Fukuoka-shi, Japan
Fukuoka-shi, Japan

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Ishida T.,Nagoya City University | Hishizawa M.,Kyoto University | Kato K.,Kyushu University | Kato K.,Red Cross | And 15 more authors.
Blood | Year: 2012

Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study ofATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL. © 2012 by The American Society of Hematology.

Nishimura J.-I.,Osaka University | Yamamoto M.,Osaka University | Hayashi S.,Tokyo Medical and Dental University | Ohyashiki K.,Tokyo Medical University | And 19 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear. METHODS: We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients. RESULTS: Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G→A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C→T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. CONCLUSIONS: The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.) Copyright © 2014 Massachusetts Medical Society.

Furusyo N.,Kyushu University | Ogawa E.,Kyushu University | Nakamuta M.,National Hospital Organization | Kajiwara E.,Steel Memorial Yawata Hospital | And 10 more authors.
Journal of Hepatology | Year: 2013

Background & Aims This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. Methods This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ≤60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. Results The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p = 0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p <0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≥100 g/L, to 85 - <100 g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p = 0.0006). Conclusions TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Ogawa E.,Kyushu University | Furusyo N.,Kyushu University | Nakamuta M.,National Hospital Organization | Kajiwara E.,Steel Memorial Yawata Hospital | And 10 more authors.
Journal of Hepatology | Year: 2013

Background & Aims Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy. Methods This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb) <85 g/L. Results 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb <135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m2 (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281). Conclusions Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Ogawa E.,Kyushu University | Furusyo N.,Kyushu University | Kajiwara E.,Steel Memorial Yawata Hospital | Takahashi K.,Hamanomachi Hospital | And 10 more authors.
Journal of Hepatology | Year: 2013

Background & Aims: The effects of pegylated interferon (PegIFN) α and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNα2b and RBV. Methods: This large-scale, prospective, multicenter study consisted of 1013 Japanese chronic hepatitis C patients with no history of HCC (non-cirrhosis, n = 863 and cirrhosis, n = 150). All patients were treated with PegIFNα2b and RBV and the follow-up period started at the end of the antiviral treatment (median observation period of 3.6 years). The cumulative incidence rate of HCC was estimated using the Kaplan-Meier method, according to treatment outcome. Results: Forty-seven patients (4.6%) developed HCC during the observation period. In the non-cirrhosis group, the 5-year cumulative incidence rates of HCC for the sustained virological response (SVR) (1.7%) and transient virological response (3.2%) (TVR: defined as relapse or breakthrough) groups were significantly lower than those of the non-virological response (NVR) group (7.6%) (p = 0.003 and p = 0.03, respectively). A significantly low rate of incidence of HCC by TVR patients in comparison with NVR patients was found for patients aged 60 years and over, but not for those under 60 years of age. In the cirrhosis group, the 5-year cumulative incidence rates of HCC for the SVR (18.9%) and TVR groups (20.8%) were also significantly lower than those of the NVR group (39.4%) (p = 0.03 and p = 0.04, respectively). Conclusions: SVR and complete viral suppression during treatment with relapse (TVR) were associated with a lower risk of HCC development when compared with NVR.

Ogawa E.,Kyushu University | Furusyo N.,Kyushu University | Nakamuta M.,National Hospital Organization | Kajiwara E.,Steel Memorial Yawata Hospital | And 10 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. Aim To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. Methods This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin (RBV). Results The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNα2b (≥1.2 μg/kg/week) and RBV (≥7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. Conclusions The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment-naïve and prior relapse. © 2013 John Wiley & Sons Ltd.

Odate S.,Kyushu University | Nakamura K.,Kyushu University | Onishi H.,Kyushu University | Kojima M.,Red Cross | And 5 more authors.
Lung Cancer | Year: 2013

