PURPOSE Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively ( P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.
1. The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro. 2. The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated. 3. The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125-64 microg/mL) were also investigated. The in vitro effects of two anti-oxidants, namely N-acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA. 4. Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose-dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA. 5. In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose-dependently decreased the activity of FCZ. 6. The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.
The crystal structure transformation and step-by-step thermal decomposition behavior of dihydroxylammonium 5,50 -bistetrazole-1,1 0 -diolate (TKX-50) under thermal stimulation were studied and the whole process included thermal expansion, primary decomposition and secondary decomposition.The thermal expansion and primary decomposition of TKX-50 were studied using in situ powder X-ray diffraction (in situ XRD) together with Rietveld refinement, by which the crystal structure transformation process can be accurately traced. The results showed that the thermal expansion of TKX-50 was anisotropic. In particular, the a-axis exhibited a negative thermal expansion (NTE) that may be attributed to the distortion of the six-membered ring, which results in H-transfer between the cation and dianion.The crystal structure of the intermediate product after primary decomposition was also obtained. The secondary decomposition process was analysed using thermogravimetric-differential scanning calorimetry (TG-DSC) due to the safety risk of TKX-50 analyzed by in situ XRD. The crystal structure transformation process from TKX-50 to the intermediate product under heat stimulation was deduced.Meanwhile, the morphological change of the whole process was obtained using hot stage microscopy (HSM). Combined with TG-FTIR technology, the gaseous decomposition products at each step were analysed and the thermal decomposition mechanism of TKX-50 was proposed. This study further reveals the thermal decomposition behavior of TKX-50 and is helpful for better understanding the thermal decomposition mechanism.
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