Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real-world treatment outcomes.

Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography-tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure-response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (Ctrough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed Ctrough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related Ctrough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population.Clinical trial registry: Not applicable.

Substrate recognition of the catalytic α-subunit of glucosidase II from Schizosaccharomyces pombe.

The recombinant catalytic α-subunit of N-glycan processing glucosidase II from Schizosaccharomyces pombe (SpGIIα) was produced in Escherichia coli. The recombinant SpGIIα exhibited quite low stability, with a reduction in activity to <40% after 2-days preservation at 4 °C, but the presence of 10% (v/v) glycerol prevented this loss of activity. SpGIIα, a member of the glycoside hydrolase family 31 (GH31), displayed the typical substrate specificity of GH31 α-glucosidases. The enzyme hydrolyzed not only α-(1→3)- but also α-(1→2)-, α-(1→4)-, and α-(1→6)-glucosidic linkages, and p-nitrophenyl α-glucoside. SpGIIα displayed most catalytic properties of glucosidase II. Hydrolytic activity of the terminal α-glucosidic residue of Glc2Man3-Dansyl was faster than that of Glc1Man3-Dansyl. This catalytic α-subunit also removed terminal glucose residues from native N-glycans (Glc2Man9GlcNAc2 and Glc1Man9GlcNAc2) although the activity was low.

Secondary Hemochromatosis Caused by Iron Overdose During Pregnancy and the Postpartum Period: A Case Report.

Iron deficiency anemia is the most common cause of anemia in pregnancy. Therefore, iron administration is recommended for treatment. Iron deficiency anemia during pregnancy does not always result in microcytic anemia. Thus, iron may continue to be administered as diagnostic therapy, even in patients with normocytic anemia. In the present case, although the patient had normocytic anemia, repeated intravenous iron administration resulted in liver dysfunction due to secondary iron overload, which required intensive care. In pregnant women with perinatal hepatic dysfunction, iron overload secondary to iron therapy administered to correct anemia during pregnancy should be considered in the differential diagnosis.

Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation.

Melanoma is the most deadly tumor of the skin, and systemic therapies for the advanced stage are still limited. Recent genetic analyses have revealed the molecular diversity of melanoma and potential therapeutic targets. By screening a cohort of 142 primary nonepithelial tumors, we discovered that about 10% of melanoma cases (4/39) harbored an IDH1 or IDH2 mutation. These mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant, acquired increased colony-forming and in vivo growth activities and showed enhanced activation of the MAPK and STAT3 pathways. Genome-wide gene expression profiling demonstrated that mutant IDH1 affected the expression of a set of genes. Especially, it caused the induction of growth-related transcriptional regulators (Jun, N-myc, Atf3) and the reduction of Rassf1 and two dehydrogenase genes (Dhrs1 and Adh5), which may be involved in the carcinogenesis of IDH1-mutated tumors. Our analyses demonstrate that IDH1 mutation works with other oncogenic mutations and could contribute to the metastasis in melanoma.

Establishment of six new human biliary tract carcinoma cell lines and identification of MAGEH1 as a candidate biomarker for predicting the efficacy of gemcitabine treatment.

The aim of this study was to establish new biliary tract carcinoma (BTC) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy. Surgical specimens of BTC were transplanted directly into immunodeficient mice to establish xenografts, then subjected to in vitro cell culture. The gemcitabine sensitivity of each cell line was determined and compared with the genome-wide gene expression profile. A new predictive biomarker candidate was validated using an additional cohort of gemcitabine-treated BTC cases. From 55 BTC cases, we established 19 xenografts and six new cell lines. Based on their gemcitabine sensitivity, 10 BTC cell lines (including six new and four publicly available ones) were clearly categorized into two groups, and MAGEH1 mRNA expression in the tumor cells showed a significant negative correlation with their sensitivity to gemcitabine. Immunohistochemically, MAGEH1 protein was detected in three (50%) out of six sensitive cell lines, and four (100%) out of four resistant cell lines. In the validation cohort of gemcitabine-treated recurrence cases, patients were categorized into "effective" and "non-effective" groups according to the RECIST guidelines for assessment of chemotherapeutic effects. MAGEH1 protein expression was detected in two (40%) out of five "effective" cases and all four (100%) "non-effective" cases. We have established a new BTC bioresource that covers a wide range of biological features, including drug sensitivity, and is linked with clinical information. Negative expression of MAGEH1 protein serves as a potential predictive marker for the effectiveness of gemcitabine therapy in BTC.

Detection and validation of predictors of successful extubation in critically ill children.

INTRODUCTION: Availability of objective criteria for predicting successful extubation could avoid unnecessary prolongation of mechanical ventilation and/or inadvertent premature extubation, but the predictors of successful extubation in children are unclear. This study was performed to detect and validate respiratory function predictors of successful extubation in children admitted to the pediatric critical care unit. METHODS: A retrospective chart review from 2010 to 2012 identified 463 patients, who were divided into a derivation cohort (n = 294) and a validation cohort (n = 169). RESULTS: The incidence rate of failed extubation was 5% and 9% in the derivation and validation cohorts, respectively. The optimal cut-off values of crying vital capacity (CVC), peak inspiratory flow rate (PIFR), and maximum inspiratory pressure (MIP) were 17 ml/kg, 3.5 ml/sec/cm, and 50 cmH2O, respectively. The pass rates of CVC, PIFR, and MIP were 54.2%, 92.7%, and 55.5%, respectively. In the validation cohort, the successful extubation rate was 97.9% for patients who passed all 3 respiratory tests, 88.8% for those who passed at least one test, and 66.7% for those who failed all of the tests. Extubation failed in 5 patients who passed all three respiratory tests and failure was due to postoperative respiratory muscle fatigue or upper airway impairment. CONCLUSIONS: We detected and validated predictors of successful extubation in critically ill children. A combination of CVC, PIFR, and MIP may be used to predict successful extubation for critically ill children. It is necessary to pay attention when extubating patients with postoperative respiratory muscle fatigue or upper airway impairment due to disturbance of consciousness and/or glottal edema even if they pass the respiratory function tests.

