Rituximab is widely used for the treatment of B‐cell non‐Hodgkin's lymphoma (NHL), and encouraging results have been obtained. However, some CD20‐positive NHL show minimal response to rituximab, ...indicating that the treatment effect depends on the presence or absence of an unidentified factor. We analyzed the relationship between the effect of rituximab plus chemotherapy and expression of Ki‐67, p53 and bcl‐2 and several clinical variables in cases of B‐NHL, particularly follicular lymphoma (FL) and diffuse large B‐cell lymphoma (DLBCL). Forty‐four patients were included in the present study, and the overall treatment response rate was 68%. Twelve of 30 patients (40%) achieved a complete response, five (16%) reached an unconfirmed complete response and 13 (43%) achieved a partial response. A high serum lactate dehydrogenase level and International Prognostic Index of high or high intermediate risk were associated with a decreased response in the case of FL. Immunohistochemical assays were performed in 18 FL patients (55%) and 15 DLBCL patients (45%). Significant correlation was found between an inferior response to treatment and high Ki‐67 expression in the cases of FL (P = 0.006). p53 and bcl‐2 expression did not correlate significantly with the response rate. The cell cycle appears to be an important factor in the efficacy of rituximab treatment. Ki‐67 expression might be a predictor of efficacy of rituximab plus chemotherapy.
Many medical institutions have recently conducted studies on the relationship between patients with hematopoietic neoplasms and oral cavity. Statistical analysis of the bacterial populations was ...performed in this study to identify how oral microflora and health conditions （e.g., dental caries and periodontal diseases） affect the prognosis of patients with hematopoietic neoplasms. Patients undergoing inpatient treatment from January to December 2020 at the Department of Hematology at Showa University, Japan, who required perioperative oral management were included in the study. The oral health of the patients was examined at the initial dental visit, and oral bacterial samples were collected from the tongue, buccal mucosa, and palate of 47 patients who consented to participate after receiving an explanation about the study. Statistical analyses performed after dividing the subjects into two groups following the treatment course showed that Stenotrophomonas maltophilia and Gemella sanguinis were significantly more common in the poor-course group. However, no significant difference in bacterial examination results was noted among the four groups （myeloid neoplasm chemotherapy, myeloid neoplasm hematopoietic stem cell transplantation （HSCT）, lymphoid neoplasm chemotherapy, and lymphoid neoplasm HSCT groups） classified based on disease and treatment method. The detection rate of bacteria potentially causing infectious diseases at the initial dental examination tended to be higher in this study in the poor-course group. The findings of the current study suggest that early detection of pathogenic bacteria after commencing hematology treatment could predict the poor-course that may lead to mortality or severe infections.
To study hematopoietic reconstitution in umbilical cord blood transplantation (CBT), bone marrow (BM) histology was investigated in 35 biopsies after bone marrow transplantation (BMT) and in 40 ...biopsies after CBT. BM biopsies were obtained at different times after transplantation and were evaluated for cellularity, number of megakaryocytes and CD34‐positive cells, and fibrosis. In biopsies up to 29 days after BMT, cellularity was increased and megakaryocytes were observed, but at 29 days after CBT, biopsies showed severe cellular depletion and almost no megakaryocytes. In addition, fewer CD34‐positive cells were observed after CBT compared to after BMT. After day 30 after CBT, hematopoietic recovery of the BM was gradually observed and after day 100 after transplantation, no essential differences were observed between BMT and CBT. Hematopoietic recovery of the BM after CBT was delayed compared to that after BMT, but engraftment of donor cells after CBT was also observed in histopathologically. To the best of the authors' knowledge this is the first histopathological description of BM reconstitution after CBT.
Introduction
Approximately 70%-90% patients receiving hematopoietic stem-cell transplantation (HSCT) have oral mucositis (OM). HSCT-induced OM is a major complication of preparative regimens. The ...oral cavity of healthy individuals harbor several bacterial species. For example, the cheek and tongue harbor a number of Streptococcus species, while the predominant genera in the saliva are Prevotella, Streptococcus, and Veillonella. The resident flora are considered to be deeply linked with OM because they prevent colonization by exogenous organisms having pathogenic potential for local and systemic infections. However, the precise bacterial substitution occurring in HSCT patients with OM remains unclear. Here, we prospectively examined oral bacterial flora changes using VITEK MSTM (SYSMEX bioMérieux Co., Ltd., Tokyo, Japan)-an automated mass spectrometry (MS) microbial-identification system using matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) technology. It can detect about 650 bacterial and 105 fungal species. We aimed to determine whether oral microbial in HSCT can be detected by VITEK MSTM.
