Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

Interpretable AI Explores Effective Components of CAD/CAM Resin Composites.

High flexural strength of computer-aided manufacturing resin composite blocks (CAD/CAM RCBs) are required in clinical scenarios. However, the conventional in vitro approach of modifying materials' composition by trial and error was not efficient to explore the effective components that contribute to the flexural strength. Machine learning (ML) is a powerful tool to achieve the above goals. Therefore, the aim of this study was to develop ML models to predict the flexural strength of CAD/CAM RCBs and explore the components that affect flexural strength as the first step. The composition of 12 commercially available products and flexural strength were collected from the manufacturers and literature. The initial data consisted of 16 attributes and 12 samples. Considering that the input data for each sample were recognized as a multidimensional vector, a fluctuation range of 0.1 was proposed for each vector and the number of samples was augmented to 120. Regression algorithms-that is, random forest (RF), extra trees, gradient boosting decision tree, light gradient boosting machine, and extreme gradient boosting-were used to develop 5 ML models to predict flexural strength. An exhaustive search and feature importance analysis were conducted to analyze the effective components that affected flexural strength. The R2 values for each model were 0.947, 0.997, 0.998, 0.983, and 0.927, respectively. The relative errors of all the algorithms were within 15%. Among the high predicted flexural strength group in the exhaustive search, urethane dimethacrylate was contained in all compositions. Filler content and triethylene glycol dimethacrylate were the top 2 features predicted by all models in the feature importance analysis. ZrSiO4 was the third important feature for all models, except the RF model. The ML models established in this study successfully predicted the flexural strength of CAD/CAM RCBs and identified the effective components that affected flexural strength based on the available data set.

Correlation between magnesium pre-loading and cisplatin-induced nephrotoxicity in 5-fluorouracil/cisplatin combination therapy for esophageal cancer.

The use of cisplatin may cause nephrotoxicity in patients. Hydration solutions supplemented with magnesium could reduce cisplatin-induced nephrotoxicity. In this study, we evaluated the preventive effect of magnesium pre-loading on cisplatin-induced nephrotoxicity in patients with esophageal cancer. We retrospectively evaluated the prevalence of, and risk factors for, nephrotoxicity in 160 patients with esophageal cancer treated with the 5-fluorouracil/cisplatin regimen from 2014 to 2016 with and without magnesium supplementation. Significant differences were observed between the magnesium and non-magnesium groups in terms of frequency of estimated creatinine clearance of grade 2 or higher that was at 4% (n = 3) and 13% (n = 10) (p = 0.027), respectively. The logistic regression analysis revealed that eCcr of grade 2 or higher was significantly associated with the non-magnesium regimen (odds ratio (OR), 4.175; 95% confidence interval (CI) = 1.061-16.430; p = 0.041) and age ≥ 65 years (OR, 13.951; 95% CI = 1.723-112.974; p = 0.014). This study suggests that 20 mEq magnesium pre-loading significantly reduces the prevalence of cisplatin-induced nephrotoxicity. Furthermore, when cisplatin is administered to individuals older than 64 years, a close observation for the onset of cisplatin-induced nephrotoxicity is crucial.

Longitudinal changes in life-space mobility and the factors influencing it among chronic community-dwelling post-stroke patients.

