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K C Fearon

Publications and source records attributed to K C Fearon.

At least 19 recordsLinked to original sources
PubMed2001

Tolerance and incorporation of a high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia.

Chemotherapy and radiotherapy offer little benefit to patients with advanced pancreatic cancer. Eicosapentaenoic acid (EPA) has anticancer effects both in vitro and in animal models. The dose of EPA that can be administered to cancer patients has previously been limited by the low purity of available preparations and the tolerability of large capsules. A high-purity preparation of EPA as a 20% oil-in-water diester emulsion allowed a small study of the tolerance, incorporation, and effects of EPA in high doses in five patients with advanced pancreatic cancer. Patients underwent assessment at baseline and every 4 wk thereafter. All patients managed to tolerate a dose providing 18 g EPA per day, with doses between 9 and 27 g daily being taken for at least a month. Dosage was limited by a sensation of fullness, cramping abdominal pain, steatorrhea, and nausea. All such symptoms were controlled by dose reduction or pancreatic enzyme supplements. No other adverse effects attributable to the trial agent were observed. Plasma phospholipid EPA content increased from around 1% at baseline to 10% at 4 wk and 20% at 8 wk. Incorporation of EPA into red blood cell phospholipids reached levels of around 10%. The present study has shown that a novel, high-purity, EPA diester emulsion can be tolerated at a dose providing around 18 g EPA per day with side-effects being easily controlled. The acceptibility of large doses of oral EPA should allow larger controlled clinical studies into potential anticancer effects of EPA.

Antineoplastic Agents↗
PubMed2001

Acute-phase protein response, survival and tumour recurrence in patients with colorectal cancer.

INTRODUCTION: An acute-phase protein response (APPR) has been associated with reduced crude survival rates and increased recurrence following apparently curative resection in patients with colorectal cancer. This study investigated the prognostic significance of a preoperative and postoperative APPR in relation to disease-specific mortality rate. METHODS: Some 202 patients with colorectal cancer were followed for at least 5 years. C-reactive protein concentration, measured before and at 3 months after operation, was used as an index of the APPR. Univariate and multivariate analyses were performed on a number of potential prognostic factors. RESULTS: Thirty-six per cent of patients had an APPR and this was associated with a higher rate of local tumour invasion, fewer curative resections and a higher carcinoembryonic antigen (CEA) concentration. There was no difference in Dukes' stage between patients with or without an APPR. The most important prognostic factor related to both disease-specific and crude survival was Duke's stage (P < 0.0001). Subgroup analysis demonstrated that APPR had prognostic significance only in patients with advanced disease (P = 0.013). An APPR was present in a minority of patients (11 per cent) after operation and was not associated with increased likelihood of tumour recurrence. CONCLUSION: The APPR is increased in more than a third of patients presenting with colorectal cancer and is associated with more frequent local tumour invasion, fewer curative resections and a higher CEA level. An APPR at 3 months after operation does not have the prognostic significance reported by earlier studies.

Acute-Phase Reaction↗
PubMed2001

Leptin and its relation to weight loss, ob gene expression and the acute-phase response in surgical patients.

BACKGROUND: Patients with cachexia suffer from anorexia, weight loss and hypermetabolism. This study examined the relationship between plasma leptin concentration, leptin gene expression, weight loss and the acute-phase response in a group of surgical patients. METHODS: Body composition, plasma leptin, interleukin (IL) 6, soluble tumour necrosis factor receptor (sTNF-R) 55, sTNF-R75 and C-reactive protein were analysed in a cohort of 28 patients undergoing elective surgery. Subcutaneous and omental leptin messenger RNA (mRNA) was analysed in a subgroup of 14 patients. RESULTS: After adjustment for fat mass (FM), a significant partial correlation coefficient was found between plasma leptin and serum IL-6 concentration (P = 0.037). A positive correlation was found only between plasma leptin and omental leptin mRNA (P = 0.009). Patients with an acute-phase response had a significantly higher level of plasma leptin per unit FM (P = 0.049). Stepwise multiple regression showed that FM (P < 0.0005) and serum IL-6 (P = 0.018) were independent predictors of plasma leptin level. CONCLUSION: Plasma leptin levels appear to be influenced by proinflammatory cytokines. Omental fat may have more influence on plasma leptin than subcutaneous fat. Accelerated weight loss in patients with cancer with an ongoing inflammatory response could be mediated in part by inappropriately high plasma levels of leptin.

Acute-Phase Reaction↗
PubMed2001

Evidence against a role for polymorphisms at tumor necrosis factor, interleukin-1 and interleukin-1 receptor antagonist gene loci in the regulation of disease severity in acute pancreatitis.