Patient and Methods
This prospective study included 16 patients (10 males, 6 females; median age 52 years) who underwent HSCT for hematological malignancies (auto-PBSCT = 3 patients, allo-PBSCT = 3 patients, CBT = 10 patients; preparative regimen: MAC = 11 patients, RIC = 2 patients, auto = 3 patients) in our hospital between December 2015 and July 2016. All were treated in reverse isolation in a laminar airflow-equipped room and received drugs to prevent bacterial, fungal, and herpes virus infection. We used VITEK MS for analyzing oral bacterial flora. OM was diagnosed according to NCICTCAE v4.0 and WHO scale, and oral health was assessed using the Revised Oral Assessment Guide (ROAG). Microbial samples were obtained using swabs from bilateral buccal mucosa, palate, and tongue. Samples were then incubated at 37‹C for 72-96 hours both aerobically and anaerobically. Finally, VITEK MS was used to identify bacterial species in samples. We evaluated the patients before initiating preparative regimen (1st), day −1 before HSCT (2nd), 7 days after HSCT (3rd), 14 days after HSCT (4th), and 30 days after HSCT (5th).
Results
The percentage of patients with high-grade OM (CTCAE Grade 2-5, and WHO Grade 1-4) increased in days 7-14 and decreased at day 30 (Table). Total bacterial species numbers gradually decreased from days -1 through to 30. Many Streptococcus sp could be detected at the 1st or 2nd time point, but these speciesgradually decreased and were replaced with coagulase-negative staphylococci (CNS; Staphylococcus epidermidis in 10 patients, S. haemolyticus in 5 patients, S. lentus in 3 patients, andS. warneri in 3 patients). Before HSCT, Prevotella sp and Veillonella sp in the oral flora were detected in 10 and 9 patients, respectively. However, by 14 days after HSCT, Prevotella sp and Veillonella sp were isolated less often than other points. Candida sp was detected only after the preparative regimen.
Discussion and Conclusion
This is the first prospective study to demonstrate microbial substitution in oral bacterial spices in HSCT patients using VITEK MS. VITEK MS allowed for the reliable identification of clinically relevant bacteria. We found that the oral bacterial species changed from Streptococcus sp, Prevotella sp, or Veillonella sp to CNS or Candida sp after HSCT. Our results suggest that oral microbial substitution possibly underlies high-grade OM after HSCT. We also suspect that microbial substitution is partly modified by antibiotics, considering that all study patients were treated with antimicrobial agents (including beta-lactam antibiotics). Indeed, the presence of many beta-lactam sensitive Streptococcus sp decreased, whereas that of beta-lactam resistant strains (CNS and Candida sp)increased. Finally, this study involved a small and heterogeneous patient population with varying characteristics. Therefore, our results require confirmation in a larger number of patients over a longer period.
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Hironaka:MEXT Supported Program for the Strategic Research Foundation at Private Universities: Research Funding.
•Red cell distribution width (RDW) in MDS might reflect dyserythropoiesis.•The hemoglobin concentration was inversely correlated with RDW.•The percentage of ringed sideroblasts in bone marrow was ...correlated with RDW.•Increased RDW might have potential to be a prognostic factor in low-risk MDS.
Studies showed red cell distribution width (RDW) can improve the detection of morphological changes in red blood cells and the understanding of their contribution to dyserythropoiesis in myelodysplastic syndrome (MDS). The purpose of the study was to evaluate dyserythropoiesis in MDS by RDW analysis and to explore the utility of RDW in clinical practice. We retrospectively analyzed laboratory and clinical data of 101 patients (59 patients was refractory anemia (RA) according to the French-American-British (FAB) classification). In patients with RA, RDW was showed weak inverse correlation with both hemoglobin concentration (Hb) (rs = −0.37, P = 0.0035) and mean corpuscular hemoglobin concentration (MCHC) (rs = −0.36, P = 0.0047). On the other hand, RDW was showed weak correlation with the number of ringed sideroblasts in bone marrow (rs = 0.31, P = 0.023). The increased RDW (≥15.0%) was associated with shorter overall survival (OS) (P = 0.0086). In patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-t), effect of RDW on OS was less evident. These results suggested that increased RDW might reflect dyserythropoiesis, associated with deregulated hemoglobin synthesis and iron metabolism in MDS. Furthermore, increased RDW may have potential to be a prognostic significance in RA.
