Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts.

Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118-MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm(3) and continued until tumors reached approximately 1.5-2.0 cm(3). Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy.

Leaving distal colorectal hyperplastic polyps in place can be achieved with high accuracy by using narrow-band imaging: an observational study.

BACKGROUND: Accurate colonoscopic assessment of colorectal polyp histology could avoid resection of distal nonadenomatous polyps and reduce costs and risk. OBJECTIVE: To assess the accuracy of predicting histology by using narrow-band imaging (NBI) in real time for distal colorectal polyps. DESIGN: Prospective observational study. SETTING: University hospital and ambulatory surgery center. PATIENTS: This study involved 225 consecutive adults undergoing elective screening or surveillance colonoscopy. INTERVENTION: We evaluated real-time histology of 235 distal (rectosigmoid) colorectal polyps from 31 patients by using high-definition colonoscopy and NBI without optical magnification. For each polyp, the endoscopist described size, Paris classification, and surface characteristics (vascular and pit pattern, color, pseudodepression). Before resection, histology was predicted, and a level of confidence (high or low) was assigned. MAIN OUTCOME MEASUREMENTS: Sensitivity and negative predictive value of high-confidence endoscopic predictions of adenomatous versus hyperplastic histology for polyps ≤ 5 mm. RESULTS: The accuracy of a high-confidence endoscopic prediction was 97.7%, sensitivity for adenomatous histology 93.9%, specificity 98.4%, negative predictive value 97.9%, and positive predictive value 75.6%. The performance characteristics for predicting diminutive distal polyps (≤ 5 mm) with high confidence were sensitivity 96.0%, specificity 99.4%, negative predictive value 99.4%, and positive predictive value 96.0%. LIMITATIONS: Single-center study with a single endoscopist. CONCLUSION: NBI without optical magnification is sufficiently accurate to allow distal hyperplastic polyps to be left in place without resection and small, distal adenomas to be discarded without pathologic assessment. These findings validate NBI criteria based on color, vessels, and pit characteristics for predicting real-time colorectal polyp histology.

Split-dose bowel preparation for colonoscopy and residual gastric fluid volume: an observational study.

BACKGROUND: Split-dose bowel preparations for colonoscopy are more effective and better tolerated than preparations given entirely the day or evening before the procedure; however, some resistance to split-dose preparation stems from concerns about an increased risk of aspiration with same-day preparation. OBJECTIVE: We sought to evaluate residual gastric volumes in patients after split-dose bowel preparations. DESIGN: Prospective measurement of residual gastric volumes in patients undergoing same-day EGD and colonoscopy after split-dose bowel preparations, patients undergoing EGD alone, or patients undergoing EGD and colonoscopy after bowel preparation given entirely the evening before the procedure. SETTING: Tertiary care hospital-based endoscopy unit. PATIENTS: This study involved 712 patients, including 254 in the split-dose bowel preparation group, 411 in the EGD-only group, and 47 in the evening-before-procedure bowel preparation group. INTERVENTION: Measurement of residual gastric volume before endoscopic procedures. MAIN OUTCOME MEASUREMENTS: Residual gastric volume. RESULTS: The mean residual gastric volume in patients receiving split-dose bowel preparation (19.7 mL) was higher than in patients undergoing EGD alone (14.6 mL) but not different from that in patients receiving bowel preparation the evening before the procedure (20.2 mL). Within the split-dose preparation group, there was no association between the interval from last actual fluid ingestion and procedure start time and the residual gastric volume. The range of residual gastric volumes between study arms was similar. LIMITATIONS: Nonrandomized study. The number of inpatients undergoing split-dose bowel preparation was small. CONCLUSION: These data support the safety of split-dose bowel preparation for outpatients undergoing colonoscopy.

Willingness to undergo split-dose bowel preparation for colonoscopy and compliance with split-dose instructions.

BACKGROUND: Split-dose bowel preparations for colonoscopy have superior effectiveness compared with giving all the preparation the evening before colonoscopy. Some physicians believe that split-dose preparations would be unpopular with patients scheduled for early morning colonoscopies. AIMS: To determine the willingness of potential patients to undergo split-dose bowel preparation for colonoscopy and the actual adherence of colonoscopy patients to split-dose instructions. METHODS: We performed a survey of esophagogastroduodenoscopy patients and drivers of colonoscopy patients asking whether they would accept split-dose preparations for early morning colonoscopy appointments. We also asked colonoscopy patients scheduled in the early morning if they had complied with the written preparation instructions. RESULTS: Of the 300 individuals surveyed, the majority (85%) stated they would be willing to get up during the night to take the second dose of preparation. Of 107 colonoscopy patients with early morning appointments, 78% actually got up during the night to take the second dose of preparation. CONCLUSIONS: Acceptance of and compliance with split-dose bowel preparations is high and should not be a deterrent to prescribing split-dose preparations for colonoscopy.

Underlying mechanisms of pharmacology and toxicity of a novel PPAR agonist revealed using rodent and canine hepatocytes.

Marked species-specific responses to agonists of the peroxisome proliferator-activated alpha receptor (PPAR alpha) have been observed in rats and dogs, two species typically used to assess the potential human risk of pharmaceuticals in development. In this study, we used primary cultured rat and dog hepatocytes to investigate the underlying mechanisms of a novel PPAR alpha and -gamma coagonist, LY465608, relative to fenofibrate, a prototypical PPAR alpha agonist. As expected, rat hepatocytes incubated with these two agonists demonstrated an increase in peroxisome number as evaluated by electron microscopy, whereas the peroxisome number remained unchanged in dog hepatocytes. Biochemical analysis showed that rat hepatocytes responded to PPAR agonists with an induction of both peroxisomal and mitochondrial beta-oxidation (PBox and MBox) activities. Dog hepatocytes treated with both PPAR agonists, however, did not show increased PBox activity but did demonstrate increased MBox activity. Analysis of peroxisomal beta-oxidation gene expression markers by quantitative real-time PCR confirmed that PPAR agonists induced the peroxisomal enzymes, acyl-coenzyme A (CoA) oxidase (Acox), enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase (Ehhadh), and 3-ketoacyl-CoA thiolase (Acaa1) at the transcriptional level in rat hepatocytes, but not dog hepatocytes. Expression of mRNA for the mitochondrial beta-oxidation gene hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase (Hadhb), however, increased in both rat and dog hepatocytes, consistent with biochemical measurements of peroxisomal and mitochondrial beta-oxidation. Repeat-dose nonclinical safety studies of LY465608 revealed abnormities in mitochondrial morphology and evidence of single-cell necrosis following 30 days of dosing exclusively in dogs, but not in rats. Microarray analysis indicated that dog hepatocytes, but not rat hepatocytes, treated with LY465608 had an expression profile consistent with abnormalities in the regulation of cell renewal and death, oxidative stress, and mitochondrial bioenergetics, which may explain the canine-specific toxicity observed in vivo with this compound. This increased sensitivity to mitochondrial toxicity of canine hepatocytes relative to rat hepatocytes identified using gene expression was confirmed using the fluorescent indicator tetramethylrhodamine ethyl ester (TMRE) and flow cytometry. At doses of 0.1 microM LY465608, canine hepatocytes showed a greater shift in fluorescence indicative of mitochondrial damage than observed with rat hepatocytes treated at 10 microM. In summary, using rat and dog primary hepatocytes, we replicated the pharmacologic and toxicologic effects of LY465608 observed in vivo during preclinical development and propose an underlying mechanism for these species-specific effects.