ALBERT

Description: The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases have been shown in solid tumors and considered to associate with aneuploidy and carcinogenesis. This study found that Aurora kinase A and B were aberrantly expressed in human leukemia cell lines (n=15, e.g., PALL-1, -2, HL-60, NB4, MV4-11, etc.) as well as freshly isolated leukemia cells from individuals with acute myeloid leukemia (n=44) compared to peripheral blood mononuclear cells from healthy volunteers (n=12), as measured by real-time PCR. In addition, ZM447439, a novel selective Aurora kinase inhibitor, induced growth inhibition, accumulation of cells with 4N DNA content and apoptosis in human leukemia cells as measured by thymidine-uptake, cell cycle analysis and annexin V staining, respectively. Especially, profound growth inhibition occurred in PALL-1 and -2 cells which possess wild-type p53 gene. Of note, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy volunteers. Taken together, inhibition of Aurora kinase may be a promising treatment strategy for the individuals with leukemia.

Description: Recombinant human soluble thrombomodulin (rTM) comprises the active, extracellular domain of thrombomodulin (TM), and inactivates coagulation by binding to thrombin. In addition, the thrombin-rTM complex activates protein C to produce activated protein C (APC), which inactivates factors VIIIa and Va in the presence of protein S, further inhibiting thrombin formation. The use of rTM for the treatment of DIC was approved in Japan in in 2008, and since then it has proved effective in individuals with DIC complicated by a variety of underling diseases including sepsis and acute leukemia. Of note, rTM possesses anti-inflammatory and cytoprotective effects and the use of rTM successfully rescued individuals with sinusoidal obstruction syndrome, engraftment syndrome and transplantation-associated microangiopathy complicated by hematopoietic stem cell transplantation (HSCT). The present study retrospectively investigated whether the use of rTM improved the clinical outcome of individuals who received HSCT in our institution. From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed coagulopathy in association with various underlying conditions. The patients who developed coagulopathy after 2008 (n=23) were treated by rTM, and the others (n=11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment of coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (p=0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy. Disclosures: No relevant conflicts of interest to declare.

Description: Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.

Description: Abstract 1079 Recombinant human soluble thrombomodulin (rTM) is composed of the active, extracellular domain of thrombomodulin, and inactivates coagulation by binding to thrombin. In addition, the thrombin-rTM complex activates protein C to produce activated protein C (APC), which in the presence of protein S, inactivates factors VIIIa and Va, thereby inhibiting further thrombin formation. Use of rTM for treatment of disseminated intravascular coagulation (DIC) associated with haematological malignancies or infections has been approved in Japan, although its effects on hyperfibrinolysis caused by acute promyelocytic leukemia (APL), as well as all-trans retinoic acid (ATRA)-mediated anti-fibrinolytic activity, remain to be fully elucidated. This study examined the effects of rTM on the plasmin activity in APL NB4 cells in vitro and found that rTM (100 nM, 48 h) alone inhibited the plasmin activity by approximately 35% when compared to the control diluent-treated NB4 cells. ATRA (100 nM, 48 h) also inhibited the plasmin activity by 40%, and when ATRA (100 nM, 48 h) was combined with rTM (100 nM, 48 h), the plasmin activity was inhibited by 60%. In further studies, neither anti-proliferative nor pro-differentiative activity was noted in NB4 cells after exposure to rTM (3-100 nM, 48 h). However, rTM significantly enhanced the ability of ATRA to induce growth arrest, differentiation and apoptosis in NB4 cells, as measured by colony forming assay, quantification of CD11b cell surface antigens and nitroblue tetrazolium reduction test, respectively. Western blot analyses showed that ATRA (30 or 100 nM, 48 h) increased nuclear levels of CCAAT/enhancer binding protein e in NB4 cells, a critical transcription factor for myeloid differentiation, which was further increased in the presence of rTM (3-100 nM, 48 h). Furthermore, we treated individuals with DIC caused by APL (n=4) with rTM (380 U/kg) in combination with ATRA (45 mg/m2) and chemotherapy (idarbicine and cytarabine), and compared their clinical outcomes with historical control patients (n=6) treated with ATRA and/or chemotherapy (idarbicine and cytarabine). Notably, treatment with rTM rescued patients from DIC earlier than historical controls (8.3 ± 4.5 days vs 12.5 ± 5.2 days in historical controls) and significantly reduced the transfusion of fresh frozen plasma to maintain plasma levels of fibrinogen at more that 150 mg/dl (0.13 ± 0.25 U/day vs 3.93 ± 1.18 U/day in historical control, p=0.0131). Taken together, the present results suggest that administration of rTM be considered in the treatment of individuals with DIC associated with APL. Disclosures: Honda: Asahi Kasei Pharma: Employment.

