Peter R. Ellis

Randomized Phase IIB Trial of BLP25 Liposome Vaccine in Stage IIIB and IV Non–Small-Cell Lung Cancer

PURPOSE To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

Phase II Study of Vandetanib or Placebo in Small-Cell Lung Cancer Patients After Complete or Partial Response to Induction Chemotherapy With or Without Radiation Therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20

PURPOSE This double-blind randomized phase II trial examined whether vandetanib, an inhibitor of vascular endothelial and epidermal growth factor receptors, could prolong progression-free survival in responding patients with small-cell lung cancer. PATIENTS AND METHODS Eligible patients with complete response (CR) or partial response (PR) to combination chemotherapy (+/- thoracic or prophylactic cranial radiation) received oral vandetanib 300 mg/d or matched placebo. With 100 patients and 77 events, the study had 80% power to detect an improvement in median progression-free survival from 4 to 6.5 months (one-sided, 10%-level test). RESULTS Between May 2003 and March 2006, 107 patients were accrued; 46 had limited disease and 61 extensive disease. There were fewer patients with a performance status of 0 (n = 11 v 20), and fewer had CR to initial therapy (n = 4 v 8) in the vandetanib arm. Vandetanib patients had more toxicity and required more dose modifications for gastrointestinal toxicity and rash. Asymptomatic Corrected QT interval (QTC) prolongation was observed in eight vandetanib patients. Median progression-free survival for vandetanib and placebo was 2.7 and 2.8 months, respectively (hazard ratio [HR], 1.01; 80% CI, 0.75 to 1.36; one-sided P = .51). Overall survival for vandetanib was 10.6 versus 11.9 months for placebo (HR, 1.43; 80% CI, 1.00 to 2.05; one-sided P = 0.9). In planned subgroup analyses, a significant interaction was noted (P = .01): limited-stage vandetanib patients had longer overall survival (HR, 0.45; one-sided P = .07) and extensive-stage vandetanib patients shorter survival compared with placebo (HR, 2.27; one-sided P = .996). CONCLUSION Vandetanib failed to demonstrate efficacy as maintenance therapy for small-cell lung cancer.

Release of Protein, Lipid, and Vitamin E from Almond Seeds during Digestion

The evaluation of the bioaccessibility of almond nutrients is incomplete. However, it may have implications for the prevention and management of obesity and cardiovascular disease. This study quantified the release of lipid, protein, and vitamin E from almonds during digestion and determined the role played by cell walls in the bioaccessibility of intracellular nutrients. Natural almonds (NA), blanched almonds (BA), finely ground almonds (FG), and defatted finely ground almonds (DG) were digested in vitro under simulated gastric and gastric followed by duodenal conditions. FG were the most digestible with 39, 45, and 44% of lipid, vitamin E, and protein released after duodenal digestion, respectively. Consistent with longer residence time in the gut, preliminary in vivo studies showed higher percentages of nutrient release, and microscopic examination of digested almond tissue demonstrated cell wall swelling. Bioaccessibility is improved by increased residence time in the gut and is regulated by almond cell walls.

An investigation of the action of porcine pancreatic α-amylase on native and gelatinised starches

The action of pancreatic alpha-amylase (EC 3.2.1.1) on various starches has been studied in order to achieve better understanding of how starch structural properties influence enzyme kinetic parameters. Such studies are important in seeking explanations for the wide differences reported in postprandial glycaemic and insulinaemic indices associated with different starchy foodstuffs. Using starches from a number of different sources, in both native and gelatinised forms, as substrates for porcine alpha-amylase, we showed by enzyme kinetic studies that adsorption of amylase to starch is of kinetic importance in the reaction mechanism, so that the relationship between reaction velocity and enzyme concentration [E0] is logarithmic and described by the Freundlich equation. Estimations of catalytic efficiencies were derived from measurements of kcat/Km performed with constant enzyme concentration so that comparisons between different starches were not complicated by the logarithmic relationship between E0 and reaction velocity. Such studies reveal that native starches from normal and waxy rice are slightly better substrates than those from wheat and potato. After gelatinisation at 100 degrees C, kcat/Km values increased by 13-fold (waxy rice) to 239-fold (potato). Phosphate present in potato starch may aid the swelling process during heating of suspensions; this seems to produce a very favourable substrate for the enzyme. Investigation of pre-heat treatment effects on wheat starch shows that the relationship between treatment and kcat/Km is not a simple one. The value of kcat/Km rises to reach a maximum at a pre-treatment temperature of 75 degrees C and then falls sharply if the treatment is conducted at higher temperatures. It is known that amylose is leached from starch granules during heating and dissolves. On cooling, the dissolved starch is likely to retrograde and become resistant to amylolysis. Thus the catalytic efficiency tends to fall. In addition, we find that the catalytic efficiency on the different starches varies inversely with their solubility and we interpret this finding on the assumption that the greater the solubility, the greater is the likelihood of retrogradation. We conclude that although alpha-amylase is present in high activity in digestive fluid, the enzymic hydrolysis of starch may be a limiting factor in carbohydrate digestion because of factors related to the physico-chemical properties of starchy foods.