BACKGROUND: Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and their endogenous antagonists such as IL-1 receptor antagonist (IL-1RA) are important mediators of disease severity in acute pancreatitis. Because the level of secretion of these cytokines is determined in part by genetic factors, the aim of this study was to examine the influence of genetically determined cytokine secretion upon disease severity in acute pancreatitis. METHODS: TNF (TNF-308, TNFB), IL-1beta, and IL-1 receptor antagonist (IL-1RA) genotypes were determined for 190 patients with acute pancreatitis and 102 healthy volunteers. To further assess the influence of genetic factors, the cytokine phenotype for TNF-alpha, IL-1beta, and IL-1RA was determined by using a whole blood culture technique in 51 patients after recovery. RESULTS: The distributions of TNF-308, TNFB, IL-1beta, and IL-1RA gene polymorphisms were similar in patients with mild or severe acute pancreatitis. Further, no difference in gene polymorphism frequencies was observed between patients with acute pancreatitis and healthy controls. With respect to phenotype, the secretion of TNF-alpha was similar in patients with previous mild and severe acute pancreatitis; however, the IL-1beta: IL-1RA ratio was significantly lower in patients with previous severe acute pancreatitis than in those with mild disease. CONCLUSIONS: Our observations suggest that genetic factors are not important in determining TNF-alpha secretion in patients with acute pancreatitis. However, a predetermined imbalance between IL-1beta and its antagonist IL-1RA would appear to exist in patients with severe acute pancreatitis, although the genetic basis for this altered relationship could not be determined.

Acute Disease↗
PubMed2001

Endothelial-derived selectins in the development of organ dysfunction in acute pancreatitis.

OBJECTIVE: The development of organ dysfunction is the principal determinant of outcome in acute pancreatitis and is mediated through a systemic inflammatory response characterized by leukocyte and endothelial cell activation. Up-regulation of the endothelial cell adhesion molecules, E-selectin and P-selectin, is important for endothelial/leukocyte interactions. Levels of serum-soluble E-selectin and P-selectin have been suggested as markers of endothelial activation. This study examines the kinetics of serum-soluble selectins in patients with acute pancreatitis complicated by organ dysfunction. DESIGN: Prospective observational study. SETTING: University teaching hospital with a specialist hepato-pancreatico-biliary service. PATIENTS: Eighteen patients with acute pancreatitis were studied, nine of whom had organ dysfunction. MEASUREMENTS AND MAIN RESULTS: Serial venous blood samples were collected on the first 3 days after admission for measurement of soluble E-selectin and P-selectin by enzyme-linked immunosorbent assay. In all patients, soluble P-selectin concentrations decreased significantly during the study period. Nonsurvivors had significantly higher levels of soluble P-selectin than survivors. In contrast, soluble E-selectin increased significantly during the study period in patients with organ dysfunction, whereas it remained constant in patients without evidence of organ dysfunction. CONCLUSIONS: These results suggest a role for endothelial-derived selectins in the development of organ dysfunction in patients with acute pancreatitis. The observed temporal differences in serum selectin concentrations is in keeping with in vitro observations of endothelial selectin expression.

APACHE↗
PubMed2001

Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia.

Weight loss in advanced cancer patients is refractory to conventional nutritional support. This may be due to metabolic changes mediated by proinflammatory cytokines, hormones, and tumor-derived products. We previously showed that a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia. The present study examines the effect of this supplement on a number of mediators thought to play a role in cancer cachexia. Twenty weight-losing patients with pancreatic cancer were asked to consume a nutritional supplement providing 600 kcal and 2 g of eicosapentaenoic acid per day. At baseline and after 3 wk, patients were weighed and samples were collected to measure serum concentrations of interleukin (IL)-6 and its soluble receptor tumor necrosis factor receptors I and II, cortisol, insulin, and leptin, peripheral blood mononuclear cell production of IL-1 beta, IL-6, and tumor necrosis factor, and urinary excretion of proteolysis inducing factor. After 3 wk of consumption of the fish oil-enriched nutritional supplement, there was a significant fall in production of IL-6 (from median 16.5 to 13.7 ng/ml, P = 0.015), a rise in serum insulin concentration (from 3.3 to 5.0 mU/l, P = 0.0064), a fall in the cortisol-to-insulin ratio (P = 0.0084), and a fall in the proportion of patients excreting proteolysis inducing factor (from 88% to 40%, P = 0.008). These changes occurred in association with weight gain (median 1 kg, P = 0.024). Various mediators of catabolism in cachexia are modulated by administration of a fish oil-enriched nutritional supplement in pancreatic cancer patients. This may account for the reversal of weight loss in patients consuming this supplement.

