophageal carcinoma without hypercalcemia and determined whether PTHrP was associated with systemic inflammation and adverse nutritional status. METHODS: Patients were recruited at the time of diagnosis. Serum was collected for determination of c-terminal fragment PTHrP (cPTHrP) levels (by radioimmunoassay) and calcium levels as well as levels of serum cytokines and acute-phase proteins (with an enzyme-linked immunosorbent assay). Nutritional assessment of patients was undertaken at the same time as serum collection. Patients underwent routine staging, and survival duration was recorded. RESULTS: One hundred fifty-one patients with esophagogastric carcinoma were recruited. Six of 151 patients (4.0%) patients were hypercalcemic, and 26 patients (17.2%) had elevated serum cPTHrP levels. There was no association between the cPTHrP level and either serum calcium concentrations (P = 0.72) or adverse nutritional status. Elevated cPTHrP, however, was associated with significantly higher serum levels of soluble tumor necrosis factor receptor (P = 0.008) and with significantly lower levels of transferrin (P = 0.009) and albumin (P = 0.02). There was also a weak association with C-related protein levels (P = 0.06). Elevated cPTHrP levels also were associated with an adverse prognosis, as determined by reduced survival duration, on univariate analysis (P = 0.038), but not on multivariate analysis (P = 0.15). CONCLUSIONS: Elevated serum cPTHrP levels were present in approximately 17% of patients with gastroesophageal carcinoma in the absence of hypercalcemia and was associated with markers of systemic inflammation and with an adverse prognosis.

Adenocarcinoma↗
PubMed2005

Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia.

Cachexia contributes to nearly a third of all cancer deaths, yet the mechanisms underlying skeletal muscle wasting in this syndrome remain poorly defined. We report that tumor-induced alterations in the muscular dystrophy-associated dystrophin glycoprotein complex (DGC) represent a key early event in cachexia. Muscles from tumor-bearing mice exhibited membrane abnormalities accompanied by reduced levels of dystrophin and increased glycosylation on DGC proteins. Wasting was accentuated in tumor mdx mice lacking a DGC but spared in dystrophin transgenic mice that blocked induction of muscle E3 ubiquitin ligases. Furthermore, DGC deregulation correlated positively with cachexia in patients with gastrointestinal cancers. Based on these results, we propose that, similar to muscular dystrophy, DGC dysfunction plays a critical role in cancer-induced wasting.

Adult↗
PubMed2005

Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency?

BACKGROUND: The disturbances leading to cancer cachexia remain to be unraveled. Preliminary evidence suggests that arginine availability in cancer is reduced. However, no valid data are available on plasma arginine concentrations in cancer patients. OBJECTIVE: We aimed to determine whether there is evidence for disturbed arginine metabolism in cancer. DESIGN: We measured plasma arginine concentrations postabsorptively in patients with various types of tumors, hypothesizing that arginine concentrations would be lower than those in age- and sex-matched control subjects. Patients with localized tumors with a range of metabolic implications were studied: breast cancer (no weight loss), colonic cancer (sometimes weight loss), and pancreatic cancer (usually weight loss). Plasma amino acid concentrations were measured by HPLC. RESULTS: Plasma arginine concentrations were lower in patients with cancer (breast cancer: 80 +/- 3 compared with 103 +/- 9 micromol/L; colonic cancer: 80 +/- 3 compared with 96 +/- 7 micromol/L; pancreatic cancer: 76 +/- 5 compared with 99 +/- 7 micromol/L; P < 0.05 versus respective age- and sex-matched control subjects), irrespective of tumor type, weight loss, tumor stage, or body mass index (correlations with P > 0.05). CONCLUSIONS: Malignant tumors associated with various degrees of metabolic derangements are all associated with decreased plasma arginine concentrations, even without weight loss. This suggests that decreased arginine availability is a specific feature of the presence of cancer. These disturbances in arginine metabolism could contribute to the cascade of metabolic events leading to cancer cachexia.

Adult↗
PubMed2005

Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia.