PURPOSE: To identify longitudinal changes in life-space mobility and the factors influencing it among chronic, stable post-stroke patients. MATERIALS AND METHODS: This prospective study included Japanese post-stroke patients who received day-care rehabilitation services and could undergo three life-space mobility assessments (at baseline, 12, and 24 months) for over 2 years, using the Life-Space Assessment (LSA) tool. Physical function, cognitive function, and activities of daily living were assessed by self-selected comfortable gait speed, Mini-Mental State Examination (MMSE), and Functional Independence Measure Motor subscale (FIM motor) scores, respectively, in addition to age, sex, time from onset, stroke type, and comorbidities. A multivariable linear mixed-effects model was used to examine the longitudinal changes in LSA scores and associated factors. RESULTS: A total of 89 participants were enrolled. At baseline, the median age was 74 years, 33% were women, and median time from onset was 75 months. The LSA scores significantly declined over the two-year period. In the multivariate linear mixed-effects model adjusted for clinical characteristics, comfortable gait speed and age were significantly associated with changes in the LSA score, independent of FIM motor scores and MMSE scores. CONCLUSIONS: Life-space mobility may persistently decline, and gait function may be a determinant influencing these changes in community-dwelling chronic post-stroke patients.Implications for RehabilitationLimited life-space mobility leads to less frequent participation in social activities and an increased risk of adverse health outcomes such as hospitalization.Changes in life-space mobility should be considered in the rehabilitation care plan for chronic post-stroke patients.Life-space mobility may decline persistently in stable post-stroke patients, even if they have periodically received day-care rehabilitation services.Since gait speed is a predominant factor affecting life-space mobility, regular assessment of gait function and appropriate strategies are needed to prevent deterioration of gait speed in chronic post-stroke patients.

A novel clinical prognostic index for patients with advanced gastric cancer: possible contribution to the continuum of care.

BACKGROUND: The Japan Clinical Oncology Group (JCOG) prognostic index, consisting of performance status, primary tumor resected, number of metastases, and serum alkaline phosphatase, has been one of the robust prognostic indices for patients with advanced gastric cancer on the basis of which clinical trials have stratified prognosis. Only a few studies, however, have utilized the JCOG prognostic index in daily practice. METHODS: We conducted a retrospective study on patients with advanced gastric cancer who received first-line platinum-containing chemotherapy at a single institute between 2011 and 2017. Prognostic factors were evaluated using a Cox proportional regression model. RESULTS: A total of 608 patients were enrolled. Multivariate analysis showed that performance status ≥1, presence or absence of primary tumor, serum alkaline phosphatase, neutrophil-to-lymphocyte ratio ≥4, and diffuse-type histology were significantly associated with worse prognosis, whereas the number of metastases was not. Although the original prognostic index could not adequately stratify patients into three risk groups, the modified index (good: 0 and 1, moderate: 2 and 3, poor: 4-6), which was established by incorporating diffuse-type histology and high neutrophil-to-lymphocyte ratio, demonstrated excellent stratification. The median overall survival of the good (n = 315), moderate (n = 243), and poor (n = 54) risk groups was 20.5, 13.5, and 10.2 months, respectively. Hazard ratios (HRs) were 1.69 [95% confidence interval (CI), 1.40-2.04; good versus moderate] and 1.52 (95% CI, 1.11-2.08; moderate versus poor). This novel index also demonstrated a statistically significant stratification of survival after progression following first-line chemotherapy (good versus moderate: HR, 1.41; 95% CI, 1.16-1.70; moderate versus poor: HR, 2.00; 95% CI, 1.45-2.74). CONCLUSIONS: The modified JCOG prognostic index showed excellent stratification of overall survival in real-world patients, which could also help determine the need for treatment changes throughout the continuum of chemotherapy.

Comparison of Hospitalization and Death Frequencies in Influenza Outpatients Treated with Baloxavir marboxil or Neuraminidase Inhibitors： an Observational Database Study / 薬剤疫学

