Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment

The effect of high-intensity breastfeeding on postpartum glucose tolerance in women with recent gestational diabetes

Abstract Background Although breastfeeding is expected to reduce the incidence of diabetes in women with gestational diabetes, the effect has not been clearly confirmed. We examined whether or not high-intensity breastfeeding reduces the incidence of abnormal glucose tolerance and investigated the effect of high-intensity breastfeeding on insulin resistance during the first year postpartum in Japanese women with current gestational diabetes. Methods In this retrospective study, we included women with gestational diabetes who underwent postpartum 75 g oral glucose tolerance test during the first year (12-14 months) postpartum from 2009 to 2011 at a single tertiary perinatal care center in Japan. High-intensity breastfeeding was defined as the condition in which infants were fed by breastfeeding alone or 80% or more of the volume. We investigated the effect of high-intensity breastfeeding on the prevalence of postpartum abnormal glucose tolerance and the postpartum homeostasis model of assessment of insulin resistance (HOMA-IR), after controlling for confounders, including prepregnancy obesity and weight changes during pregnancy and postpartum. Results Among 88 women with gestational diabetes, 46 (52%) had abnormal glucose tolerance during the postpartum period. High-intensity breastfeeding women (n = 70) were significantly less likely to have abnormal glucose tolerance than non-high-intensity breastfeeding women (n = 18) (46% vs. 78%, p = 0.015). High-intensity breastfeeding was also associated with a lower HOMA-IR at 12-14 months postpartum than non-high-intensity breastfeeding (1.41 ± 1.02 vs. 2.28 ± 1.05, p = 0.035). Those associations remained significant after controlling for confounders. At least six months of high-intensity breastfeeding had a significant effect on lowering both the abnormal glucose tolerance prevalence and HOMA-IR compared with non-high-intensity breastfeeding. Conclusions In Japanese women with gestational diabetes, high-intensity breastfeeding ≥6 months had a protective effect against the development of abnormal glucose tolerance during the first year postpartum through improving insulin resistance, independent of obesity and postpartum weight change

Lipid Accumulation in Peripheral Blood Dendritic Cells and Anticancer Immunity in Patients with Lung Cancer

We studied the subsets of peripheral blood dendritic cells (DCs) and lipid accumulation in DCs to investigate the involvement of DCs in the decreased anticancer immunity of advanced lung cancer patients. We analyzed the population of DC subsets in peripheral blood using flow cytometry. We then determined lipid accumulation in the DCs using BODIPY 650/665, a fluorophore with an affinity for lipids. Compared with healthy controls, the number of DCs in the peripheral blood of treatment-naive cancer patients was significantly reduced. In patients with stage III + IV disease, the numbers of myeloid DCs (mDCs) and plasmacytoid DCs were also significantly reduced. Lipid accumulation in DCs evaluated based on the fluorescence intensity of BODIPY 650/665 was significantly higher in stage III + IV lung cancer patients than in the controls. In the subset analysis, the fluorescence was highest for mDCs. The intracellularly accumulated lipids were identified as triglycerides. A decreased mixed leukocyte reaction was observed in the mDCs from lung cancer patients compared with those from controls. Taken together, the results show that lung cancer patients have a notably decreased number of peripheral blood DCs and their function as antigen-presenting cells is decreased due to their high intracellular lipid accumulation. Thereby, anticancer immunity is suppressed

Funding innovation for treatment for rare diseases: adopting a cost-based yardstick approach

長崎大学学位論文 [学位記番号]博（医歯薬）甲第982号 [学位授与年月日]平成29年6月7

Measurement of Fractional Exhaled Nitric Oxide with a Stationary Analyzer（NOA280i®）or Hand-held Analyzer（NIOX MINO®）Shows a Strong Correlation but Weaker Correlation at Higher Levels

