Exploratory study on relative dose intensity and reasons for dose reduction of adjuvant CAPOX therapy in elderly patients with colorectal cancer.

Capecitabine plus oxaliplatin, CAPOX, therapy is one of the standardized options for adjuvant chemotherapy for colorectal cancer, but the efficacy and the safety of CAPOX in elderly patients are unclear. In this study, we investigated the relative dose intensity (RDI) and reasons for dose reduction in patients over the age of 70 (elderly group) (n = 12) and those under the age of 70 (non-elderly group) (n = 24) receiving adjuvant CAPOX therapy for colorectal cancer. The median RDIs were 71.1% in the elderly group and 67.9% in the non-elderly group for oxaliplatin (p = 0.416), and 81.6% and 86.4% for capecitabine (p = 0.166), respectively. The rate of peripheral neuropathy which was the reason for dose reduction of oxaliplatin was approximately 4.5-fold higher in the non-elderly group than in the elderly group. In addition, hematologic toxicity was the most common reason for dose reduction at 50.0% in the elderly group. The results of this study suggested that a similar therapeutic intensity can be maintained in elderly patients relative to non-elderly patients by appropriate dose reduction and discontinuation of drug treatments. Elderly patients are more susceptible to hematologic toxicity than to peripheral neuropathy.

[Study for Management Status of Hepatitis B Virus Reactivation Caused by Cancer Chemotherapy in High-Risk Cases].

The reactivation of the hepatitis B virus(HBV)induced by chemotherapy can cause fulminant hepatitis, followed by death. In Japan, the Ministry of Health, Labor and Welfare released the guideline on the prevention of chemotherapy- induced reactivation of HBV in 2009. The NCGM's pharmacy department conducted a study on the HBV screening rate and the guideline compliance rate in patients undergoing chemotherapy who met the criteria for monthly HBV DNA monitoring during chemotherapy and 12 months after. We also conducted a study on the influence on the guideline compliance rate with inquiries by pharmacists. The HBV screening rate was 100%(68/68 cases), and there were inquiries in 10.3% (7/68 cases). This suggests that inquiries contributed to the improvement in the HBV screening rate. However, the guideline compliance rate in high-risk cases was 75.0%(12/16 cases). It is necessary to raise awareness in physicians and patients on the management of HBV reactivation and to establish a follow-up system for HBV DNA monitoring.

Identification and characterization of extracellular enzymes secreted by Aspergillus spp. involved in lipolysis and lipid-antioxidation during katsuobushi fermentation and ripening.

A mild-flavored soup stock made from katsuobushi is an important element of traditional Japanese cuisine and is the basic seasoning responsible for the taste. Fermented and ripened katsuobushi, known as karebushi, is manufactured by simmering skipjack tuna that is then smoke-dried, fermented, and ripened in a repeated molding process by five dominant Aspergillus species. Here, our aim was to characterize and identify the lipolytic enzymes secreted by the dominant Aspergillus species, especially A. chevalieri and A. pseudoglaucus, which are involved in hydrolyzing lipids during the molding process. The crude enzyme preparations from the five Aspergillus spp. cultivated on katsuobushi solid medium hydrolyzed triglycerides in fish oil, and more saturated and unsaturated fatty acids (C16:0, C16:1, C18:0, C18:1) were produced than major polyunsaturated fatty acids (C20:5, C22:6). On the basis of ion exchange chromatograms, the composition of the lipolytic enzymes was different in the five species. There was at least one active fraction with high hydrolytic activity toward fish oil in four of the Aspergillus spp., but not A. sydowii; the lipolytic enzyme secreted by A. sydowii had quite high activity toward the artificial substrate p-nitrophenyl butyrate, but low activity toward the natural oil. The lipolytic fractions from A. chevalieri and A. pseudoglaucus were further purified by hydrophobic interaction chromatography then gel-filtration chromatography; LC-MS-MS Mascot analysis identified a variety of lipolytic enzymes, including cutinase, esterase, phospholipase, and carboxyl esterase in the lipolytic fractions from these species. The identified enzymes had 30%-70% identity to previously reported or manually annotated lipases or esterases from taxa other than Aspergillus. The different lipolytic enzymes likely acted on triglycerides in the katsuobushi fish oil. Furthermore, catalase B and Cu/Zn superoxide dismutase, which limit oxidative damage of lipids, were also identified. These antioxidant enzymes may prevent lipid oxidation and rancidity as the lipolytic enzymes hydrolyze lipids during the long fermentation and ripening process. Umami and richness tastes tended to increase in extracts from culture of protease- and peptidase-producing A. sydowii. Our results will aid in the selection and application of desirable strains of Aspergillus species as starter cultures to improve the storage and quality of fermented and ripened karebushi.

