Mizuta S.,Fujita Health University Hospital |
Matsuo K.,Kyushu University |
Nishiwaki S.,Nagoya University |
Imai K.,Sapporo Hokuyu Hospital |
And 13 more authors.
Blood | Year: 2014
We aimed to evaluate the impact of pretransplant imatinib administration on the outcome of allogeneic hematopoietic stem cell transplantation(allo-HSCT) in adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We retrospectively analyzed 738 patients with Ph+ ALL that underwent allo-HSCT between 1990 and 2010 using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We compared the allo-HSCT outcomes between 542 patients who received imatinib before allo-HSCT during the initial complete remission period (imatinib cohort) and 196 patients who did not receive imatinib (non-imatinib cohort). The 5-year overall survival after allo-HSCT was significantly higher in the imatinib cohort than in the non-imatinib cohort (59% vs 38%; 95% confidence interval [CI], 31-45%; P < .001). Multivariate analysis indicated that pretransplant imatinib administration had beneficial effects on overall survival (hazardratio [HR], 0.57; 95%CI, 0.42-0.77; P < .001), relapse (HR, 0.66; 95% CI, 0.43-0.99; P = .048), and nonrelapse mortality (HR, 0.55; 95% CI, 0.37-0.83; P = .005). In conclusion, our study showed that imatinib administration before allo-HSCT had advantageous effects on the clinical outcomes of allo-HSCT in patients with Ph+ ALL. © 2014 by The American Society of Hematology.
Kaneko K.,Tohoku University |
Furuyama K.,Tohoku University |
Furuyama K.,Iwate University |
Fujiwara T.,Tohoku University |
And 4 more authors.
Haematologica | Year: 2014
Erythroid-specific 5-aminolevulinate synthase (ALAS2) is the rate-limiting enzyme for heme biosynthesis in erythroid cells, and a missense mutation of the ALAS2 gene is associated with congenital sideroblastic anemia. However, the gene responsible for this form of anemia remains unclear in about 40% of patients. Here, we identify a novel erythroid-specific enhancer of 130 base pairs in the first intron of the ALAS2 gene. The newly identified enhancer contains a cis-acting element that is bound by the erythroid-specific transcription factor GATA1, as confirmed by chromatin immunoprecipitation analysis in vivo and by electrophoretic mobility shift assay in vitro. A promoter activity assay in K562 human erythroleukemia cells revealed that the presence of this 130-base pair region increased the promoter activity of the ALAS2 gene by 10-15-fold. Importantly, two mutations, each of which disrupts the GATA-binding site in the enhancer, were identified in unrelated male patients with congenital sideroblastic anemia, and the lower expression level of ALAS2 mRNA in bone marrow erythroblasts was confirmed in one of these patients. Moreover, GATA1 failed to bind to each mutant sequence at the GATA-binding site, and each mutation abolished the enhancer function on ALAS2 promoter activity in K562 cells. Thus, a mutation at the GATA-binding site in this enhancer may cause congenital sideroblastic anemia. These results suggest that the newly identified intronic enhancer is essential for the expression of the ALAS2 gene in erythroid cells. We propose that the 130-base pair enhancer region located in the first intron of the ALAS2 gene should be examined in patients with congenital sideroblastic anemia in whom the gene responsible is unknown. © 2013 Ferrata Storti Foundation.
Miyatake Y.,Hokkaido University |
Miyatake Y.,University College Dublin |
Oliveira A.L.A.,University College Dublin |
Oliveira A.L.A.,ICON Central Laboratories |
And 6 more authors.