Introduction:
Immune thrombocytopenic purpura (ITP) is an acquired autoimmune disorder, which is characterized by megakaryocyte (MgK) inhibition/destruction in the bone marrow (BM) and/or platelet in ...the spleen and liver. Abnormal MgKs, which is recognized by autoantibodies, are phagocytosed by macrophages. Recently, it has been demonstrated that interleukin-(IL-)17-mediated cells contribute to the imbalance of cellular immunity in the pathogenesis of ITP. Studies of pathological findings in BM of patients with ITP using immunohistochemistry (IHC) are limited. Therefore, we examined samples of BM clots to test the hypothesis that IL-17-mediated immunological changes are involved in the BM of patients with ITP.
Methods:
We enrolled 35 patients with a median age of 61 years (range, 19-91 years), who were retrospectively selected at random and were referred to our hospital between 2005 and 2016. All patients were diagnosed with chronic ITP. Twenty-five patients underwent first- or second-line therapies such as glucocorticosteroids, cyclosporine A, azathioprine, danazol and intravenous immunoglobulin and/or splenectomy as conventional therapies. Twenty-three patients who could not undergo those therapies were administered with eltrombopag. BM clots were obtained before treatment and stained with hematoxylin and eosin for morphological examination. Formalin-fixed and paraffin-embedded specimens were used for IHC using antibodies for the following markers: CD3, CD4, CD8, CD20 (L26), CD25, CD68, CD163, and IL-17. Pathological findings and clinical information including laboratory data were compared between the patients with ITP and control subjects, which were obtained from 11 untreated malignant lymphoma patients without the infiltration of lymphoma cells in BM. We also compared those between 2 groups: an IL-17-high-expression group and IL-17-low-expression group.
Results:
A univariate analysis revealed increased cells expressing the following markers in patients with ITP than in the control subjects: CD20 (5.80 ± 3.46% vs. 3.06 ± 1.90%; p= 0.02), CD68 (11.3 ± 11.1% vs. 3.14 ± 3.23%; p= 0.02), CD163 (5.10 ± 2.74% vs. 2.13 ± 1.10%; p= 0.001), and IL-17 (3.13 ± 1.48% vs. 1.49 ± 1.00%; p= 0.002) and decreased cells expressing following markers: CD4 (0.33 ± 0.71% vs. 1.96 ± 1.13%; p < 0.0001) and CD25 (0.09 ± 0.18% vs. 0.23 ± 0.10%; p= 0.01). The difference of cells expressing CD3 (p= 0.96) and CD8 (p= 0.41) were not statistically significant. There were significant correlations between CD68 and CD163 expressions (r= 0.61). The expressions of both CD68 and CD163 showed correlations with IL-17 expressions (r= 0.61, 0.51). We found significant increased expressions of CD3 (3.98 ± 2.96% vs. 6.37 ± 3.33%; p= 0.03), CD25 (0.05 ± 0.08% vs. 0.17 ± 0.22%; p= 0.03), CD68 (7.84 ± 5.09% vs. 17.3 ± 15.6%; p= 0.01), and CD163 (4.23 ± 2.37% vs. 6.57 ± 2.77%; p= 0.01) in the IL-17-high-expression group (N = 13) compared with IL-17-low-expression group (N = 22). The expressions of CD4 (p= 0.98), CD8 (p= 0.54), and CD20 (p= 0.85) were not statistically significant. Responses to eltrombopag were significantly better in the IL-17-low-expression group than in the IL-17-high-expression group (p= 0.03).