Safety and Effectiveness of Ixazomib Dose-escalating Strategy in Ixazomib-Lenalidomide-Dexamethasone Treatment for Relapsed/Refractory Multiple Myeloma.

BACKGROUND/AIM: Gastrointestinal toxicity is common in patients receiving common therapy of ixazomib with lenalidomide and low-dose dexamethasone (IRd) for relapsed/refractory multiple myeloma. Here, we investigated the safety and effectiveness of ixazomib dosing schedules. PATIENTS AND METHODS: We retrospectively evaluated 17 consecutive patients treated with IRd (10 patients on ixazomib dose-escalation strategy (2.3 mg starting dose); seven patients on standard dose). RESULTS: The incidence of grade 3 or more haematological and grade 2 or more non-haematological adverse events was lower in the dose-escalation group than in the standard-dose group, and only that of diarrhoea was significantly lower. The median time to treatment interruption was significantly longer in the dose-escalation group than in the standard-dose group. There was no significant difference in the overall response rate (20% vs. 43%) and disease control rate (70% vs. 86%). CONCLUSION: A dose-escalation strategy to optimise ixazomib dosing may reduce treatment interruption due to adverse events without compromising its antitumor activity.

Characterization of surface Aspergillus community involved in traditional fermentation and ripening of katsuobushi.

A soup stock made from katsuobushi is an important element of, and the basic seasoning responsible for the taste of, traditional Japanese cuisine. Fermented and ripened katsuobushi, called karebushi, is manufactured via a repeated molding process on the katsuobushi surface. Our aim was to characterize the surface Aspergillus community and their enzymes involved in the fermentation and ripening. Five dominant Aspergillus species isolated from the karebushi surface were identified-A. amstelodami, A. chevalieri, A. pseudoglaucus, A. ruber, and A. sydowii. Analyses were performed on final molding stage-samples from different manufacturers, and 1st to 4th molding stage-samples from the same manufacturer. The composition ratios of the five Aspergillus spp. varied according to the manufacturer of the karebushi. A. amstelodami and A. chevalieri tended to be detected as dominant species when the water content of the karebushi fillet was >15% and the fat content was >3.5%, respectively. In samples from a given manufacturer, the dominant species in the final molding stage tended to be A. chevalieri and A. pseudoglaucus. Mixed molds were cultured by solid-state fermentation using katsuobushi powder medium at two different water activity (aw) levels. Crude extracts from each culture showed lipase, aminopeptidase, carboxypeptidase, and protease activities. Notably, the crude extracts cultivated at 0.85 aw showed higher protease activity toward hemoglobin and lipase activity toward p-nitrophenyl palmitate than those at 0.95 aw. These hydrolytic enzymes are probably involved in decolorization of katsuobushi and lipid degradation during the long fermentative and ripening period. In addition, mixed cultures could transform 2,6-dimethoxyphenol into 1,2,3-trimethoxybenzene, previously reported as an attractive and mild flavor component. Our results may help promote the use of desirable Aspergillus spp. as starter cultures for manufacturers to stabilize and improve the quality of fermented and ripened karebushi.

Analysis of inline-filter blockage with trastuzumab formulation using scanning-electron microscopy.