Aim/Objective：Baloxavir marboxil (baloxavir) is an anti-influenza drug with a novel mechanism of action. The objective of this study is to compare the frequency of hospitalization and death in outpatients treated by baloxavir with other anti-influenza drugs, neuraminidase inhibitors.Study design：Cohort studyMethod：Using a Japanese acute hospital-based claims database, we identified outpatients with age≥1 years old who had the starting date of influenza medical care (Day 1) during the 2018-2019 influenza season. According to the anti-influenza drug prescribed on Day 1, the patients were divided into baloxavir group and three controls； oseltamivir group, zanamivir group, and laninamivir group. We calculated the proportion of hospitalization which occurred during Day 2 to Day 14 and estimated odds ratio (OR) and 95％ confidence intervals (CIs) by adjusting imbalanced age among drugs. In addition, we calculated the proportion of in-hospital death.Results：The proportion of hospitalization in patients with baloxavir (1.37％ (223/16,309)) was comparable with that in oseltamivir (1.37％ (655/47,843)), and slightly greater than that in zanamivir (0.77％ (19/2,474)) and laninamivir (0.91％ (234/25,831)). Age-adjusted OR (vs baloxavir, as denominator) and 95％ CIs was 1.125［0.961-1.317], 1.173［0.726-1.897］and 0.944［0.783-1.140］for oseltamivir, zanamivir and laninamivir, respectively. In addition, the proportion of death in patients with baloxavir (0.03％, n＝5) was comparable with that in oseltamivir (0.03％, n＝16), laninamivir (0.01％, n＝3), while there were no deaths in zanamivir due to the small number of patients.Conclusion：In an observational study of Japanese acute hospital-based claims database, the frequency of severe events in influenza outpatients was comparable with that in other treatment groups, supporting that baloxavir may help prevent severe influenza as a new treatment option.

Comparison of Hospitalization and Death Frequencies in Influenza Outpatients Treated with Baloxavir marboxil or Neuraminidase Inhibitors： an Observational Database Study / 薬剤疫学

Aim/Objective：Baloxavir marboxil (baloxavir) is an anti-influenza drug with a novel mechanism of action. The objective of this study is to compare the frequency of hospitalization and death in outpatients treated by baloxavir with other anti-influenza drugs, neuraminidase inhibitors.Study design：Cohort studyMethod：Using a Japanese acute hospital-based claims database, we identified outpatients with age≥1 years old who had the starting date of influenza medical care (Day 1) during the 2018-2019 influenza season. According to the anti-influenza drug prescribed on Day 1, the patients were divided into baloxavir group and three controls； oseltamivir group, zanamivir group, and laninamivir group. We calculated the proportion of hospitalization which occurred during Day 2 to Day 14 and estimated odds ratio (OR) and 95％ confidence intervals (CIs) by adjusting imbalanced age among drugs. In addition, we calculated the proportion of in-hospital death.Results：The proportion of hospitalization in patients with baloxavir (1.37％ (223/16,309)) was comparable with that in oseltamivir (1.37％ (655/47,843)), and slightly greater than that in zanamivir (0.77％ (19/2,474)) and laninamivir (0.91％ (234/25,831)). Age-adjusted OR (vs baloxavir, as denominator) and 95％ CIs was 1.125［0.961-1.317], 1.173［0.726-1.897］and 0.944［0.783-1.140］for oseltamivir, zanamivir and laninamivir, respectively. In addition, the proportion of death in patients with baloxavir (0.03％, n＝5) was comparable with that in oseltamivir (0.03％, n＝16), laninamivir (0.01％, n＝3), while there were no deaths in zanamivir due to the small number of patients.Conclusion：In an observational study of Japanese acute hospital-based claims database, the frequency of severe events in influenza outpatients was comparable with that in other treatment groups, supporting that baloxavir may help prevent severe influenza as a new treatment option.

Azathioprine-induced Agranulocytosis and Severe Alopecia After Kidney Transplantation Associated With a NUDT15 Polymorphism: A Case Report.

BACKGROUND: Azathioprine (AZA) is the drug recommended for the continuation of immunosuppressive treatment after renal transplant in women during pregnancy. CASE REPORT: A 37-year-old Japanese female developed agranulocytosis and severe alopecia after initiation of AZA (50 mg), used as an alternative to mycophenolate mofetil (MMF, 1000 mg) therapy in anticipation of a planned pregnancy. Within 4 days of the initiation of AZA therapy, the patient developed a high fever, leucopenia, and cranial alopecia. Genetic testing revealed a homozygous polymorphism of NUDT15 (rs116855232, NM_018283.3:c.415C>T: p.Arg139Cys), which has previously been identified as a risk factor for AZA-related complications in patients with inflammatory bowel disease. CONCLUSION: Genetic screening for NUDT15 could contribute to the prevention of serious adverse reactions to AZA and provide the opportunity for personalized medicine. Identification of a safe alternative to MMF during pregnancy after a renal transplant is a problem to be resolved in the future.

Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) ≥3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus. Patients and methods: Patients with high-risk (IPI ≥3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety. Results: Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0-76.9). Overall, 47% of patients were ≥65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69-1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7-82.1) with everolimus and 77.0% (95% CI 72.1-81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes. Conclusions: Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained. ClinicalTrials.gov: NCT00790036.

Failure of neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma.

Neoadjuvant treatment has become standard care for patients with resectable esophageal cancer. However, some patients cannot undergo surgery or curative resection because of disease progression during neoadjuvant treatment. The aim of this study is to identify the pretreatment characteristics of patients in whom neoadjuvant treatment failed. The study enrolled 231 patients who underwent chemotherapy with cisplatin and 5-fluorouracil (CF) as neoadjuvant therapy for T1N1-3 or T2-3 any-N esophageal squamous cell carcinoma (ESCC). Of these patients, 201 (87.0%) underwent curative resection (R0) and 30 (13.0%) could not undergo curative resection; 19 patients (8.2%) underwent incomplete resection (R1 or R2), and 11 patients (4.8%) could not undergo surgery because of disease progression. We compared clinical characteristics and survival between patients who underwent curative resection (curative group) and those who could not undergo curative resection (noncurative group) to determine the factors predicting noncurative treatment. The noncurative group had significantly worse disease-specific survival than the curative group (P < 0.001). All patients in the noncurative group had cT3 tumors. In 141 patients with cT3 tumors, those in the noncurative group were more likely to have higher serum SCC antigen concentration (P = 0.021), location of the main tumor in the upper to the middle third of the esophagus (P = 0.071), intramural metastases (P < 0.001), advanced N category (P = 0.016), and bulky lymph node metastases (P = 0.060). Multivariate logistic regression analysis identified location of the main tumor in the upper to the middle third of the esophagus (P = 0.047), intramural metastases (P = 0.002), and nodal metastases (N1, P = 0.014; N2, P = 0.015, respectively) as independent predictors of treatment failure in patients with cT3 tumors. Neoadjuvant CF therapy alone may not be effective for patients with cT3 tumors accompanied by these risk factors, and the efficacy of alternative strategies, such as triplet chemotherapy or chemoradiotherapy, should be evaluated.

Near-field correction in the first-principles calculations by the exact two-center expansion for the inverse of the distance.

We propose a method to deal with the so-called near-field corrections to the solution of the Poisson equation for full-potential first-principles calculations using the exact two-center expansion for the inverse of the distance between two points. It is demonstrated that the method gives a very satisfying solution to the Poisson equation for plane-wave charge densities which can be solved analytically. The present method gives reasonable total energy for lattice distortions where the conventional multipole expansion gives large errors.

The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation.

Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The blockade of transcription factors has been a central part of T cell-depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein-1 (AP-1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP-1 inhibition are available. In this study, we investigated the immunosuppressive effects of T-5224, a c-Fos/AP-1-selective inhibitor, on murine T cells activated by αCD3+αCD28 mAbs. T-5224 inhibited proliferation, CD25 up-regulation, and the production of IL-2 and interferon-γ. In addition, T-5224 blocked the nuclear translocation of c-Fos/AP-1 in activated murine T cells. In BALB/c (H-2(d) )-to-C57BL/6J (H-2(b) ) mouse PIT, the 2-week administration of T-5224 prolonged survival of 600 islet allografts in a dose-dependent manner. When combined with a 2-week low-dose tacrolimus, the T-5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c-Fos/AP-1 inhibition by T-5224 is a potentially attractive strategy for allogeneic PIT.

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL).

BACKGROUND: Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. PATIENTS AND METHODS: A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. RESULTS: None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.

ASKP1240, a fully human anti-CD40 monoclonal antibody, prolongs pancreatic islet allograft survival in nonhuman primates.

A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti-CD154 monoclonal antibodies (mAbs). Previously, we demonstrated that ASKP1240, which is a fully human anti-CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201-12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n = 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n = 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post-PITx 6 months (maintenance treatment, n = 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both anti-donor cellular responses and development of anti-donor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PITx.

