Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma.

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

Small intestine bacterial overgrowth in patients with irritable bowel syndrome.

Recent investigations in patients with irritable bowel syndrome (IBS) undergoing a breath test (BT) with lactulose, have shown inconclusive results on a possible association between IBS and a small intestine bacterial overgrowth (SIBO), as well as on the effective prevalence of SIBO in IBS patients, because of different geographic areas involved and different criteria adopted for the BT positivity. The aim of this study was to estimate the prevalence of SIBO among IBS patients by means a lactulose BT. Between January 2005 and December 2006, all the patients who were sent to our Gastroenterology Unit by general practitioners (GPs) for "functional" gastrointestinal (GI) symptoms, underwent a lactulose BT for diagnosis of SIBO. The test was considered positive if the hydrogen concentrations in the expired air increased more than 20 ppm over basal values within 90 minutes. A total of 127 patients have been selected, 28 males and 99 females, aged between 17 and 76 (mean age: 41.4 years), with an IBS diagnosis based on the Roma II criteria. Fifty-five patients (43%) resulted positive to the lactulose BT. No significant difference was observed between IBS patients with (SIBO+) and without (SIBO-) an intestinal bacteria contamination. In conclusion, our results indicate that SIBO is relatively frequent in IBS patients and that execution of a lactulose BT should be encouraged in all these patients, being the only way to make correct diagnosis of SIBO and establish a valid therapeutic treatment.

High-fiber diet supplementation in patients with irritable bowel syndrome (IBS): a multicenter, randomized, open trial comparison between wheat bran diet and partially hydrolyzed guar gum (PHGG).

High-fiber diet supplementation is commonly used in IBS, although it poses several management problems. Partially hydrolyzed guar gum (PHGG) has shown beneficial effects in animal and human studies, but its potential role in IBS symptom relief has not been evaluated yet. We investigated PHGG in IBS patients and compared it to a wheat bran diet. Abdominal pain, bowel habits, and subjective overall rating were longitudinally evaluated in 188 adult IBS patients (139 women and 49 men) for 12 weeks. Patients were classified as having diarrhea-predominant, constipation-predominant, or changeable bowel habits and were randomly assigned to groups receiving fiber (30 g/day of wheat bran) or PHGG (5 g/day). After four weeks, patients were allowed to switch group, depending on their subjective evaluation of their symptoms. Significantly more patients switched from fiber to PHGG (49.9%) than from PHGG to fiber (10.9%) at four weeks. Per protocol analysis showed that both fiber and PHGG were effective in improving pain and bowel habits, but no difference was found between the two groups. Conversely, intention-to-treat analysis showed a significantly greater success in the PHGG group (60%) than in the fiber group (40%). Moreover, significantly more patients in the PHGG group reported a greater subjective improvement than those in the Fiber group. In conclusion, improvements in core IBS symptoms (abdominal pain and bowel habits) were observed with both bran and PHGG, but the latter was better tolerated and preferred by patients, revealing a higher probability of success than bran and a lower probability of patients abandoning the prescribed regimen, suggesting that it can increase the benefits deriving from fiber intake in IBS, making it a valid option to consider for high-fiber diet supplementation.

Peripheral markers of oxidative stress in Parkinson's disease. The role of L-DOPA.

Oxidative stress plays a central role in the pathogenesis of Parkinson's disease (PD). L-DOPA, the gold standard in PD therapy, may paradoxically contribute to the progression of the disease because of its pro-oxidant properties. The issue, however, is controversial. In this study, we evaluated peripheral markers of oxidative stress in normal subjects, untreated PD patients and PD patients treated only with L-DOPA. We also measured platelet and plasma levels of L-DOPA, 3-O-methyldopa (the long-lasting metabolite of the drug), and dopamine. We found that isolated platelets of treated PD patients form higher amounts of 2,3-dihydroxybenzoate, an index of hydroxyl radical generation, than platelets of controls or untreated patients. In treated patients, platelet levels of 2,3-dihydroxybenzoate were positively correlated with platelet levels of L-DOPA, 3-O-methyldopa, and with the score of disease severity. Disease severity was correlated with platelet and plasma levels of L-DOPA, as well as with the daily intake of the drug. No significant differences in platelet levels of cytosolic and mitochondrial isoforms of the antioxidant enzyme superoxide dismutase were found between PD patients, either treated or untreated, and controls. Our findings lend further support to the hypothesis that L-DOPA might promote free radical formation in PD patients.