American Journal of Pathology | Year: 2013
Adult T-cell leukemia/lymphoma (ATL) is a highly invasive and intractable T-cell malignancy caused by human T-cell leukemia virus-1 infection. We demonstrate herein that normal tissue-derived epithelial cells (NECs) exert protective effects on the survival of leukemic cells, which may partially account for high resistance to antileukemic therapies in patients with ATL. Viral gene-silenced, ATL-derived cell lines (ATL cells) dramatically escaped from histone deacetylase inhibitor-induced apoptosis by direct co-culture with NECs. Adhesions to NECs suppressed p21Cip1 expression and increased a proportion of resting G0/G1 phase cells in trichostatin A (TSA)-treated ATL cells. ATL cells adhering to NECs down-regulated CD25 expression and enhanced vimentin expression, suggesting that most ATL cells acquired a quiescent state by cell-cell interactions with NECs. ATL cells adhering to NECs displayed highly elevated expression of the cancer stem cell marker CD44. Blockade of CD44 signaling diminished the NEC-conferred resistance of ATL cells to TSA-induced apoptosis. Co-culture with NECs also suppressed the expression of NKG2D ligands on TSA-treated ATL cells, resulting in decreased natural killer cell-mediated cytotoxicity. Combined evidence suggests that interactions with normal epithelial cells augment the resistance of ATL cells to TSA-induced apoptosis and facilitate immune evasion by ATL cells. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Kukita K.,Sapporo Hokuyu Hospital
Journal of Vascular Access | Year: 2015
Introduction: The Japanese Society for Dialysis Access (JSDA) has held the practical skills trainings for the doctors working for the vascular access (VA) access since 2014 in order to improve both quality and quantity of the VA construction. Terumo Medical Pranex (Kanagawa, Japan) is the institution of the general medical training established for the creation and the spread of medical technique, and it also has the hybrid simulator of VA. Methods and results: In the training institute in 2014, not only the practical skills but also the training on the simulator from the basic lecture of VA construction were conducted. The dummy of a radical artery and a cephalic vein is faked in the forearm on the simulator. Two carotid arteries of a pig are made as the position of a pair of artery and vein. The pig’s skin taken from the neck to the chest is covered on the proceed part, then the dummy forearm was completed. We can make recognize the beats in the artery. We also can make a fake avf in the dummy forearm instead. The instructor is directly able to give the trainees the lectures while watching the scenes. jsda will continue to make such efforts from now. Conclusions: We are concerned that the more the VA access would be demanded, the more the VA construction would be needed. So, the matter of the urgency is the training of the doctors working for VA construction. © 2015 Wichtig Publishing.
Kishimoto K.,Sapporo Hokuyu Hospital
Journal of Pediatric Hematology/Oncology | Year: 2015
Hyponatremia is the most common electrolyte abnormality in hospitalized patients. The objective of this study was to identify risk factors for hyponatremia during chemotherapy in children. A total of 111 consecutive pediatric patients (age, 0 to 18 y) with hematological malignancy (n=87) or solid tumor (n=24) who received chemotherapy in our hospital between 2010 and 2014 were enrolled. The number of chemotherapy cycles reviewed was 472, with a median of 3 (range, 1 to 8) per patient. Hyponatremia was defined as a serum sodium level of <135 mmol/L. Hyponatremia was observed in 80 of 111 (72%) patients, and 138 of 472 (29%) cycles. Neurological sequelae were seen in 2 of 111 (2%) patients, and 2 of 472 (0.4%) cycles. Multivariate logistic regression identified age 10 to 18 years (odds ratio [OR]=3.24, 95% confidence interval [CI], 2.07-5.07), total parenteral nutrition (OR=8.15, 95% CI, 2.17-30.5), first or second chemotherapy cycle (OR=1.74, 95% CI, 1.12-2.70) as independent risk factors for hyponatremia. Clinical conditions of patients and chemotherapeutic agents may have a profound impact on the development of hyponatremia. Patients with these factors should be managed carefully to prevent severe symptoms and sequelae caused by hyponatremia. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Mori M.,Yokohama City University |
Kobayashi R.,Sapporo Hokuyu Hospital |
Kato K.,Red Cross |
Maeda N.,National Hospital Organization Nagoya Medical Center |
And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015
The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-tooral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and ≥50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC0-12,ss) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC0-12,ss values for the intravenous and oral regimens were 51.1 μg • h/ml (68%) and 45.8 μg • h/ml (90%), respectively; there was a high correlation between AUC0-12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.) Copyright © 2015 American Society for Microbiology. All Rights Reserved.
Sano H.,Sapporo Hokuyu Hospital |
Kobayashi R.,Sapporo Hokuyu Hospital |
Iguchi A.,Hokkaido University |
Suzuki D.,Sapporo Hokuyu Hospital |
And 3 more authors.