Blood glucose, plasma insulin and sensory responses to guar-containing wheat breads: effects of molecular weight and particle size of guar gum

The effectiveness of guar gum in reducing post-prandial blood glucose and plasma insulin levels in human subjects seems to depend mainly on its ability to increase the viscosity of digesta in the small intestine. However, the precise relationship between the rheological properties of guar gum (either in vitro or in vivo) and the changes in blood metabolites and hormones is unknown. The aim of the present study, therefore, was to investigate the effects of wheat breads containing guar gum samples varying in molecular weight (Mw) and particle size (characteristics that strongly influence the rheological properties of guar gum) on post-prandial blood glucose and plasma insulin levels in healthy subjects. The sensory qualities of breads containing guar-gum flours of different Mw were also evaluated using a hedonic scoring technique. No significant differences in the post-prandial blood glucose responses were found between the control and guar breads. However, all the guar breads elicited significant (P less than 0.05) decreases in the post-prandial rise in plasma insulin, an effect that did not appear to be influenced by large variations in Mw or particle size of guar gum. Moreover, the sensory qualities of guar bread were markedly improved by using low Mw grades of guar gum.

A physico-chemical perspective of plant polysaccharides in relation to glucose absorption, insulin secretion and the entero-insular axis

There is a growing realization that studies of the physico-chemical structure and properties of foods in the gut lumen will greatly assist our understanding of the function of the gastrointestinal (GI) tract in relation to human health and disease (British Nutrition Foundation, 1990). However, it is difficult to make reliable predictions of the behaviour of foods in the gut, because there are serious deficiencies in our knowledge and methodology in this area. Our knowledge of GI function at the luminal, mucosal and cellular levels is unlikely to make significant progress until we have a detailed and basic understanding of the structure and properties of foods. Thus, for example, the behaviour of a food matrix in the GI environment is of critical importance to our understanding of the kinetics of nutrient bioavailability. Interestingly, the mechanical properties of foods have been studied extensively in relation to their behaviour in the mouth, in order to understand, for example, the process of mastication and how human subjects perceive texture (Blanshard & Mitchell, 1988; Vincent, 1990). This approach has not been used in any fundamental way, however, to study the relationship between the physical properties of foods and their effects on GI function and systemic responses, such as meal-stimulated blood metabolite and hormone levels. Non-starch polysaccharides (NSP) from plant food sources are of special interest to nutritionists in that they have marked effects on the physical properties of digesta at all sites of the GI tract (Selvendran et al. 1987; Eastwood & Morris, 1992; Moms, 1992). Thus, the consumption of NSP (‘dietary fibre’) in the form of plant cell walls or purified extracts can strongly influence GI function, including the rate and extent of nutrient absorption in the small intestine and bacterial fermentation in the colon. The present paper is a brief review of the possible physico-chemical mechanisms by which NSP, mainly the water-soluble polymers, influence glucose absorption, insulin secretion and the entero-insular axis.

The effect of consuming instant black tea on postprandial plasma glucose and insulin concentrations in healthy humans

Objective: To determine the effects of black tea on postprandial plasma glucose and insulin concentrations in healthy humans in response to an oral glucose load. Methods: A four-way randomised, crossover trial was designed in which 16 healthy fasted subjects would consume 75g of glucose in either 250ml of water (control), 250ml of water plus 0.052g of caffeine (positive control) or 250 ml of water plus 1.0g or 3.0g of instant black tea. Blood samples were collected at fasting and at 30min intervals for 150min from commencement of drink ingestion. Glucose and insulin concentrations were measured using standard methodology. The tea was chemically characterised using colorimetric and HPLC methods. Results: Chemical analysis showed that the tea was rich in polyphenolic compounds (total, 350mg/g). Results from only 3 treatment arms are reported because the 3.0g tea drink caused gastrointestinal symptoms. Plasma glucose concentrations <60min in response to the drinks were similar, but were significantly reduced at 120min (P<0.01), following ingestion of the 1.0g tea drink, relative to the control and caffeine drinks. Tea consumption resulted in elevated insulin concentrations compared with the control and caffeine drinks at 90min (P<0.01) and compared with caffeine drink alone at 150min (P<0.01). Conclusions: The 1.0g tea drink reduced the late phase plasma glucose response in healthy humans with a corresponding increase in insulin. This may indicate that the attenuation in postprandial glycemia was achieved as a result of an elevated insulin response following stimulation of pancreatic β-cells. This effect may be attributable to the presence of phenolic compounds in the tea