Muscle wasting in experimental cancer cachexia has been associated with increased ubiquitin proteasome proteolytic system activity and increased uncoupling protein (UCP) expression. Increased ubiquitin proteasome pathway activity has also been found in gastric, but not lung, cancer patients. It therefore remains unclear in which patients modulation of this proteolytic system could be a therapeutic target. We investigated markers of systemic inflammation, hypermetabolism and expression of ubiquitin and uncoupling proteins 2 and 3 in muscle of pancreatic cancer patients. Rectus abdominis muscle was sampled from 15 weight-losing pancreatic cancer patients and 11 controls. UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting. Resting energy expenditure and plasma IL-6, sTNF-R and C-reactive protein (CRP) were also measured. Cancer patients had lost 18% of pre-illness stable weight, but were not significantly hypermetabolic compared with controls. IL-6, sTNF-R and CRP levels and ubiquitin 2.4 kb, but not 1.2 kb, mRNA expression were increased in cancer patients. UCP-2 and 3 mRNA and UCP-3 protein were similar in both groups. Weight loss correlated with systemic inflammation and ubiquitin 1.2 and 2.4 kb mRNA expression. Weight loss in pancreatic cancer is associated with systemic inflammation and increased mRNA expression for ubiquitin but not uncoupling proteins in skeletal muscle. The pro-inflammatory network and ubiquitin proteasome pathway may be targets for intervention in pancreatic cancer cachexia.

Aged↗
PubMed2004

Early stress protein gene expression in a human model of ischemic preconditioning.

Intermittent clamping of the porta hepatis (PHC) is commonly performed during liver surgery to reduce blood loss and has been reported to precondition livers resulting in improved outcome after liver surgery (humans) and transplantation (animals). This study investigated the early expression of cytoprotective stress proteins during ischemia-reperfusion induced by PHC. Liver samples were taken before and after each event in a two-cycle ischemia-reperfusion protocol using 15 minutes of PHC followed by 5 minutes of reperfusion. Liver tissue was analyzed by real-time polymerase chain reaction for heme oxygenase (HO)-1 and heat shock protein (HSP)-70 mRNA expression. Extracted protein was analyzed by Western blot for HO-1, and HSP-70 and nuclear extracts were analyzed by DNA mobility shift assay for hypoxia inducible factor (HIF)-1alpha and heat shock factor (HSF)-1. Within minutes of PHC, significant increases in HO-1 mRNA expression were detected, and these were maintained throughout the protocol (P < 0.01). Protein expression of HO-1 (P < 0.03) and HO-1 activity (P < 0.05) were similarly increased between the start and end of ischemia- reperfusion (40 minutes). Binding of active HIF-1alpha to its consensus sequence was increased within 15 minutes of the start of the ischemia-reperfusion cycle. Although evidence of the transcriptionally active form of HSF-1 was detected at the same time point, this was not reflected in measurable changes in HSP-70 mRNA or protein. In conclusion, expression of the cytoprotective protein HO-1 is significantly up-regulated in the liver within minutes of PHC. It is likely that HO-1 contributes to the early protective effects of ischemic preconditioning.

Adenosine Triphosphate↗
PubMed2004

Patterns and clinical outcomes associated with routine intravenous sodium and fluid administration after colorectal resection.