Tropomyosin-related kinase B (TrkB) plays an important role in tumor progression in various kinds of cancers; however, little is known about biological significance of TrkB in human lung cancer, especially large cell neuroendocrine carcinoma (LCNEC). We hereby investigated the expressions of TrkB and its ligand brain-derived neurotrophic factor (BDNF) in clinical specimens and their influences on phenotypes of invasiveness and tumorigenicity for LCNEC. The expressions of TrkB and BDNF analyzed by immunohistochemistry for patients samples with lung cancer (n=104) were significantly higher in neuroendocrine tumor (NET) compared with non-NET. In particular, LCNEC, a subtype of NET, exhibited significantly higher TrkB and BDNF expressions than another NET type: small cell lung cancer (SCLC), and a significant correlation between TrkB and BDNF expressions was noted in LCNEC but not in SCLC. In vitro assay, exogenous BDNF addition enhanced the invasion into matrigels of LCNEC cells, whereas inhibition of TrkB or BDNF suppressed matrix metalloproteinase-2 and -9 activities and the invasiveness. Exogenous BDNF also increased anchor-independent colony formation on soft agar gels for LCNEC, while inhibition of TrkB or BDNF suppressed the anchorage-independency. In vivo experiments, implanted LCNEC cells pretreated with TrkB-siRNA developed no subcutaneous tumor in all six nude mice, although those with control-siRNA formed tumors in four of six nude mice. In conclusion, BDNF/TrkB signal is involved in malignant progression of invasiveness and tumorigenicity for LCNEC, and may be a potential target for LCNEC without standard therapy. © 2012 Elsevier Ireland Ltd.

Kikushige Y.,Kyushu University | Ishikawa F.,Kyushu University | Ishikawa F.,RIKEN | Miyamoto T.,Kyushu University | And 11 more authors.
Cancer Cell | Year: 2011

We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors. © 2011 Elsevier Inc.

Segawa Y.,Hamanomachi Hospital | Yasumatsu R.,Kyushu University | Shiratsuchi H.,Hamanomachi Hospital | Tamae A.,Hamanomachi Hospital | And 3 more authors.
Auris Nasus Larynx | Year: 2014

Background: Inflammatory pseudotumor (IPT) is a tumefactive lesion characterized by fibroblastic proliferations and a prominent inflammatory component. It behaves as a locally benign or aggressive lesion, clinically and radiologically mimicking a neoplastic process. Numerous entities can be diagnosed as IPT, from reactive lesions to true neoplasms. The diagnosis of IPT requires further elaboration, and IPT should be distinguished from other similar entities such as inflammatory myofibroblastic tumor and IgG4-related sclerosing disease. Case summary: We report two cases of IPT arising from the head and neck region. One occurred at the orbit and the other at the parapharyngeal space. Histologically, they showed aggregates of myofibroblasts and inflammatory cells. Immunohistochemically, the number of IgG4-positive cells was less than 40% of the number of IgG positive cells, and the myofibroblastic cells were negative for anaplastic lymphoma kinase. The diagnosis was IPT/not otherwise specified. One patient was treated by systemic administration of corticosteroid and had good response. The other, who was treated by local administration of corticosteroid, partially responded and is currently stable with limited disease. Discussion: IPT has been reported to occur in various anatomical sites, most commonly in the lungs. The incidence in the head and neck area is extremely rare. Treatment of IPT is controversial and may involve corticosteroids or surgical resection, or both. Other chemotherapeutic agents and radiotherapy may be considered in steroid-resistant patients. The pathological subtype, safety of resection, and safety of corticosteroid use must be included in the decision-making process for treatment. © 2013 Elsevier Ireland Ltd.

Tamae A.,Hamanomachi Hospital | Komune S.,Kyushu University
The Journal of laryngology and otology | Year: 2015

MATERIALS AND METHODS: We used an artificial dermis (Terdermis), which is an atero-collagen sponge covered with a sheet of silicon.PATIENTS: Nineteen ears of 17 patients with perforation of the tympanic membrane under various conditions, including large and wet perforations, underwent operation using this collagen sponge.RESULTS: The success rate of closure after the initial surgery was 8/19. The overall success rate of closure after initial and re-operation was 14/19. The success rate of closure was 12/14 for small-sized perforations, 1/4 for middle-sized perforations and 1/1 for a large-sized perforation. Middle- and large-sized perforations required multiple surgeries. The success rate of closure was 11/11 for dry perforations, 3/4 for perforations with light otorrhoea and 0/4 for perforations with extensive otorrhoea.CONCLUSION: This surgery is a low-cost and minimally invasive surgery and has a high closure rate. This surgery is effective on small-sized, dry perforations although it can also close middle- and large-sized dry perforations.

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