Adolescent↗
PubMed2001

Endogenous production of IL-8 by human colorectal cancer cells and its regulation by cytokines.

This study investigated the endogenous production of the pro-inflammatory and angiogenic cytokine IL-8 by human colorectal cancer cells. We describe substantial (>0.5 ng/ml) constitutive production of IL-8 by certain human colorectal cancer cell lines without the requirement for exogenous stimulation. Tumour cell-derived IL-8 production was upregulated by the addition of the pro-inflammatory type 1 cytokines TNF alpha, IL-1 beta and IFN gamma. Addition of the regulatory type 2 cytokines IL-4 and IL-10 produced paradoxical stimulation of IL-8 production in certain cell lines and downregulation of IL-8 production in others. These results suggest that tumour-derived cytokine production may have an important role in patients with colorectal cancer. Furthermore, they demonstrate the complexity of tumour cell cytokine production and highlight the difficulties in developing effective therapeutic biological response strategies.

Colorectal Neoplasms↗
PubMed2001

The cancer cachexia syndrome.

The provision of additional calories and protein alone has not been shown to be efficacious in patients with cancer cachexia. Although primary research continues to unravel the complex metabolic derangements and diverse mediator pathways underlying cancer cachexia, the future lies in drugs and neutracenticals that may modulate this altered metabolism and enable conventional nutritional support to effectively replenish vital lean tissue.

Acute-Phase Proteins↗
PubMed2000

Disordered metabolic response with cancer and its management.

The metabolic changes in cancer cachexia appear to be mediated by a complex network of proinflammatory cytokines, neuroendocrine hormones, neurotransmitters, eicosanoids, and tumor-derived factors produced by the body in response to the tumor and by the tumor itself. The relative importance of these various mediator pathways in relation to either the anorexia or hypermetabolism associated with weight loss in cancer remains to be fully elucidated. Our current understanding suggests that proinflammatory mediators may indeed be a valid target for therapeutic intervention. Trials attempting to modify the inflammatory response to cancer with the hope of improving appetite and reversing catabolism and perhaps thereby improving qualityof life and survival are currently underway.

Animals↗
PubMed2000

Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor.

BACKGROUND: Recently a novel tumour-derived cachectic factor was identified in the murine MAC16 colonic adenocarcinoma model of cachexia. This factor, provisionally named proteolysis-inducing factor (PIF), was subsequently identified in the urine of weight-losing patients with cancer but not in the urine of weight-stable patients with cancer or weight-losing controls with benign disease. This study determined the nutritional characteristics of patients with pancreatic cancer who excrete PIF in the urine and investigated the relationship between PIF and the acute-phase protein response. METHODS: PIF was isolated from urine by precipitation and ultrafiltration and was then identified by Western blotting of nitrocellulose membranes using a previously developed monoclonal antibody. Full nutritional assessment of patients was undertaken at the same time as urine collection. RESULTS: PIF was detected in the urine of 80 per cent of patients (n = 55). These patients had a significantly greater total weight loss and rate of weight loss than patients whose urine did not contain PIF (median 12.5 (range 4-43) kg versus 4.5 (0-14) kg; P < 0.0002). No association was evident between the presence of PIF in patients' urine and serum C-reactive protein (CRP) concentration. Furthermore, the accelerated weight loss associated with PIF expression also appeared to be independent of the acute-phase response. Overall the presence of PIF was not associated with reduced survival, although the previously reported association between raised CRP concentration and poor prognosis was confirmed. CONCLUSION: PIF is associated with an accelerated rate of weight loss in patients with a tumour of the pancreatic head. This observation appears to be independent of the effect of an increased hepatic acute-phase protein response.

Aged↗
PubMed2000

Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis.

BACKGROUND: Recent evidence suggests that intestinal dysfunction has a role in sustaining the systemic inflammatory response in acute pancreatitis and may be ameliorated by the introduction of enteral nutrition. This study therefore assessed the effect of early enteral nutrition on the systemic inflammatory response in patients with prognostically severe acute pancreatitis. METHODS: Patients with prognostically severe acute pancreatitis within 72 h of disease onset were randomized to receive either enteral nutrition or conventional therapy consisting of a nil-by-mouth regimen. Serum interleukin (IL) 6, soluble tumour necrosis factor receptor I (sTNFRI) and C-reactive protein (CRP) were used as markers of the inflammatory response. Intestinal function was assessed using a differential sugar permeability technique. RESULTS: Of 27 patients, 13 received enteral nutrition. A median of 21 (range 0-100) per cent of calorific requirements was delivered over the first 4 days by enteral nutrition. There were no significant complications of enteral nutrition. The introduction of enteral nutrition did not affect the serum concentrations of IL-6 (P = 0.28), sTNFRI (P = 0.53) or CRP (P = 0.62) over the first 4 days of the study. Although there were no significant differences in intestinal permeability between the two patient groups at admission (chi2 = 2.33, d.f. = 1, P = 0.13), by day 4 abnormal intestinal permeability occurred more frequently in patients receiving enteral nutrition (chi2 = 4.94, d.f. = 1, P = 0.03) CONCLUSION: Early enteral nutrition did not ameliorate the inflammatory response in patients with prognostically severe acute pancreatitis. Furthermore, it did not have a beneficial effect on intestinal permeability. Presented in part to the Pancreatic Society of Great Britain and Ireland in Leeds, UK, November 1998 and at Digestive Disease Week in Orlando, Florida, USA, May 1999