Description: Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFRα/β). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G0/G1 cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFRα fusion gene. Ki11502 decreased levels of p-PDGFRα and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRαT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation.

Description: Background: Recent advance in genetic analysis has revealed that many mutations are associated with the development, progression and/or prognosis of core-binding factor acute myeloid leukemia (CBF-AML). Although KIT mutation is the most frequently identified in CBF-AML, its prognostic relevance remains controversial. We conducted the prospective, multicenter cooperative study (JALSG CBF-AML209-KIT, UMIN Clinical Trials Registry UMIN000003434, http://www.umin.ac.jp/ctr/) to evaluate the prognostic impact of KIT mutation, the incidence and clinical relevance of the other gene mutations and prognostic impact of the minimal residual disease (MRD) in CBF-AML. Methods: A total of 199 patients 16 to 64 years of age with newly diagnosed de novo AML were enrolled in this study if they had a RUNX1-RUNX1T1 or CBFB-MYH11 chimeric transcript and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received 3 courses of high-dose cytarabine therapy (2 g/m2 by 3-hour infusion every 12 hours for 5 days) and no further chemotherapy until relapse. MRD level was evaluated in BM after the completion of the 3-course of consolidation therapy by the quantitation of RUNX1-RUNX1T or CBFB-MYH11 transcript in 112 patients. Target sequencing of 56 genes frequently identified in myeloid malignancies including exons 8, 10, 11 and 17 of the KIT gene were analyzed using the preserved DNA extracted from AML cells at diagnosis. Results: A total of 68 KIT mutations were identified in 63 of 199 patients (31.7%); 42 of 132 (31.8%) and 21 of 67 (31.3%) patients with RUNX1-RUNX1T1 and CBFB-MYH11, respectively. Mutation in exon 17 was the most frequently identified (73.5%), followed by in exon 8 (20.6%) and in exon 10-11 (5.9%). Mutation in exon 8 was more frequent in AML with CBFB-MYH11 (37.5%) than that with RUNX1-RUNX1T1 (11.4%, P=0.014). Although mutation at N822 residue in exon 17 was identified in 13/44 (29.5%) KIT mutations of the patients with RUNX1-RUNX1T1, no patient with CBFB-MYH11 had this mutation (P=0.008); however, mutation at the D816 residue was equally identified in patients with RUNX1-RUNX1T1 (21/44, 47.7%) and CBFB-MYH11 (13/24, 54.1%). The median BM blast percentage of the KIT mutation positive-patients (73.5%) was significantly higher than that of negative-patients (53.8%, P

Description: The addition of rituximab to the CHOP (R-CHOP) regimen has had a dramatic impact on therapy of B-NHL. To clarify the effect of rituximab plus CHOP, we conducted a retrospective multicenter analysis to compare clinical outcomes of R-CHOP and CHOP in Japanese patients with diffuse large B cell lymphoma (DLBCL). Between 1/2000 and 6/2005, unselected 293 Japanese patients with DLBCL recruited from 13 institution, received CHOP with or without rituximab as the first line therapy. CHOP or R-CHOP was given 3 courses following radiotherapy for localized, and 6–8 courses for advanced disease. Rituximab was given at 375 mg/m2 concurrently with each course. The median age of total patients was 68 (range 26–99). After median follow-up of 21 months, PFS at 1, 2 year was 70.7% (95% confidence interval [CI]; 64.9–75.8), 59.1%(95%CI;64.9–75.8), respectively. Ninety-six patients received rituximab in combination with CHOP and 197 patients received CHOP alone. No statistically significantly differences of clinical characteristics such as sex, age and international prognostic index (IPI) were documented between two groups. The median follow-up for living patients was 15 and 28 months for R-CHOP and CHOP, respectively. In multivariate analysis, R-CHOP therapy significantly reduced the risk of treatment failure (hazard ratio [HR] 0.62; 95%CI 0.40–0.96, p=0.033), although the risk of death was similar in both group (HR0.78; 95%CI 0.44–1.37, p=0.38). In conclusion, in this multicenter analysis, R-CHOP therapy prolongs progression-free survival in Japanese DLBCL patients. There was a trend to better OS with rituximab than without rituximab at 2-year, however, this was not statistically significant. Longer follow-up will be required to assess the effect rituximab plus CHOP on survival. Retrospective comparison of R-CHOP versus CHOP R-CHOP (n=96) CHOP(n=197) P HR 95%CI PFS;progression free survival, OS;overall survival, HR;hazard ratio, CI;confidence interval. PFS(2yr) 62.9% 57.2% 0.033 0.62 0.40–0.96 OS(2yr) 77.5% 70.4% 0.38 0.78 0.44–1.37