Bone Marrow Transplantation | Year: 2014
Idiopathic pneumonia syndrome (IPS) is a critical complication following allogeneic hematopoietic SCT (HSCT); however, few reports have analyzed the risk factors for IPS in children. A total of 210 consecutive pediatric patients, including 131 boys and 79 girls, with various hematologic malignancies, aplastic anemia or solid tumors who underwent allogeneic HSCT were analyzed to clarify the incidence and risk factors for IPS. Patient and transplantation characteristics after allogeneic HSCT were compared between patients with and without IPS. Cumulative incidence rates of IPS 120 days after allogeneic HSCT were 6.7% (14/210). Of 14 patients with IPS, 11 (78.6%) died after developing IPS. The presence of prior HSCT was more frequent in patients with IPS (IPS group) than in those without IPS (non-IPS group; 35.7 vs 12.8%, respectively, P=0.018). The IPS group contained more patients with acute GVHD (grade II-IV) than the non-IPS group (50.0 vs 18.9%, respectively, P=0.006). The association of these two factors with IPS was further confirmed by multivariate analysis. We should be aware of these risk factors in patients who have undergone allogeneic HSCT.
Imamura M.,Sapporo Hokuyu Hospital |
Shigematsu A.,Sapporo Hokuyu Hospital
Experimental Hematology and Oncology | Year: 2015
The outcomes of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) are unsatisfactory. Therefore, allogeneic (allo) HSCT has been applied to those patients in first complete remission (CR1), and has shown a long-term survival rate of approximately 50%. In terms of myeloablative conditioning (MAC) regimen, higher dose of cyclophosphamide (CY) and total body irradiation (TBI) (the standard CY+TBI) has been generally applied to allo HSCT. Other MAC regimens such as busulfan-based or etoposide-based regimens have also been used. Among those, medium-dose etoposide (ETP) in addition to the standard CY+TBI conditioning regimen appears to be promising for allo HSCT in adult ALL when transplanted in ALL patients aged under 50years in CR1 and also in CR2, showing an excellent outcome without increasing relapse or transplant-related mortality (TRM) rates. By contrast, reduced-intensity conditioning (RIC) regimens have also been applied to adult ALL patients and favorable outcomes have been obtained; however, relapse and TRM rates remain high. Therefore, an allo HSCT conditioning regimen which deserves further study for adult ALL patients aged under 50years in CR1 and CR2 appears to be medium-dose ETP+CY+TBI and RIC is suitable for patients aged over 50years or for younger patients with comorbid conditions. On the contrary, new therapeutic strategies for adult ALL patients are increasingly utilized with better outcomes; namely, various tyrosine kinase inhibitors for Philadelphia chromosome (Ph)-positive ALL, human leukocyte antigen-haploidentical HSCT, and pediatric-inspired regimens for Ph-negative ALL. Therefore, the optimal treatment modality should be selected considering patient's age, Ph-positivity, donor availability, risk classification, efficacy, and safety. © 2015 Imamura and Shigematsu.
Kunishima S.,National Hospital Organization Nagoya Medical Center |
Okuno Y.,University of Tokyo |
Okuno Y.,Nagoya University |
Yoshida K.,University of Tokyo |
And 17 more authors.
American Journal of Human Genetics | Year: 2013
Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP. © 2013 The American Society of Human Genetics.
Iguchi A.,Hokkaido University |
Kobayashi R.,Sapporo Hokuyu Hospital |
Kaneda M.,Hokkaido University |
Kobayashi K.,Sapporo Hokuyu Hospital
Pediatric Blood and Cancer | Year: 2010
Background. Hepatic veno-occlusive disease (VOD) is one of the most serious complications in stem cell transplantation (SCT). Although plasma protein C activity decreases in VOD after SCT, the timeframe of plasma protein C activity decreases during SCT is not known. Procedure. We examined levels of plasma protein C serially during the course of SCT to determine the critical level and risk factors for VOD. Results. Of 151 children who received SCT, 12 of them (7.9%) developed VOD. The mean minimum protein C activity in patients with VOD was significantly lower compared to that in patients without VOD (P<0.0001). Receiver operating characteristic curve analysis revealed that the critical plasma protein C activity (cut-off point) for VOD was identified to be 34.5% with high sensitivity (100%) and specificity (83.3%), and the reduction of plasma protein C below the cut-off level (day +6.50±2.43) was observed mostly prior to the onset of VOD (day +7.33±2.64). The patients receiving melphalan in conditioning were found to be at high risk for VOD (P=0.003). Among the melphalan containing regimens, melphalan+carboplatin+etoposide was a significant risk factor for depression of plasma protein C (P=0.037). Conclusion. Plasma protein C level was a useful parameter of VOD after SCT, and activity below 34.5% was critical for VOD. The use of melphalan in conditioning causes a high risk for VOD. © 2009 Wiley-Liss, Inc.