The effect of guar galactomannan and water availability during hydrothermal processing on the hydrolysis of starch catalysed by pancreatic α-amylase

The effects of water-soluble nonstarch polysaccharides (sNSP) on human metabolism are considered to be beneficial because they decrease postprandial glycaemia and insulinaemia following ingestion of starch-rich foods. The mechanisms by which sNSP attenuate the postprandial rise in blood glucose are not well understood but their presence increases the viscosity of gastrointestinal contents, which affects physiological functions, e.g. gastric emptying and peristalsis. Increased viscosity and decreased water activity during hydrothermal treatment of starch could influence alpha-amylase action. Using guar galactomannan as a representative of sNSP, we found that galactomannan has a direct noncompetitive inhibitory effect on alpha-amylase with a K(i) value of approximately 0.5% (3.3 microM). The inhibition is not time dependent and studies suggest direct binding of the enzyme to galactomannan; the resulting galactomannan-amylase complex being inactive. Processing of starch at low water levels greatly affects the catalytic efficiency of alpha-amylase. The Km value for starch heat treated in limited water is raised and kcat is lowered relative to starch gelatinised in excess water. Since galactomannan has no effect on the Km of alpha-amylase, we conclude that the inhibitory action of the polymer is not secondary to a decrease in available water. Neither does it seem to be a consequence of impaired diffusion of enzyme, substrate and products because of an increase in viscosity of the medium.Thus, the effects of sNSP in lowering postprandial glycaemia not only involve modifications of gut physiology, but also include direct inhibition of the first stage in the biochemical degradation of starch.

A new breakfast cereal containing guar gum reduces postprandial plasma glucose and insulin concentrations in normal-weight human subjects

A new guar-containing wheatflake product was developed to assess its effect on carbohydrate tolerance in normal-weight, healthy subjects. The extruded wheatflake breakfast cereals containing 0 (control) or approximately 90 g guar gum/kg DM were fed to ten fasting, normal-weight, healthy subjects using a repeated measures design. The meals were similar in energy (approximately 1.8 MJ), available carbohydrate (78 g), protein (15 g) and fat (5.4 g) content. The guar gum content of the test meals was 6.3 g. Venous blood samples were taken fasting and at 15, 30, 45, 60, 90, 120, 150 and 240 min after commencing each breakfast and analysed for plasma glucose, insulin and C-peptide. The guar wheatflake meal produced a significant main effect for glucose and insulin at 0-60 min and 0-240 min time intervals respectively, but not for the C-peptide levels compared with the control meal. Significant reductions in postprandial glucose and insulin responses were seen following the guar wheatflake meal compared with the control meal at 15 and 60 min (glucose) and 15, 60, 90 and 120 min (insulin). The 60 and 120 min areas under the curve for glucose and insulin were significantly reduced by the guar gum meal, as was the 240 min area under the curve for insulin. Thus, it can be concluded that the use of a severe method of heat extrusion to produce guar wheatflakes does not diminish the physiological activity of the guar gum.

Rheological properties of guar galactomannan and rice starch mixtures— I. Steady shear measurements

The effect of particulate inclusions, or ‘fillers’, on the rheological properties of a typical polysaccharide entanglement solution (guar galactomannan/water) have been studied. A number of equations have been proposed to describe the shearthinning behaviour of ‘random-coil’ polysaccharides such as guar gum. However, on increasing particulate concentration the system becomes more rate-dependent at low shear rates and there is evidence of an apparent yield stress associated with this increase in particulate inclusions. In the present paper, this flow behaviour has been described with reasonable accuracy, by a yield stress modified Cross equation: η = η∞ + [ηox-η∞][1 + (aγp] + (τxγ) The use of such a model can lead to a prediction of the rheological behaviour of similar systems when the proportion of the relative components is known. The present study determines the effect of particulate and composite properties on the apparent zero-shear viscosity and yield stress of guar galactomannan and rice starch mixtures.