Acute Disease↗
PubMed2000

A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer.

Pro-inflammatory cytokines contribute to the cachexia associated with pancreatic cancer and stimulate the acute phase response which has been associated with shortened survival in such patients. Polymorphisms of cytokine genes may influence their production. The present study examined the effect of a polymorphism of the interleukin (IL)-1b gene upon the inflammatory state and survival in pancreatic cancer. Genomic DNA was obtained from 64 patients with pancreatic cancer and 101 healthy controls. Using the polymerase chain reaction and subsequent TaqI restriction enzyme digestion the subject's genotype for a diallelic polymorphism of the interleukin-1b gene was established. IL-1b production by peripheral blood mononuclear cells and serum C-reactive protein (CRP) levels from patients were also examined and survival noted. Patients homozygous for allele 2 of the IL-1b gene had significantly shorter survival than other groups (P = 0.0001). These patients also exhibited higher IL-1b production (P = 0.022). Possession of allele 2 was also associated with significantly shorter survival (median 144 vs 256 days, P = 0.034) and significantly higher CRP level (P = 0.0003). The possession of a genotype resulting in increased IL-1b production was associated with shortened survival and increased serum CRP level. This may reflect the role of IL-1b in inducing an acute phase protein response and cachexia in cancer or may be related to changes in tumour phenotype.

Adult↗
PubMed2000

Liver export protein synthetic rates are increased by oral meal feeding in weight-losing cancer patients.

We have demonstrated previously that, in the fasting state, whereas albumin synthesis is similar in cachectic cancer patients compared with controls, fibrinogen synthesis is increased. Whether synthesis of these proteins is altered after an oral meal was examined in eight weight-losing pancreatic cancer patients and six healthy controls by use of an intravenous flooding dose of [(2)H(5)]- or [(2)H(8)]phenylalanine. Cancer patients had a median weight loss of 19%, a significantly lower serum albumin concentration, and a significantly higher plasma fibrinogen concentration than controls (P < 0.005). Fasting albumin synthesis rates were similar between cancer patients and controls (median total synthesis rate 11.3 vs. 13.9 g/day, respectively) and rose on feeding by a similar degree (median 29 and 24%). The fasting fibrinogen total synthetic rate was significantly higher in cancer patients than in controls (median 3.3 vs. 1.0 g/day, P = 0.0019). In cancer patients in the fed state, fibrinogen synthetic rate rose by a median of 38% (P = 0.012), whereas in controls there was no significant change. These findings demonstrate significant upregulation by feeding of acute-phase protein synthesis in cachectic cancer patients.

Adult↗
PubMed2000

Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer.

Eicosapentaenoic acid (EPA) has been shown to modulate aspects of the inflammatory response that may contribute to weight loss in cancer. This study aimed to evaluate the acceptability and effects of oral supplementation with high-purity EPA in weight-losing patients with advanced pancreatic cancer. Twenty-six patients were entered into the study. EPA (95% pure) was administered as free acid starting at 1 g/day; the dose was increased to 6 g/day over four weeks, and then a maintenance dose of 6 g/day was administered. Patients were assessed before EPA and at 4, 8, and 12 weeks while receiving EPA, for weight, body composition, hematologic and clinical chemistry variables, acute-phase protein response, and performance status. Overall survival was noted. Supplementation was well tolerated, with only five patients experiencing side effects possibly attributable to the EPA. Before starting EPA, all patients had been losing weight at a median rate of 2 kg/mo. In general, after EPA supplementation, weight was stable. After four weeks of EPA supplementation, patients had a median weight gain of 0.5 kg (p = 0.0009 vs. rate of weight loss at baseline), and this stabilization of weight persisted over the 12-week study period. Total body water as a percentage of body weight remained stable, as did the proportion of patients with an acute-phase protein response, patients' nutritional intake, and performance status. Overall median survival from diagnosis in this study was 203 days. This study suggests that EPA is well tolerated, may stabilize weight in cachectic pancreatic cancer patients, and should be tested as an anticachectic agent in controlled trials.