Photoluminescence properties of CdS and CdMnS quantum dots prepared by a reverse-micelle method.

We have investigated photoluminescence properties of CdS and CdMnS quantum dots (QDs) prepared by a reverse-micelle method. Before the surface modification, a broad luminescence band that originates from defects is dominant in CdS QDs. By the modification, the intensity of the band-edge luminescence is remarkably increased. The surface modification also causes drastic changes of decay profiles of the band-edge luminescence. The intensity of Mn2+ luminescence originating from the intra-3d shell transition of Mn2+ is also increased by the surface modification of CdMnS QDs. The decay time of the band-edge luminescence in surface-modified CdMnS QDs is faster than that in CdS QDs, which is due to the energy transfer from excitons to Mn2+.

Living-related right lobe liver transplantation for a patient with fulminant hepatic failure during the second trimester of pregnancy: report of a case.

A 28-year-old pregnant Japanese woman developed fulminant hepatic failure (FHF) with coma grade IV at 15 weeks' gestation and underwent emergency orthotopic living-related liver transplantation (LRLT) using the right hepatic lobe of her father. Blood type was identical. On postoperative day 2, she regained consciousness and was extubated. For fear of possible negative effects of exposure to various drugs and from x-ray examinations on the fetus as well as the maternal burden of a continuing pregnant state on the patient, artificial abortion was a treatment choice in this woman on posttransplant day 31. The patient was discharged and is currently doing well. Until the present, 11 pregnant women were reported to have liver transplantation during the second trimester of pregnancy, including 2 pregnant women with LRLT. This is the third case of LRLT, and the first successful case in which the right hepatic lobe was used for graft.

Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism.

OBJECTIVE: We aimed to determine the serum level of fibroblast growth factor-23 (FGF-23) in patients with primary hyperparathyroidism (pHPT) to understand its physiological role in the disorder. PATIENTS AND METHODS: Ninety-eight patients with pHPT who underwent parathyroidectomy formed the study group. We also measured serum FGF-23 in 11 of these patients on postoperative day 6. RESULTS: Serum FGF-23 levels was significantly higher in pHPT patients than in healthy controls (35.6+/-17.8 ng/l vs 28.9+/-11.2 ng/l (mean+/-s.d.); P<0.001 (Pearson's correlation coefficient)), but there was no significant difference in the serum FGF-23 level between pHPT patients with normal renal function (creatinine clearance (Ccr) of >or=70 ml/min) and healthy controls. Serum FGF-23 correlated positively with serum calcium (P<0.0001) and intact parathyroid hormone (PTH) (P<0.01), and negatively with Ccr (P<0.001), serum phosphate (P<0.05), and serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) (P<0.05). Multiple linear regression analysis of factors potentially determining serum FGF-23 levels in pHPT patients showed serum calcium (P<0.01) and Ccr (P<0.001) to be significant predictors. The serum levels of FGF-23 did not change after parathyroidectomy despite the normalization of serum calcium values. Multiple linear regression analysis revealed that serum FGF-23 was not a significant predictor of serum phosphate or 1,25(OH)(2)D in pHPT patients. CONCLUSIONS: FGF-23 may not play a significant role in regulating phosphate or 1,25(OH)(2)D in pHPT patients, especially in those with normal renal function. Further studies are warranted to determine the role of FGF-23 in renal insufficiency or failure.

Transient central diabetes insipidus in pregnancy with a peculiar change in signal intensity on T1-weighted magnetic resonance images.

A 38-year-old woman was admitted with severe thirst and polyuria at 31 weeks' gestation. The plasma concentration of vasopressin (AVP) was very low (0.73 pg/ml) under conditions of high plasma osmolality (316 mOsm/ kg). T1-weighted magnetic resonance (MR) images revealed enlargement of the pituitary posterior lobe with absence of the hyperintense signal. After delivery, restoration of the hyperintense signal was demonstrated. This depletion-repletion process, which reflects the decrease and increase in amount of neurosecretory granules, is recognized in the case of transient central diabetes insipidus during pregnancy. We consider that an increase in cystine-aminopeptidase (CAP) activity is implicated in the pathogenesis.

[Analytical method of cereulide in processed cereal-based foods and milk powder by LC-MS/MS].

An LC-MS/MS method for analysis of cereulide, an emetic toxin produced by Bacillus cereus, was developed. Cereulide was extracted from samples, fried rice, pan-fried noodles, red bean paste and baby formula, with methanol and purified using Oasis HLB cartridges. LC separation was performed on a C18 column with a mixture of formic acid solution and methanol containing ammonium formate as a mobile phase, and the mass spectrometer was operated in the positive electrospray ionization mode. Performance evaluation showed that trueness was higher than 70% and repeatability and reproducibility were within 10%. The limits of quantification were lower than 1 µg/kg.