Excess intravenous water and sodium may be associated with postoperative complications and an adverse outcome. However, the effect of the magnitude of the surgery on such a relation has not been studied. This study assesses current practice in intravenous fluid and sodium administration after colonic and rectal resection and its relation to the postoperative outcome. A series of 100 consecutive patients undergoing elective colonic (n = 44) or rectal resection (n = 56) were included in a retrospective case-cohort study. The volumes of water and sodium from intravenous fluid and antibiotic administration on the day of surgery and the next 5 days were recorded together with the clinical outcome. The mean +/- SEM fluid and sodium administration on the day of operation was greater after rectal than colonic resection (4.6 +/- 0.2 vs. 3.6 +/- 0.2 liters and 507 +/- 34 vs. 389 +/- 22 mmol, respectively (p < 0.05). The mean +/- SEM rate of daily fluid and sodium administration for the 5 subsequent days was greater following rectal than colonic resection (2.1 +/- 0.1 vs. 1.8 +/- 0.1 L/day and 155 +/- 8.7 vs. 128 +/- 8.0 mmol/day; p < 0.05). For all resections, there were no differences in fluid and sodium administration on the day of surgery in patients with or without postoperative complications. During the subsequent 5 days, patients with complications after colonic resection had a higher postoperative mean rate of intravenous sodium administration than those who did not (149 +/- 12 vs. 115 +/- 10 mmol; p < 0.05). A similar pattern was not observed following rectal resection. Current postoperative intravenous fluid prescription delivers approximately 2 liters of fluid and 140 mmol of sodium per day. Complications after colonic, but not rectal, resection are associated with more early postoperative daily intravenous sodium administration. Because colonic resection poses less of a physiologic insult than rectal resection, the overall outcome in the former group may be more sensitive to the interplay between fluid and sodium overload and patient co-morbidity.

Adult↗
PubMed2004

Modulation of the liver export protein synthetic response to feeding by an n-3 fatty-acid-enriched nutritional supplement is associated with anabolism in cachectic cancer patients.

The acute-phase protein response is associated with accelerated weight loss and shortened survival in cancer. This may be due to hepatic protein synthesis increasing demand for amino acids. An n -3 fatty-acid-enriched nutritional supplement will moderate aspects of cachexia in cancer patients. The present study examined the effect of such a supplement on hepatic synthesis of albumin and fibrinogen. Albumin and fibrinogen synthesis were measured in the fed and fasting state in eight weight-losing patients with pancreatic cancer by an intravenous flooding dose technique. Tracer incorporation into proteins was measured by GC/MS. Patients were restudied after 3 weeks of oral supplement enriched with fish oil (providing 2510 kJ/day and 2 g of eicosapentaenoic acid/day). At baseline, all patients were losing weight (median, 2.4 kg/month). After 3 weeks of consumption of the fish-oil-enriched nutritional supplement, patients' weight stabilized (median change, +1 kg; P = 0.01). At baseline, albumin and fibrinogen synthesis rates were stimulated in the fed compared with the fasting state [14.2 compared with 11.3 g/day (29% rise; P = 0.01) and 4.5 compared with 3.3 g/day (38% rise; P = 0.01) respectively]. After 3 weeks of the supplement, this stimulation in the fed state was no longer observed for albumin and was reduced for fibrinogen [11.2 compared with 10.5 g/day (3% rise; P = 0.21) and 3.7 compared with 2.9 g/day (17% rise; P = 0.01) respectively]. After 3 weeks, the combined albumin plus fibrinogen synthetic rate tended to fall in the fasting state (14.7 compared with 12.3 g/day; P = 0.09) and was significantly reduced in the fed state (18.7 compared with 14.6 g/day; P = 0.01). Modulation of hepatic export protein synthesis with feeding may have contributed to the net whole-body anabolism observed with administration of the n -3 fatty-acid-enriched oral supplement.

Aged↗
PubMed2004

Renal metabolism of amino acids: its role in interorgan amino acid exchange.

The kidneys play a role in the synthesis and interorgan exchange of several amino acids. The quantitative importance of renal amino acid metabolism in the body is not, however, clear. We review here the role of the kidney in the interorgan exchange of amino acids, with emphasis on quantitative aspects. We reviewed relevant literature by using a computerized literature search (PubMed) and checking relevant references from the identified articles. Our own data are discussed in the context of the literature. The kidney takes up glutamine and metabolizes it to ammonia. This process is sensitive to pH and serves to maintain acid-base homeostasis and to excrete nitrogen. In this way, the metabolism of renal glutamine and ammonia is complementary to hepatic urea synthesis. Citrulline, derived from intestinal glutamine breakdown, is converted to arginine by the kidney. Renal phenylalanine uptake is followed by stoichiometric tyrosine release, and glycine uptake is accompanied by serine release. Certain administered oligopeptides (eg, glutamine dipeptides) are converted by the kidneys to their constituent components before they can be used in metabolic processes. The kidneys play an important role in the interorgan exchange of amino acids. Quantitatively, for several important amino acids, the kidneys are as important as the gut in intermediary metabolism. The kidneys may be crucial "mediators" of the beneficial effects of specialized, disease-specific feeding solutions such as those enriched in glutamine dipeptides.