Description: We studied anti-tumor effects of the class III receptor tyrosine kinase inhibitor SU11248 against a wide variety of hematological malignancies including the following leukemias: acute myeloid (THP-1, U937, Kasumi-1, MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, -2), blast crisis of chronic myeloid (KU812, Kcl-22, K562) and adult T-cell (MT-1, -2, -4), as well as, non-Hodgkin’s lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine-uptake studies showed that SU11248 was active against MV4-11 and Kasumi-1 cells which possessed activating mutations of the FLT-3 and the c-Kit gene, respectively, with IC50s of approximately 30 nM. In addition, SU11248 inhibited the proliferation of Bcr/Abl-expressing KU812, Kcl-22, K562, PALL-1, and -2 cells with IC50s ranging from 2 to 5 uM. SU11248 induced apoptosis of these cells via activation of caspase 3 as measured by Annexin V staining and caspase assay. SU11248 inhibited phosphorylation of c-Abl and its downstream effectors Akt and STAT5 in these cells. Interestingly, mTOR inhibitor rapamycin enhanced the ability of SU11248 to inhibit the proliferation of Bcr/Abl-expressing cells. For example, SU11248 (2 uM, 48 h) or rapamycin (100 nM, 48 h) alone inhibited the proliferation of KU812 cells by 47 ± 6 % or 8 ± 6 %, respectively. When both were combined, their proliferation was inhibited by approximately 90 %. Furthermore, SU11248 (10 nM to 1 uM, 48 h) inhibited the proliferation of freshly-isolated leukemia cells from individuals with AML (15 cases) as well as Ph-positive ALL (1 case), who relapsed after treatment with conventional chemotherapy with imatinib. Profound growth inhibition by SU11248 (IC50s