Simultaneous determination of L-dopa and 3-O-methyldopa in human platelets and plasma using high-performance liquid chromatography with electrochemical detection.

Various high-performance liquid chromatographic (HPLC) methods for the determination of plasma levels of L-dopa and of its metabolite, 3-O-methyldopa (3-OMD), have been previously described. In this study, we report a modification of these methods, that enables the assay of these two compounds in platelets and plasma obtained from the same sample of whole blood. Reversed-phase (RP) HPLC with electrochemical (coulometric) detection was used. The within-run and between-run coefficients of variations, for the two compounds, were less than 10%, in both platelets and plasma; the detection limits for platelet levels of L-dopa and 3-OMD were 2 and 6 ng/10(9) platelets, respectively. In plasma, the detection limits for L-dopa and 3-OMD were 1 and 3 ng/ml, respectively. The method is rapid and simple. When applied to a population of patients with Parkinson's disease under treatment with L-dopa, this method revealed detectable levels of L-dopa and 3-OMD in the platelets of all patients. The application of this technique may provide new insights into the pharmacokinetics of L-dopa in patients with Parkinson's disease.

Effect of regain of body weight on regional body fat distribution: comparison between pre- and postmenopausal obese women.

The aim of our study was to determine if regain of body weight increases visceral fat in obese women and if regain of weight has a different effect upon pre- and postmenopausal women. Twenty obese women (11 pre- and 9 postmenopausal) underwent a very low energy diet (VLED) for 2 weeks to lose weight. They then regained body weight in spite of the recommended hypocalorie diet. No significant modifications in body fat distribution indexes were found by computed tomography between VLED and after regain of weight. No significant changes were found in metabolic variables. No interactions between menopausal status and regain of body weight were observed. In conclusion, regain of weight does not seem to cause an increase in visceral fat; both pre- and postmenopausal women showed the same body fat distribution before weight loss and after regain of weight.

Coated oral 5-aminosalicylic acid (Claversal) is equivalent to sulfasalazine for remission maintenance in ulcerative colitis. A double-blind study.

In a double-blind, single-center, 1-year prospective trial, we compared a pH-dependent Eudragit L-coated formulation of oral 5-aminosalicylic acid (5-ASA) (Claversal), 0.5 g b.i.d., and sulfasalazine (SASP), 1 g b.i.d., in the prophylactic treatment of quiescent ulcerative colitis. Forty-four patients received 5-ASA and 44 received SASP. Clinical, sigmoidoscopic, and histologic findings were assessed at 6 and 12 months. The two groups were comparable in all pretrial characteristics. No significant difference was observed in the relapse rate in the two groups either after 6 months [5-ASA 20.5%, SASP 27.5%, p = 0.32, 95% confidence interval (CI) 0.28 +/- 0.13] or after 12 months (5-ASA 38.4%, SASP 51%, p = 0.18, 95% CI 0.38 +/- 0.1). We conclude that (a) 5-ASA was as effective as SASP in maintaining remission of ulcerative colitis; (b) the relapse rate was, however, higher than expected in both groups; (c) the incidence of side effects was similar with both treatments.

Efficacy and tolerability of polyethylene glycol-electrolyte lavage solution with and without simethicone in the preparation of patients with inflammatory bowel disease for colonoscopy.

This placebo-controlled study assessed the efficacy and tolerability of polyethylene glycol-electrolyte lavage solution (PEG-ELS), with and without simethicone, in the preparation of patients with inflammatory bowel disease for colonoscopy. PEG-ELS 4 L plus placebo, or PEG-ELS 4 L plus simethicone 120 mg. was administered according to a randomized double-blind protocol to 115 patients with ulcerative colitis or Crohn's disease. The parameters assessed were: presence of bubbles, degree of haziness, degree of bowel cleansing and patient acceptance. In the 105 patients completing the study, the efficacy of colonic lavage was found to be essentially comparable for the two preparations, although the addition of simethicone showed a significant reduction in the formation of bubbles. Significantly better results were reported by patients treated with the drug combination regarding reduction of general malaise (P = 0.01) and sleep disturbance (P = 0.01). The PEG-ELS solution represents an effective bowel cleansing method which can also be used for patients suffering from inflammatory bowel disease. The addition of simethicone to the traditional formulation is an acceptable development in terms of clinical efficacy and tolerability.