This study investigated the difference of measured values between two types of analyzer over a wider range of fractional exhaled nitric oxide （FeNO） levels than in previous reports because some asthma patients have high FeNO levels. The equation for conversion of measured FeNO levels between the two analyzers was also determined.Methods：Patients underwent assessment of FeNO for the diagnosis and management of asthma or for differential diagnosis of cough, FeNO levels were measured sequentially using both a stationary analyzer（NOA280i®, Sievers Inc, USA） and a hand-held analyzer（NIOX MINO®, Aerocrine Inc, Sweden）. FeNO levels were measured in a total of 167 subjects. Regression analysis of the FeNO data showed a strong positive correlation between values obtained with the two analyzers （r＝0.938, p＜0.0001）, and the regression line was calculated as：FeNO （NOA280i®）×0.63＋3.79＝FeNO （NIOX MINO®）. The correlation between the two analyzers was strongest at low FeNO values and it decreased as the FeNO level increased ［FeNO （NOA280i®）£50 （r＝0.730, p＜0.0001） FeNO （NOA280i®） 50 to £100 （r＝0.641, p＜0.0001）, FeNO （NOA280i®）＞100 to £150 （r＝0.607, p＝0.0008）, and FeNO （NOA280i®）＞150 （r＝0.523, p＝0.0180）］. Bland-Altman plot analysis between the two analyzers was 0.167 （95％ confidence interval＝－0.038 to 0.357, suggesting a positive difference.Some caution is needed because the correlation between the two analyzers is weaker when the FeNO level exceeds 150

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome

Secondary pulmonary alveolar proteinosis (sPAP) is a complication of myelodysplastic syndrome (MDS). A 60-year-old woman was diagnosed with MDS with excess blasts-1. Fifty-four months after the initial diagnosis, treatment with azacitidine was initiated. Seventy-three months after the diagnosis, a bone marrow examination revealed increased myeloblasts, at which time computed tomography showed diffuse ground-glass opacities and interlobular septal thickening in the bilateral lower lung fields. A lung biopsy revealed the presence of PAP; therefore, the clinical diagnosis of MDS/sPAP was confirmed. Careful attention should be paid to the development of sPAP in MDS patients with pulmonary lesions during azacitidine treatment

Phase I Trial of Pemetrexed in Combination with Carboplatin Followed by Pemetrexed Maintenance Therapy in Elderly Patients with Advanced Non-small Cell Lung Cancer

Introduction： A phase I trial was conducted to evaluate the feasibility of pemetrexed in combination with carboplatin followed by pemetrexed maintenance therapy in elderly patients with advanced non-small cell lung cancer （NSCLC）. The primary objective of this study was to determine the maximum tolerated dose （MTD） and the recommended dose （RD） of pemetrexed in combination with carboplatin.Methods：Chemotherapy-naïve elderly 13 patients （age, ≥70 years） with stage IIIB/IV non-squamous NSCLC were enrolled and received pemetrexed 500 mg/m2 and carboplatin at an area under the curve （AUC）dose of 5 mg/ml/min（level 1）or 6 mg/ml/min （level 2）. Pemetrexed with carboplatin was administered on day 1 of the 21-day cycle. The treatment schedule consisted of four cycles of pemetrexed with carboplatin. Patients who did not have progressive disease after completion of four cycles subsequently received pemetrexed maintenance therapy （500 mg/m2 every three weeks） until disease progression or unacceptable toxicity was noted.Results：Three patients were enrolled in level 1, in which no dose-limiting toxicity（DLT）was observed. The carboplatin dose was escalated to AUC 6. Two of 3 patients treated in level 2 had grade 4 thrombocytopenia of DLT. MTD was determined as level 2. Consequently, pemetrexed 500 mg/m2 with carboplatin AUC 5 was recommended as the dose for elderly patients with advanced non-squamous NSCLC. An additional 7 patients who received RD showed no DLT. Nine of 13 patients received 4 cycles of combination therapy, and 5 patients were continuously treated with pemetrexed maintenance therapy. Six patients achieved a partial response, and another 6 showed stable disease. The response rate and disease control rate were 46.2％ and 92.3％, respectively. The median progression-free survival for the enrolled patients was 134 days （95％ CI, 95 to 231 days）, and the median overall survival was 346 days （95％ CI, 151 to 549 days）.Conclusions：The combination therapy of pemetrexed 500 mg/m2 with carboplatin AUC 5 followed by pemetrexed maintenance therapy showed no severe adverse events and was feasible and well-tolerated for elderly patients with advanced non-squamous NSCLC