Amino Acids↗
PubMed2003

The nutritional management of surgical patients: enhanced recovery after surgery.

Malnutrition has long been recognised as a risk factor for post-operative morbidity and mortality. Traditional metabolic and nutritional care of patients undergoing major elective surgery has emphasised pre-operative fasting and re-introduction of oral nutrition 3-5 d after surgery. Attempts to attenuate the consequent nutritional deficit and to influence post-operative morbidity and mortality have included parenteral, enteral and oral sip feeding. Recent studies have emphasised that an enhanced rate of recovery can be achieved by a multi-modal approach focused on modulating the metabolic status of the patient before (e.g. carbohydrate and fluid loading), during (e.g. epidural anaesthesia) and after (e.g. early oral feeding) surgery. Using such an approach preliminary results on patients undergoing elective colo-rectal surgery indicate a significant reduction in hospital stay (traditional care, n 48, median stay 10 d v. enhanced recovery programme, n 33, median stay 7d; P<0.01) can be achieved. Such findings emphasise the potential role of multi-modal care programmes in the promotion of early recovery from major surgical trauma.

Humans↗
PubMed2003

Eicosapentaenoic acid perturbs signalling via the NFkappaB transcriptional pathway in pancreatic tumour cells.

In addition to various roles in membrane structure and metabolism, polyunsaturated fatty acids have effects on signal transduction and on the regulation of gene expression. Eicosapentaenoic acid (EPA) is an omega-3 fatty acid which is known to induce cell cycle arrest and apoptosis in pancreatic tumour cells. NFkappaB is a key transcription factor regulating genes involved in the immune response and has been implicated in apoptotic pathways. In this study we investigated the effect of eicosapentanoic acid on the NFkappaB pathway in pancreatic tumour cells. The pancreatic cell line MIA PaCa2 was incubated in the presence of the fatty acids EPA (n-3), arachidonic acid (AA, n-6) or oleic acid (OA, n-9) before pulsing with TNF to provide a kinetic assessment of NFkappaB activation and IkappaBalpha degradation. Pre-incubation of pancreatic cells with EPA or AA for 2 h before pulsing with TNF preserved IkappaBalpha but did not prevent NFkappaB activation. Indeed, NFkappaB activation was prolonged after exposure to EPA. N-acetyl-L-cysteine did not influence the effect of EPA on TNF-stimulated IkappaBalpha degradation. These results suggest that the omega-3 fatty acid EPA perturbs the NFkappaB pathway by a novel mechanism. This mechanism may be important in delineating alternative pathways to NFkappaB activation.

Acetylcysteine↗
PubMed2002

Cancer cachexia.

Cancer cachexia is a complex, multifactorial syndrome that results from a reduction in food intake, a variety of metabolic abnormalities (including hypermetabolism) or more often a combination of the two. Multiple mediator pathways including pro-inflammatory cytokines, neuroendocrine hormones and tumour-specific factors are involved. Therapy requires a multi-model approach that addresses both reduced food intake and metabolic change. Combination treatments such as nutritional support plus metabolic/inflammation modulation promise improved functional capacity and quality of life.

Cachexia↗
PubMed2002

Eicosanoid-dependent cancer cachexia and wasting.

The reversal of catabolic processes remains a significant challenge related, in part, to their complexity and our incomplete understanding of the mechanisms involved. The eicosanoids are key players in the inflammatory process and have been implicated in the process of cancer cachexia. They are unsaturated C20 fatty acids which can be separated into two main groups: the lipoxygenase products including leukotrienes and lipoxins, and the prostanoids including prostaglandins, prostacyclin and thromboxane. This review examines the biology of the eicosanoids and the evidence of a role for the eicosanoids in cancer cachexia and wasting.

Animals↗