Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Early results of multicenter phase II trial of perioperative oxaliplatin and capecitabine without radiotherapy for high-risk rectal cancer: CORONA I study.

BACKGROUNDS: Perioperative introduction of developed chemotherapy into the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. However, the most prevalent treatment for high-risk LARC remains preoperative chemoradiotherapy (CRT) in Western countries. PATIENTS AND METHODS: A phase II trial was undertaken to evaluate safety and efficacy of perioperative XELOX without radiotherapy (RT) for patients with high-risk LARC. Patients received 4 cycles of XELOX before and after surgery, respectively. Primary endpoint was disease-free survival. RESULTS: We enrolled 41 patients between June 2012 and April 2014. The completion rate of the preoperative XELOX was 90.3%. Twenty-nine patients (70.7%) could start postoperative XELOX, 15 of these patients (51.7%) completed 4 cycles. Allergic reaction to oxaliplatin was experienced by 5 patients (17.2%) during postoperative XELOX. One patient received additional RT after preoperative XELOX. Consequently, the remaining 40 patients underwent primary resection. Major complications occurred in 6 of 40 patients (15.0%). Pathological complete response (pCR) rate was 12.2%, and good tumor regression was exhibited in 31.7%. N down-staging (cN+ to ypN0) and T down-staging were detected in 56.7% and 52.5%, respectively. Clinical T4 tumor was a predictor of poor pathological response (p < 0.001). CONCLUSIONS: We could show the favorable pCR rate after preoperative XELOX alone. However, the T and N down-staging rate was likely to be insufficient. When tumor regression is essential for curative resection, the use of preoperative CRT is likely to be recommended. For patients with massive LN metastasis, the additional Bev to NAC might be a promising option.

Human liver disease decreases methacrylyl-CoA hydratase and beta-hydroxyisobutyryl-CoA hydrolase activities in valine catabolism.

BACKGROUND: Methacrylyl-coenzyme A (MC-CoA) hydratase and beta-hydroxyisobutyryl-coenzyme A (HIB-CoA) hydrolase are key enzymes regulating the toxic concentration of MC-CoA generated in valine catabolism. MATERIALS AND METHODS: We studied the activities and mRNA expression levels of these enzymes in normal human livers and in human livers with chronic hepatitis, cirrhosis, or hepatocellular carcinoma. RESULTS: The activities of both enzymes were significantly lower by 36% to 46% in livers with cirrhosis or hepatocellular carcinoma compared with normals, suggesting a decrease in the capability of detoxifying MC-CoA with these diseases. The mRNA levels for both enzymes measured by quantitative polymerase chain reaction were significantly increased in livers with cirrhosis, but were not altered in those with chronic hepatitis or hepatocellular carcinoma when compared with normal livers. CONCLUSION: Our results suggest that low levels of these enzyme activities in livers with cirrhosis or hepatocellular carcinoma are the result of posttranscriptional regulation in the damaged liver.

The alpha-ketoisocaproate catabolism in human and rat livers.

Catabolism of alpha-ketoisocaproate in liver is mediated by cytosolic alpha-ketoisocaproate dioxygenase (KICD) and mitochondrial branched-chain alpha-keto acid dehydrogenase complex (BCKDC). The latter is believed to be involved in the main pathway of the KIC catabolism. In the present study, we measured the activities of KICD and BCKDC in human and rat livers. The KICD activity in human liver was 0.9 mU/g tissue, which was 14.2% of the total activity of BCKDC, and that in rat liver was 4.2 mU/g tissue, which was only 1.0% of the total activity, suggesting that KICD in human liver plays a relatively important role in the alpha-ketoisocaproate catabolism. The KICD activity in human liver was significantly increased by cirrhosis. In rat liver, the enzyme activity was markedly increased by physical training and streptozotocin-induced diabetes, but not by feeding of a diet rich in branched-chain amino acids, although BCKDC activity was increased by feeding of the diet.

[Accidental injuries among elementary school children and some of their environmental factors].