Description: Background: Acute myeloid leukemias with KMT2A (formerly known as MLL-1) fusion genes (MLL-AML) and those with NPM1 mutations (NPM1-AML) are distinct subtypes as defined by the WHO classification. Although they have different clinical features and prognostic impact , recent studies suggest that the MLL1 co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). New targeted strategies for these AML subtypes are expected as preliminary data suggest that menin-MLL1 inhibition may inhibit malignancy. In addition to classical chromosomal analysis and prefixed fusion gene screening, next-generation sequencing (NGS) should help in identifying the precise prevalence of these alterations and understanding the relationship with other pathological mutations. We launched the HM-SCREEN-JAPAN01 study (UMIN000035233) in which gene alterations are analyzed by FoundationOne Heme® in patients with AML who are relapsed/refractory to, or ineligible for standard therapies. Aiming for 200 registrations, recruitment has reached approximately 100. The interim results are described here. Methods: HM-SCREEN-JAPAN01 is an observational study and conducted by 17 participating institutions. The eligibility criteria are as follows: 1) histological diagnosis of AML must be made by bone marrow testing; 2) one of the following conditions must be fulfilled: i) a patient with newly diagnosed AML and is ineligible for standard treatment, or ii) a patient with AML who has relapsed or is refractory to prior therapy; 3) sufficient amount of bone marrow sample must be available; 4) age at registration must be 20 or more; and 5) written informed consent must be taken. All samples were analyzed by FoundationOne Heme®. Results:Nine patients (9.9%) with MLL-AML and seventeen patients (18.7%) with NPM1-AML were found among 91 available cases (either one found in 28.6%). No patients demonstrated MLL-rearrangement and NPM1-mutation simultaneously. Median age of patients with MLL-AML (42-68 y) was a decade less than that of patients with NPM1-AML (55-74 y), and the majority of cases had a clinical relapse or were refractory to prior therapies. Translocations involving chromosome 11q23.3 (e.g. t(9;11)(p21.3;q23.3)) were found in 5 of 8 patients (62.5%) with MLL-AML (data not available due to insufficient cell count in one case) and no chromosomal abnormalities were detected in 10 of 16 patients (62.5%) with NPM1-AML (chromosomal analysis was not performed in one case). In patients with MLL-AML (see Figure), FLT3 mutations were found in 3 of 9 cases (33.3%), all of which were point mutations within the tyrosine kinase domain (FLT3-TKD). PTPN11 mutations were also found simultaneously in these three cases. Co-existing NRAS and TP53 mutations with high allele-frequency (32-50%) were also seen in two different cases. A targetable mutation of IDH2 was seen in one patient (11.1%) who had an FLT3 mutation with low allele-frequency (2%). In patients with NPM1-AML (see Figure), allele-frequency of mutated NPM1 ranged from 10 to 44%. Relatively common co-existing mutations were TET2 (7 of 17; 41.2%), DNMT3A (9 of 17; 52.9%), and FLT3 (9 of 17; 52.9%). Unlike in MLL-AML patients, all FLT3 alterations were internal tandem duplication (FLT-ITD) with one case of dual FLT3-ITD and -TKD mutation. IDH1 and IDH2 mutations were found in two (11.8%) and four (23.5%) separate cases, respectively. A rare fusion gene ETV6-NTRK3 (one of primary targets of NTRK inhibitors) was detected in one patient (5.9%) who had IDH1 mutation with moderate allele-frequency (17%). Conclusion: MLL-rearrangements and NPM1-mutations were found in approximately a quarter of the 91 AML patient (mostly relapsed or refractory) bone marrow samples analyzed. These alterations appeared to be mutually exclusive. FLT3 alterations were seen in a third of the MLL-AML cases and half of the NPM1-AML cases, seemingly more frequent than that previously reported. Interestingly, FLT3-TKDs were dominant in MLL-AML cases, whereas NPM1-AML cases carried FLT3-ITD. IDH1 and IDH2 mutations commonly co-existed in both groups. This HM-SCREEN-Japan01 study is now recruiting patients, and a further understanding of genomic distribution and correlation is expected. Figure Disclosures Yamauchi: Otsuka:Research Funding;Astellas:Research Funding;Daiichi Sankyo:Research Funding;Chugai:Honoraria;Pfizer:Honoraria, Research Funding;Abbie:Research Funding;Solasia Pharma:Research Funding;Ono Pharmaceutical:Honoraria.Shibayama:AstraZeneca:Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria;Pfizer:Honoraria;Fujimoto:Honoraria;Janssen:Honoraria, Research Funding;Teijin:Research Funding;Novartis:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Daiichi Sankyo:Honoraria;Chugai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Sumitomo Dainippon:Honoraria, Research Funding;Merck Sharp & Dohme:Research Funding;Shionogi:Research Funding;Astellas:Research Funding;Taiho:Research Funding;Otsuka:Honoraria;Bristol-Myers Squibb:Honoraria;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Eisai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Kyowa Kirin:Honoraria;Ono:Honoraria, Research Funding;Mundi Pharma:Honoraria.Yamamoto:Stemline Therapeutics:Consultancy;Meiji Seika Pharma:Consultancy, Honoraria;MSD:Consultancy, Honoraria, Research Funding;Chugai:Consultancy, Honoraria, Research Funding;Eisai:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy;IQIVA/HUYA:Honoraria;HUYA:Consultancy;IQIVA/Incyte:Research Funding;Mundipharma:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria;Mochida:Honoraria;Gilead Sciences:Research Funding;Solasia Pharma:Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Novartis:Honoraria, Research Funding;Ono:Consultancy, Honoraria, Research Funding;Aichi Cancer Center:Current Employment;AbbVie:Consultancy, Honoraria, Research Funding;Astra-Zeneca:Consultancy, Research Funding;Bayer:Research Funding;Bristol-Myers Squibb:Honoraria;Celgene:Consultancy, Honoraria, Research Funding;Zenyaku:Research Funding;Takeda:Consultancy, Honoraria, Research Funding;Yakult:Research Funding;SymBio:Research Funding;Pfizer:Honoraria;Otsuka:Consultancy, Honoraria, Research Funding;Sanofi:Honoraria;Sumitomo Dainippon:Honoraria;Janssen:Honoraria.Fujishima:Pfizer:Speakers Bureau.Takahashi:Pfizer Japan Inc.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria, Research Funding;Bristol-Myers Squibb Company:Honoraria.Usuki:Alexion:Speakers Bureau;Pfizer:Research Funding;Nippon Boehringer Ingelheim:Research Funding;Mundipharma:Research Funding;Astellas-Amgen-Biopharma:Research Funding;Nippon shinyaku:Research Funding, Speakers Bureau;Eisai:Speakers Bureau;MSD:Speakers Bureau;Takeda:Speakers Bureau;PharmaEssentia:Speakers Bureau;Yakult:Speakers Bureau;Symbio:Research Funding, Speakers Bureau;Daiichi Sankyo:Research Funding, Speakers Bureau;Sumitomo Dainippon:Research Funding;Otsuka:Research Funding, Speakers Bureau;Novartis:Research Funding, Speakers Bureau;Brisol-Myers Squibb:Research Funding, Speakers Bureau;Kyowa Kirin:Research Funding, Speakers Bureau;Ono:Research Funding, Speakers Bureau;Janssen:Research Funding;Celgene:Research Funding, Speakers Bureau;Takeda:Research Funding;Astellas:Research Funding, Speakers Bureau;Abbvie:Research Funding;Gilead:Research Funding.Ono:Celgene:Honoraria, Research Funding;Kyowa Kirin Co., Ltd.:Honoraria, Research Funding;Chugai Pharmaceutical Co., Ltd.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria;Mundipharma K.K.:Honoraria;TAIHO PHARMACEUTICAL CO., LTD.:Research Funding;Eisai Co., Ltd.:Honoraria;Otsuka Pharmaceutical Co., Ltd.:Honoraria;Astellas Pharma Inc.:Honoraria;Bristol-Myers Squibb Company:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda Pharmaceutical Company Limited.:Honoraria;ONO PHARMACEUTICAL CO., LTD.:Honoraria, Research Funding;DAIICHI SANKYO COMPANY, LIMITED.:Honoraria;Janssen Pharmaceutical K.K:Honoraria.Kuroda:Daiichi Sankyo:Honoraria, Research Funding;Pfizer:Honoraria, Research Funding;Sysmex:Research Funding;Janssen Pharmaceutical K.K:Consultancy;Eisai:Honoraria, Research Funding;Sanofi:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria, Research Funding;Otsuka Pharmaceutical:Honoraria, Research Funding;Ono Pharmaceutical:Honoraria, Research Funding;Abbvie:Consultancy, Honoraria;MSD:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Dainippon Sumitomo Pharma:Honoraria, Research Funding;Chugai Pharmaceutical:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Bristol-MyersSquibb:Consultancy, Honoraria, Research Funding;Astellas Pharma:Honoraria, Research Funding;Fujimoto Pharmaceutical:Honoraria, Research Funding;Taiho Pharmaceutical:Research Funding;Asahi Kasei:Research Funding;Shionogi:Research Funding;Nippon Shinyaku:Honoraria, Research Funding.Ishitsuka:Celgene:Other: Personal Fees;Kyowa Hakko Kirin:Other: Personal fees, Research Funding;BMS:Other: Personal fees;Chugai Pharmaceutical:Other: Personal fees, Research Funding;Takeda:Other: Personal fees, Research Funding;mundiharma:Other: Personal fees;Taiho Pharmaceuticals:Other: Personal fees, Research Funding;Janssen Pharmaceuticals:Other: Personal fees;Novartis:Other: Personal fees;Pfizer:Other: Personal fees;Astellas Pharma:Other, Research Funding;Genzyme:Other;Sumitomo Dainippon Pharma:Other, Research Funding;Eisai:Other, Research Funding;Mochida:Other, Research Funding;Shire:Other;Otsuka Pharmaceutical:Other;Ono Pharmaceutical:Other, Research Funding;Teijin Pharma:Research Funding;MSD:Research Funding;Asahi kasei:Research Funding;Eli Lilly:Research Funding;Daiichi Sankyo:Other;Huya Japan:Other.Minami:Bristol-Myers Squibb Company:Honoraria;Novartis Pharma KK:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda:Honoraria.