Acute neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease.

WHAT IS KNOWN AND OBJECTIVE: Febuxostat is a new non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricaemia in patients with gout. Febuxostat is recommended as the first-line pharmacologic urate-lowering therapy for gout in the American College of Rheumatology guidelines. Febuxostat has not been reported to cause severe complications, especially haematological abnormalities. Our objective is to report two cases of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease (CKD). CASE SUMMARY: A 74-year-old woman with liver cirrhosis and CKD was treated with febuxostat for hyperuricaemia during hospitalization. Eleven days after febuxostat administration, she developed neutropenia. A 68-year-old man with type 2 diabetes mellitus on intermittent haemodialysis was treated with febuxostat for hyperuricaemia during hospitalization. Three days after febuxostat administration, he developed neutropenia. In the two cases, febuxostat treatment was discontinued and granulocyte colony-stimulating factor was administered, with concomitant recovery of the neutrophil count. WHAT IS NEW AND CONCLUSION: We believe this to be the first published case of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia. According to the Naranjo probability scale, febuxostat was the probable cause of neutropenia. In view of the wide clinical usage of this drug, physicians and pharmacists should be alerted to this possible complication.

Efficacy and safety of switching from basal insulin to sitagliptin in Japanese type 2 diabetes patients.

Basal-supported oral therapy (BOT) is often used to treat poorly controlled type 2 diabetes. However, patients sometimes experience nocturnal and early morning hypoglycemia. Thus, maintaining targeted glycemic control by BOT is limited in some patients. We assessed the efficacy and safety of replacing basal insulin by sitagliptin therapy in Japanese type 2 diabetes patients on BOT. Forty-nine subjects were sequentially recruited for the 52-week, prospective, single arm study. Patients on BOT therapy were switched from basal insulin to sitagliptin. The primary endpoint was change in HbA1c in 52 weeks. The secondary endpoints were dropout rate, changes in body weight, frequency of hypoglycemia, and relationship between change in HbA1c and insulin secretion capacity evaluated by glucagon loading test. The average dose of basal insulin was 15.0±8.4 units. Sixteen subjects (31.3%) were dropped because replacement by sitagliptin was less effective for glycemic control. In these subjects, diabetes duration was longer, FPG and HbA1c at baseline were higher, and insulin secretion capacity was lower. Change in HbA1c in 52 weeks was - 4 mmol/mol (95% CI - 5 to - 4 mmol/mol) (p<0.05). Change in body weight was - 0.71 kg (95% CI - 1.42 to - 0.004 kg) (p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month. HbA1c level was improved if C-peptide index (CPI) was over 1.19. In conclusion, basal insulin in BOT can be replaced by sitagliptin with a decrease in HbA1c level and frequency of hypoglycemia in cases where insulin secretion capacity was sufficiently preserved.

First-principles KKR-CPA calculation of the magnetic and transport properties of La1-xXxMnO3 (X = Ca, Sr).

Electrical transport properties of (La(1-x)X(x))MnO(3) (X = Ca, Sr), which exhibits the so-called colossal magnetoresistance (CMR) effect, are investigated in the framework of linear response theory combined with first-principles calculation. The calculation is performed by applying the coherent potential approximation and Kubo-Greenwood formula to the KKR Green's function method. In order to reveal the mechanism that underlies the CMR effects, the dc conductivities of the system in A (layered)-, C (stripe)-, and G (111)-type antiferromagnetic states as well as the local moment disordered state are calculated as a function of x. It is found that the conductivity of the system strongly depends on the magnetic structure and is highly anisotropic in the cases of A- and C-type antiferromagnetic structures. Also, it is concluded that a drastic change in the conductivity is expected when the system undergoes a magnetic transition, and that this might be closely related to the observed CMR effect. It is pointed out that, for such a drastic change in the conductivity to occur associated with the magnetic transition, the half-metallic nature of the Mn local electronic structure must be essential.