I investigated 4960 accidental injuries which occurred among elementary school children between April 1991 and March 1992, using reports of school accidents submitted to the Shiga branch of the National Studium and School Health Center of Japan. Data on six school environmental factors (i.e. the areas of school land, schoolhouse, gymnasium and all classrooms, the number of children per class, and the total number of children in each school) for 223 elementary schools were gathered. From these data, the relationship between the incidence rates of injuries and the above school environmental factors were analyzed. The overall average incidence rate for all injuries combined was 5.43 cases per 100 children. For all injuries and fractures which occurred at smaller schools, the incidence rates tended to increase with the areas of school land, schoolhouse, gymnasium and all classrooms, and to decrease as the number of children per class and the number of children in the school increased. These results may have been biased by the fact that only injuries treated at a cost of at least 3000 yen were reported. In the process of stepwise multiple regression analysis between the injury-rates and environmental factors, a few variables relating to types of injuries were included as statistically significant factors in the well-fitted equations, but the coefficients of determination (squared multiple correlation coefficients) in the equations were small.

[Study on postsoldering of Ni-Cr ceramic alloys. Effect of soldering temperature and atmosphere].

The effects of soldering temperatures and atmospheres on tensile strength of solder joints were investigated for two types of Ni-Cr ceramic alloys and one type of gold solder for postsoldering. Each alloy and the gold solder were soldered with fluoride flux in an electric furnace in three different temperatures and four different atmospheres. Of the three different temperatures, one was just over the liquidus point of the solder, another 50 degrees C higher than the liquidus point and the other 100 degrees C higher than the liquidus point. Of the four different atmospheres, one was under vacuum, another under vacuum with a 6 l/h argon gas flow, another under vacuum with a 12 l/h argon gas flow and the other under vacuum with a 24 l/h argon gas flow. Tensile strength testing was performed at the solder joints. The fracture surface was observed by EPMA. Wettability of the liquid solder on each alloy was performed by the sessile drop method in high-purity argon gas. The surface tension and the contact angle of the liquid solder on MgO were determined by the sessile drop method in high-purity argon gas. The soldering was performed in the furnace used for the sessile drop method in high-purity argon gas. The results are summarized as follows. The tensile strength of UNI METAL-solder joints was significantly affected by the soldering temperature (p less than 0.01). However, the effect of the soldering atmosphere on the tensile strength was small. The effect of the soldering temperature and atmosphere on the tensile strength of Victory II-solder joints was small. Each alloy had a different adequate soldering temperature. With the increase in the soldering temperature, the diffusion layer of the solder joint interface increased, but no correlationship between the atmosphere and the diffusion layer thickness was observed. Fracture patterns of UNI METAL-solder joints were mixed adhesive-cohesive fractures with a large cohesive area. Fracture patterns of Victory II-solder joints were mixed adhesive-cohesive fractures with a large adhesive area. It was possible to perform the soldering without flux in the furnace used for the sessile drop method in a strictly controlled atmosphere of high-purity argon gas. Wettability of the liquid solder on UNI METAL was better than on Victory II. The surface tension of the solder used was 505.9 dyn/cm at 1000 degrees C. The contact angle of the solder used was 163.0 degrees at 1000 degrees C.

[Color and discoloration of dental alloys with low noble metal content].

Diffused reflectance of dental casting alloys with low noble metal content by the spectrophotometer with an integrating sphere was used to determine the color of the alloy and the tarnish in 0.1% Na2S solution, to study whether or not the tarnish can be affected by the nobility and the microstructure of the alloy. The alloys which had a high atomic ratio of Au + Pt + Pd + In + Zn to Ag had higher tarnish resistance. However the alloys which had high content of In showed two phases, but these alloys had high tarnish resistance. This suggests that alloys which have only a small difference of nobility between the compound and the matrix, and in which the low tarnish resistance area is small, may have a high tarnish resistance.

[Bone inductive activity of bone morphogenetic protein combined to beta-tricalcium phosphate].

For the development of a new delivery system for bone morphogenetic protein (BMP), BMP was bound to beta-tricalcium phosphate (beta-TCP). Powder beta-TCP was synthesized from calcium hydrogenphosphate and calcium carbonate by the dry process method to make the best use of the advantages of the BMP, which show good bone inductive activity on the surface and enhancement of new tissue by reducing the area that the implant material occupies. The beta-TCP + BMP complex and beta-TCP for the controls only were implanted in the muscle pouches of mice. Three weeks later new bone formation was observed on the exterior surface of beta-TCP + BMP complex but not of beta-TCP controls. The bone inductive activity of the beta-TCP + BMP complex is better than the BMP alone. The histological relation between the original tissue and the newly induced bone formation was normal and that of new bone and beta-TCP was also good. Consequently, the beta-TCP + BMP complex has good histocompatibility when implanted.