It has been suggested that the current dietary recommendations (low-fat-high-carbohydrate diet) may promote the intake of sugar and highly refined starches which could have adverse effects on the metabolic risk profile. We have investigated the short-term (6-d) nutritional and metabolic effects of an ad libitum low-glycaemic index-low-fat-high-protein diet (prepared according to the Montignac method) compared with the American Heart Association (AHA) phase I diet consumed ad libitum as well as with a pair-fed session consisting of the same daily energy intake as the former but with the same macronutrient composition as the AHA phase I diet. Twelve overweight men (BMI 33 : 0 (SD 3 : 5) kg/m 2 ) without other diseases were involved in three experimental conditions with a minimal washout period of 2 weeks separating each intervention. By protocol design, the first two conditions were administered randomly whereas the pair-fed session had to be administered last. During the ad libitum version of the AHA diet, subjects consumed 11695 : 0 (SD 1163 : 0) kJ/d and this diet induced a 28 % increase in plasma triacylglycerol levels (1 : 77 (SD 0 : 79) v. 2 : 27 (SD 0 : 92) mmol/l, P,0 : 05) and a 10 % reduction in plasma HDL-cholesterol concentrations (0 : 92 (SD 0 : 16) v. 0 : 83 (SD 0 : 09) mmol/l, P,0 : 01) which contributed to a significant increase in cholesterol:HDL-cholesterol ratio (P,0 : 05), this lipid index being commonly used to assess the risk of coronary heart disease. In contrast, the lowglycaemic index-low-fat-high-protein diet consumed ad libitum resulted in a spontaneous 25 % decrease (P,0 : 001) in total energy intake which averaged 8815 : 0 (SD 738 : 0) kJ/d. As opposed to the AHA diet, the low-glycaemic index-low-fat-high-protein diet produced a substantial decrease (235 %) in plasma triacylglycerol levels (2 : 00 (SD 0 : 83) v. 1 : 31 (SD 0 : 38) mmol/l, P,0 : 0005), a significant increase (+1 : 6 %) in LDL peak particle diameter (251 (SD 5) v. 255 (SD 5) Å , P,0 : 02) and marked decreases in plasma insulin levels measured either in the fasting state, over daytime and following a 75 g oral glucose load. During the pair-fed session, in which subjects were exposed to a diet with the same macronutrient composition as the AHA diet but restricted to the same energy intake as during the low-glycaemic index-low-fat-high-protein diet, there was a trend for a decrease in plasma HDL-cholesterol levels which contributed to the significant increase in cholesterol:HDLcholesterol ratio noted with this condition. Furthermore, a marked increase in hunger (P,0 : 0002) and a significant decrease in satiety (P,0 : 007) were also noted with this energy-restricted diet. Finally, favourable changes in the metabolic risk profile noted with the ad libitum consumption of the low-glycaemic index-low-fat-high-protein diet (decreases in triacyglycerols, lack of increase in cholesterol:HDL-cholesterol ratio, increase in LDL particle size) were significantly different from the response of these variables to the AHA phase I diet. T...

2006 Background: Radiotherapy with concomitant and adjuvant TMZ (TMZ/RT TMZ) is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. Compared with the standard adjuvant TMZ, dd TMZ results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial determined if intensified TMZ improves survival (OS) or progression free survival (PFS). Methods: This phase III trial was conducted by the RTOG, EORTC and NCCTG. Neurologically stable patients with adequate tissue for prospective MGMT analysis were randomized to Arm 1: standard TMZ (150-200 mg/m 2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m 2 x 21 d) q 4 wks for 6-12 cycles. Symptom, QOL and neurocognitive testing was performed in a subset of patients. The primary endpoint was OS. Secondary analyses evaluated impact of MGMT status. Eligibility criteria included age > 18 yrs, KPS 60, and tissue block with > 1cm 2 tumor. Results: A total of 833 patients were randomized from a total of 1173 registered. Inadequate tissue (n=144) and early disease progression (n =56) were the most frequent reasons for non-randomization. No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p = 0.63), or median PFS (5.5, 6.7 mo, p = 0.06), or by methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p < 0.0001), PFS (8.7, 5.7 mo, p < 0.0001) and response (p = 0.012). Cox modeling showed that MGMT status and RPA class were significant predictors of OS while the treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade 3 toxicity in Arm 2 (19%, 27%, p = 0.008); mostly lymphopenia and fatigue. Conclusions: This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM. Additionally, it demonstrated the feasibility of tumor tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial and established this as a viable clinical trial paradigm.

Physiological studies of the type we have described, when performed in patients with the WPW syndrome, can yield diagnostic information regarding the mechanism of arrhythmia, demonstrate functional properties of therapeutic import, facilitate therapeutic decision-making about drug regimens and presumptively localize the site of pre-excitation as a basis for possible surgical intervention. Based on our experience, we feel that in selected patients, surgical correction of the WPW syndrome is entirely feasible, and can be accomplished in the majority of patients in whom free wall A-V connections are present. The continuing challenge of identification and correction of septal accessory pathways directs our present work with the WPW syndrome.

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Paclitaxel is well tolerated at this dose schedule in patients with recurrent malignant glioma, and affords a modest response rate. Because minimal myelotoxicity was encountered in our patients, a dose-escalating phase I/II study of paclitaxel is planned to determine the maximal-tolerated dose (MTD).

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1 The pharmacokinetics of S-(+)-and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride.2 The values for the distribution rate constants as well as for the elimination half-lives of the two enantiomers were similar but the AUC of the S-(+)-enantiomer was always significantly higher (P < 0.01) than that of the opposite enantiomer. The mean R/S ratios for unchanged mexiletine in serum and in urine were 0.78 ± 0.12 (s.d.) and 0.80 + 0.21, respectively.3 Urinary excretion of mexiletine conjugates consisted mainly of the R-(-)-enantiomer; the mean R/S enantiomeric ratio over 48 h was 9.65 + 3.10. 4 Serum concentrations of the conjugates were measured in three subjects. The mean R/S AUC ratio was 2.94 ± 0.48 and the renal clearance of the R-(-)-enantiomer was significantly higher (P < 0.02) than that of the S-(+)-enantiomer.