Conclusions:
By IHC analysis, we report for the first time increased CD68- and/or CD163-expressing cells in the BM of patients with ITP. Those are possibly associated with the pathogenesis of ITP. Our results indicate that CD68- and/or CD163-expressing macrophages and monocytes, but not lymphocytes are involved in deregulated expression of IL-17 in ITP. We demonstrate that the response of eltrombopag is significantly better in the IL-17-low-expression group. These results indicate that patients with ITP, achieving remission early, might belong to the category of the low-IL-17, CD68, and CD163 expressions. We suggest that IHC staining in patients with ITP may be a potential indicator to understand the mechanism of ITP and to predict the prognosis for treatment.
No relevant conflicts of interest to declare.
MYD88 L265P mutation causes constitutive activation of NF-κB and possible driver mutation in B-cell lymphoid malignancies. It is frequently detected in Waldenstrom’s macroglobulinemia （WM） ...（50％-100％）, and its detection is important in diagnostic and therapeutic targets of this syndrome. Standard detection method of MYD88 L265P mutation in clinical practice has yet to be established. We developed semi-nested PCR-based restriction fragment length polymorphism （snPCR-RFLP） to detect the mutation. The snPCR-RFLP method is a modification of the PCR-RFLP method, which uses the restriction enzyme BsiEI that recognizes CGACT/CG, intending to increase detection sensitivity by amplification of mutated allele in the DNA sample using semi-nested PCR before enzyme digestion. The detection sensitivity of snPCR-RFLP was estimated as 0.1％, by detecting mutated allele in wild-type allele in the cloned plasmid DNA, which is comparable with allele-specific （AS） PCR method widely used as sensitive detection method. By analyzing 40 cases with IgM monoclonal gammopathy, snPCR-RFLP detected 29/40 （70％） of all cases, 22/31 （70.9％） of WM, and 6/9 （66.6%） of IgM-type monoclonal gammopathy with undetermined significance （IgMMGUS）, including five cases （three cases of WM and two cases of IgMMGUS） in which the mutation was detected only by snPCR-RFLP but not by Sanger sequencing method. Regarding DNA sample status, particularly five cases, a case was extracted from formalin-fixed paraffin-embedded tissue and four cases were extracted from cells by Ficoll-Hypaque density gradient. In correlation with clinical features, the MYD88 mutation detected by snPCR-RFLP method was associated with the adverse prognostic index （WMIPSS） of WM using patient age, hemoglobin （Hb） level, platelet count, β2MG level, and serum IgM level （p＝0.055）. The snPCR-RFLP method is a clinically useful MYD88 mutation detection method that can be performed in general laboratories.
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Background: Treatment-free remission (TFR) is a new treatment goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) with a sustained deep molecular response (DMR) by treatment ...with tyrosine kinase inhibitors (TKI). Although several guidelines have proposed clinical factors for successful TFR, they are based primarily on evidence with imatinib. Since 2 nd-generation TKI (2G-TKI) achieves a molecular response faster than imatinib, it may lead to TFR in a shorter treatment period. The multicenter phase II study D-FREE (Japan Registry of Clinical Trials: jRCTs031180332) was conducted to clarify optimal conditions for TFR in newly diagnosed patients with CML-CP treated with the 2G-TKI dasatinib.
Methods: Newly diagnosed CML-CP patients were enrolled and treated with dasatinib in the induction phase. When patients achieved MR4.5 (BCR-ABL1 IS ≤0.0032%) based on assessment every three months during the induction phase for up to two years, they immediately entered the consolidation phase, where dasatinib is administered for 12 months. Patients with sustained MR4.5 throughout the consolidation phase discontinued dasatinib in the stop phase. Dasatinib was re-administered at molecular relapse, defined as loss of a major molecular response (BCR-ABL1 IS > 0.1%) or confirmed loss of MR4 (BCR-ABL1 IS > 0.01% on two consecutive assessments). The primary endpoint was the proportion of patients in TFR who showed no molecular relapse and did not need to resume dasatinib 12 months after treatment discontinuation.
