Ceritinib‐associated hyperglycemia in the Japanese Adverse Drug Event Report Database

Genetic rearrangements of anaplastic lymphoma kinase contribute to the pathogenesis of non‐small‐cell lung cancer; the anaplastic lymphoma kinase inhibitor, ceritinib, is widely used, as it is effective even in patients with non‐small‐cell lung cancer resistant to other anaplastic lymphoma kinase inhibitors. Although a case of possible ceritinib‐induced hyperglycemia was reported, the association of ceritinib with hyperglycemia remains to be investigated. Disproportionality analysis was carried out using the Japanese Adverse Drug Event Report database, which contains all pharmacovigilance data based on spontaneous reports of adverse events between April 2004 and November 2018 to the Pharmaceuticals and Medical Devices Agency. The reporting odds ratio of ceritinib for hyperglycemia was 2.25 (95% confidence interval [CI] 1.24–4.08], whereas those of crizotinib and alectinib were 0.07 (95% CI 0.01–0.40) and 0.94 (95% CI 0.30–2.94), respectively. Among reported events without antidiabetes agent use, the reporting odds ratio of ceritinib was still 2.54 (95% CI 1.27–5.12). Thus, the possibility of hyperglycemia should be carefully monitored in patients receiving ceritinib.     

Relationship and factors responsible for regulating fasting and post‐challenge plasma glucose levels in the early stage development of type 2 diabetes mellitus

Aims/Introduction

Elevation of 2-h plasma glucose (2-h PG) levels keeps step with fasting plasma glucose (FPG) levels elevation, but some individuals show dominant elevation of 2-h PG and others FPG. We analyzed dependent and independent relationships between 2-h PG and FPG, and investigated the factors regulating 2-h PG and FPG.

Materials and Methods

In 1,657 Japanese participants who underwent a 75-g oral glucose tolerance test at the initial examination for a medical check-up, we carried out simple linear regression analysis between 2-h PG and FPG levels on the three patterns of independent variables. We divided the participants into two subgroups: the 2-h PG-side group and the FPG-side from the regression line, and examined the relationships between 2-h PG-FPG and factors responsible for elevation of plasma glucose levels.

Results

There was a significant positive correlation between 2-h PG and FPG levels. The regression line of both 2-h PG and FPG as independent variables was in accordance with the regression line of 2-h PG as an independent variable and FPG as a dependent variable. In 2-h PG-side group, age was the independent factor affecting 2-h PG in addition to insulinogenic index and insulin sensitivity index (ISI composite). In the FPG-side group, triglyceride was the independent factor affecting FPG in addition to insulinogenic index and ISI composite.

Conclusions

Two-hour PG was an independent predictor of FPG. In addition to the importance of decreased insulin secretion and insulin sensitivity, age was the strong factor to elevate 2-h PG levels in the 2-h PG-side group and triglyceride was the strong factor to elevate FPG levels in the FPG-side group in the early stage of development of type 2 diabetes.     

Effects of metal cation doping in CeO2 support on catalytic methane steam reforming at low temperature in an electric field

Catalytic methane steam reforming was conducted at low temperature using a Pd catalyst supported on Ce_1−xM_xO₂ (x = 0 or 0.1, M = Ca, Ba, La, Y or Al) oxides with or without an electric field (EF). The effects of the catalyst support on catalytic activity and surface proton hopping were investigated. Results show that Pd/Al-CeO₂ (Pd/Ce_0.9Al_0.1O₂) showed higher activity than Pd/CeO₂ with EF, although their activity was identical without EF. Thermogravimetry revealed a larger amount of H₂O adsorbed onto Pd/Al-CeO₂ than onto Pd/CeO₂, so Al doping to CeO₂ contributes to greater H₂O adsorption. Furthermore, electrochemical conduction measurements of Pd/Al-CeO₂ revealed a larger contribution of surface proton hopping than that for Pd/CeO₂. This promotes the surface proton conductivity and catalytic activity during EF application.

Temperature dependence of electron/ion conductivity of Pd/CeO₂ and Pd/Al-CeO₂ under wet conditions with application of an electric field.     

Criteria for the glucagon provocative test in the diagnosis of gastrinoma

Introduction

The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test.

Methods

This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 μg/kg) intravenously, followed by 20 μg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak.

Results

Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3–10 min for all patients. The increase in the peak from the basal value was 235–8,920 pg/ml, and the percentage of increase was 38–337 %.

Conclusions

These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value.     

Clonotypic analysis of T cell reconstitution after haematopoietic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency

Haematopoietic stem cell transplantation (HSCT) is performed for treatment of a broad spectrum of illnesses. Reconstitution of an intact immune system is crucial after transplantation to avoid infectious complications, and above all, the establishment of T cell receptor (TCR) diversity is the most important goal in the procedure. Until recently, little has been known of the mechanism of T cell reconstitution in the very early period after HSCT. In this study, we analysed TCR repertoires sequentially in four patients with severe combined immunodeficiency (SCID) before and after HSCT. In all patients, the TCR repertoires were extremely abnormal before HSCT, whereas after transplantation there was progressive improvement in TCR diversity, based on analysis of the TCR Vbeta repertoire and CDR3 size distributions. Somewhat unexpectedly, there was a significant but transient expansion of TCR diversity 1 month after transplantation in all cases. Clonotypic analysis of TCRs performed in one case showed that many T cell clones shared identical CDR3 sequences at 1 month and that the shared fraction decreased progressively. These results indicate that early expansion of TCR diversity may reflect transient expansion of pre-existing mature T cells from the donor blood, independent of de novo T cell maturation through the thymus.