Adenocarcinoma↗
PubMed2000

Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement.

Weight-losing patients with advanced cancer often fail to gain weight with conventional nutritional support. This suboptimal response might be explained, in part, by an increased metabolic response to feeding. It has been suggested that eicosapentaenoic acid (EPA) can modify beneficially the metabolic response to cancer. The aim of the present study was to examine the metabolic response to feeding in cancer and the effects of an EPA-enriched oral food supplement on this response. A total of 16 weight-losing, non-diabetic patients with unresectable pancreatic adenocarcinoma and six healthy, weight-stable controls were studied by indirect calorimetry in the fasting and fed states. Body composition was estimated by bioimpedence analysis. Cancer patients were then given a fish-oil-enriched nutritional supplement providing 2 g of EPA and 2550 kJ daily, and underwent repeat metabolic study after 3 weeks of such supplementation. At baseline, resting energy expenditure whether expressed per kg body weight, lean body mass or body cell mass was significantly greater in the cancer patients compared with controls. Fat oxidation was significantly higher in the fasting state in cancer patients [median 1.26 g.kg(-1).min(-1) (interquartile range 0.95-1.38)] than in controls [0.76 g.kg(-1). min(-1) (0.62-0.92); P<0.05]. Over the 4 h feeding period, changes in insulin and glucose concentrations in cancer patients suggested relative glucose intolerance. In response to oral meal feeding, the percentage change in the area under the curve of energy expenditure was significantly lower in the cancer patients [median 7.9% (interquartile range 3.4-9.0)] than in controls [12.6% (9.9-15.1); P<0.01]. After 3 weeks of the EPA-enriched supplement, the body weight of the cancer patients had increased and the energy expenditure in response to feeding had risen significantly [9.6% (6. 3-12.4)], such that it was no different from baseline healthy control values. Similarly, fasting fat oxidation fell to 1.02 g. kg(-1).min(-1) (0.8-1.18), again no longer significantly different from baseline healthy control values. While weight-losing patients with advanced pancreatic cancer have an increased resting energy expenditure and increased fat oxidation, the energy cost of feeding is, in fact, reduced. Provision of a fish-oil-enriched nutritional supplement results in some normalization of the metabolic response in both the fasted and fed states, in association with an improvement in nutritional status.

Aged↗
PubMed1999

Pancreatic cancer as a model: inflammatory mediators, acute-phase response, and cancer cachexia.

Patients with pancreatic cancer frequently develop the syndrome of cancer cachexia. Pro-inflammatory cytokines have been strongly implicated in the pathogenesis of this syndrome. In patients with pancreatic cancer an acute-phase response (an index of pro-inflammatory cytokine activity) is associated with accelerated weight loss, hypermetabolism, anorexia, and a shortened duration of survival. However, little is known about the primary significance of the acute-phase response in terms of altered hepatic export protein synthesis rates and its potential impact on the body's nitrogen economy. In a recent series of studies on weight-losing pancreatic cancer patients with hypoalbuminemia we have demonstrated albumin synthesis to be unaltered whereas fibrinogen synthesis is increased two- to threefold compared with healthy controls. Because of the mismatch in amino acid composition between the body's main labile amino acid reserve (skeletal muscle) and that of acute-phase proteins, these results lend support to the concept that in pancreatic cancer the reprioritization of body protein metabolism during an acute-phase response may well be a significant factor in the loss of lean tissue in these patients.

Acute-Phase Proteins↗
PubMed1999

Cancer cachexia.

Cachexia is a common cause of morbidity and mortality in patients with advanced cancer. It is characterised by numerous metabolic abnormalities including inefficient substrate utilisation, alterations in the balance of energy intake and expenditure and the acute-phase protein response. These changes seem to be driven by pro-inflammatory cytokines, alterations of the neuro-endocrine axis and tumour-derived catabolic factors. This results in the loss of both fat and lean tissue. Trials of conventional nutritional supplements in patients with cancer cachexia have failed to show any benefit in terms of weight gain or quality of life and this may be because the ongoing metabolic abnormalities prevent the efficient use of additional calories supplied. A variety of pharmacological agents have been studied in an attempt to normalise these metabolic changes with only limited success. However, it is possible that the combination of an agent to normalise the metabolic milieu along with the provision of additional nutritional support may have the potential to reverse cachexia in advanced cancer.

Anti-Inflammatory Agents↗