Results: Between July 2016 and May 2019, 181 patients with newly diagnosed CP-CML were enrolled in 41 centers in Japan. Four patients were excluded after screening, and no further information was available for 4 patients. Overall, 173 patients received study treatment. The median patient age was 54 years (18-83 years). The rates of Sokal low-, intermediate-, and high-risk groups were 28.6, 52.4, and 19.0%, respectively. The rates of EUTOS low- and high-risk groups were 81.0 and 19.0%, respectively. Of the 123 patients who completed the induction phase, 60 (48.8%) achieved MR4.5 for up to two years (median: 7.7 months, range: 3.0-21.1 months) and entered the consolidation phase. Single and multivariate analyses showed that the achievement of MMR at 3 months, but not sex, Sokal risk score, Hasford risk score, EUTOS risk score, or age (<60 vs. ≥60), was predictive of the achievement of MR4.5 within 2 years. During the consolidation phase, 15 patients could not sustain MR4.5 and finished study treatment. Among the first 21 patients who could sustain MR4.5 for 12 months and discontinued dasatinib treatment in the stop phase, 17 experienced molecular relapse within 12 months (median: 3.5 months, range: 2.0-6.4). In those patients, the median duration of dasatinib treatment was 18.9 months (range: 14.9-25.5) before the cessation of dasatinib. The study was terminated prematurely on December 3, 2019, based on the pre-specified interim analysis criterion that it would be stopped if the TFR rate was less than 25% in the first 20 patients of the stop phase. At termination, 46 patients were in the induction phase and 17 were in the consolidation phase. Four patients were in TFR in the stop phase. Of note, one patient remained in TFR for 18 months after receiving dasatinib treatment for only 18.6 months in induction and consolidation phases. All relapsing patients regained MR4 after a median of 2.1 months (range: 0.9-5.1) of dasatinib retreatment, except one patient who stopped study treatment because of an adverse event. No patients progressed to the accelerated/blastic phase or died due to CML.
Conclusions: D-FREE was the first trial to discontinue TKI treatment in patients with newly diagnosed CML-CP who maintained MR4.5 for 1 year by dasatinib treatment regardless of the treatment duration. Hachhaus et al. previously reported in the ENSTfreedom trial (Leukemia 2017) that CML-CP patients who received at least 2 years of front-line nilotinib treatment, achieved MR 4.5, and then underwent consolidation of nilotinib treatment for 1 year had a TFR of 51.6% at 48 weeks after nilotinib discontinuation. The median duration of TKI treatment in the study was 43.5 months, compared with 18.9 months for D-FREE, suggesting that not only the duration of DMR but also that of TKI treatment is important for successful TFR even with 2G-TKI.
Yoshida: Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Nippon Shinyaku: Honoraria; Novartis KK,: Honoraria; Janssen Pharmaceutical KK: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Yamaguchi: Bristol-Myers Squibb: Research Funding. Murai: Novartis Pharma: Honoraria; Pfizer: Honoraria; CHUGAI Pharmaceutical Co., Ltd.: Honoraria; TAKEDA Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation.: Honoraria; Bristol Myers Squibb: Honoraria. Hatta: Otsuka Pharmaceutical.: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb: Honoraria. Yokose: Bristol Myers Squibb Company: Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Fujimaki: CSL Behring K.K.: Honoraria; Novartis KK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Mundipharma K.K.: Honoraria. Oshikawa: Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Eisai Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; MSD K.K.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene Corporation: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; SymBio Pharmaceuticals.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Kumagai: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Kimura: Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ohara Pharmaceutical: Research Funding; Gilead: Research Funding; Nippon-Boehringer-Ingelheim: Research Funding; Sanifi: Speakers Bureau; Astellas: Speakers Bureau; Eisai: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; AbbVie: Research Funding, Speakers Bureau; Apellis: Research Funding; SymBio: Research Funding, Speakers Bureau; Mundi: Research Funding; Chugai: Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding, Speakers Bureau; Janssen: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Takeda: Research Funding, Speakers Bureau; Nippon-Shinyaku: Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion: Research Funding, Speakers Bureau; Incyte: Research Funding; Ono: Research Funding, Speakers Bureau; Kyowa-Kirin: Research Funding, Speakers Bureau; MSD: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Sumitomo-Dainippon: Research Funding. Usuki: Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Apellis Pharmaceuticals, Inc.: Research Funding; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Yokoyama: Kowa: Consultancy; SymBio Pharmaceuticals: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Otsuka Pharmaceutical: Honoraria; Bayer: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Pfizer: Research Funding. Yamamoto: Bristol-Myers Squibb Company: Honoraria; Novartis Japan Co.: Honoraria; Kyowa Kirin Co.: Honoraria; Fujimoto Pharmaceutical Corpor
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