The instability of pharmaceutical monoclonal antibodies are affected by physical stimuli including, temperature, denaturant, surfactant, stirring, solid phase adsorption, oxidation, and ultraviolet rays. Clinically, we frequently experience precipitation during preparation of several pharmaceutical monoclonal antibodies for cancer. Although it is possible to remove precipitates in the injection solution during the preparation procedure, potential filter blockade during administration remains a problem with adverse effects on the quality of life of patients. Therefore we sought to investigate factors contributing to this phenomenon. To closely observed the mechanisms involved in blockade of filters during trastuzumab preparation, we prepared samples under the same conditions used in clinical practice and observed them comprehensively. The precipitates that caused filter blockade were observed when the samples were vigorously shaken and left for several hours after dissolving. The precipitates were identified as proteins. The vigorous shaking caused contact between the protein and air, which induced protein precipitation caused by the surfactants derived from the foam formation. We discovered that the external stimulation may cause the instability of monoclonal antibody preparations and, so, it is important for procedures to be as rapid to avoid precipitate formation as much as possible.

[Comparison of Chemical Behavior of Original and Generic Docetaxel Formulations as Non-alcoholic Preparations: Discussion about Diluent Solvents for Docetaxel].

　Although generic anti-tumor agents are in wide clinical use, they have not in all cases been shown to be equivalent to the original agents after preparation. In the present study, original and generic docetaxel formulations were compared with respect to stability when prepared as a non-alcoholic solution for use. When the original formulation was diluted with physiological saline solution to make a non-alcoholic preparation, the concentration decreased with time, whereas no such decrease occurred when a preparation of the generic formulation was made in a similar manner. With both the original and generic formulations, no decrease in docetaxel concentration with time was found after dilution with 5% glucose solution. On the basis of these results, it is concluded that the behaviors of original and generic docetaxel formulations are not equivalent when prepared, but that the original and generic formulations can be taken to be equivalent if they are diluted with 5% glucose solution at preparation.

Influence of Varying Dietary Protein Levels on Glycation of Albumin, Tryptophan and Valine in the Plasma of Chickens.

Glycation is a chemical reaction in which reducing sugars bind non-enzymatically to compounds containing amino groups. Avian species like chickens are hyperglycemic animals and have high body temperature compared to mammalian species, which enables avian species to accelerate the glycation of proteins and amino acids with glucose. Although varying dietary crude protein (CP) levels alter plasma concentrations of proteins and amino acids, the influence of varying CP levels on the glycation of plasma proteins and amino acids has not been studied so far. In the present study, therefore, glycation of albumin, tryptophan and valine in the plasma of chickens fed diets with varying CP levels (0, 10, 20, 40 and 60%) was examined. At the end of the experimental period, blood samples were collected and plasma concentrations of glycoalbumin, glycated tryptophan (tryptophan-Amadori product and (1R, 3S) - 1 - (D - gluco - 1, 2, 3, 4, 5 - pentahydroxypentyl) - 1, 2, 3, 4 - tetrahydro - ß - carboline - 3 - carboxylic acid (PHP-THßC)), and valine-Amadori product were measured. Although plasma albumin concentration was reduced along with the decrease in dietary CP levels from 20% to 0%, glycoalbumin in the plasma was increased under such dietary conditions. Similar increase in the ratios of tryptophan-Amadori product to tryptophan and valine-Amadori product to valine in the plasma of chickens fed a protein-free diet was observed. These results suggest that dietary protein deficiency might enhance the non-enzymatic glycation of plasma proteins and amino acids in chickens.

Construction of a model for predicting creatinine clearance in Japanese patients treated with Cisplatin therapy.

BACKGROUND/AIM: There exist various useful predictive models, such as the Cockcroft-Gault model, for estimating creatinine clearance (CLcr). However, the prediction of renal function is difficult in patients with cancer treated with cisplatin. Therefore, we attempted to construct a new model for predicting CLcr in such patients. PATIENTS AND METHODS: Japanese patients with head and neck cancer who had received cisplatin-based chemotherapy were used as subjects. A multiple regression equation was constructed as a model for predicting CLcr values based on background and laboratory data. RESULTS: A model for predicting CLcr, which included body surface area, serum creatinine and albumin, was constructed. The model exhibited good performance prior to cisplatin therapy. In addition, it performed better than previously reported models after cisplatin therapy. CONCLUSION: The predictive model constructed in the present study displayed excellent potential and was useful for estimating the renal function of patients treated with cisplatin therapy.