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[Abstract] Background: Thrombopoietin (TPO) and its receptor, c-Mpl are essential for megakaryopoiesis. Two TPO receptor agonists (TPO-RAs),Eltrombopag (ETP) and Romiplostim (Rom), which also activate c-Mpl, thereby transmitting signals to downstream molecules, are currently used for immune thrombocytopenia purpura and aplastic anemia. Furthermore, recent clinical trials demonstrated that ETP and Rom would be useful for Myelodysplastic syndromes (MDS) patients with thrombocytopenia. Lusutrombopag (LTP) is a novel TPO-RA, which is approved for thrombocytopenia associated with liver diseases. In this study, we examined the effects of LTP on the growth and differentiation of MDS CD34+ cells as a preclinical study. Method: Effects of LTP on the proliferation, differentiation, and long-term self-renewal activities of bone marrow CD34+ cells from MDS patients were assessed with liquid cultures, CFU-megakaryocyte assays, and serial replating assays, respectively. We also analyzed the effects of LTP on cytokine secretion from cultured MDS CD34+ cells with a cytokine antibody array. Results: LTP effectively promotes the growth and differentiation of MDS CD34+ cells with comparable efficacy to that exerted on CD34+ cells from healthy controls. The megakaryopoietic potential of LTP was comparable to that exerted by ETP and TPO. LTP did not stimulate growth of CD34+ MDS/AML blasts, a concern that has been associated with ETP and Rom. Both ETP and TPO induced higher levels of FGF7 than LTP from CD34+ MDS cells. Conclusion: Although LTP and ETP revealed some different biologic activities, LTP would be as effective as ETP in promoting the growth and megakaryocytic differentiation of MDS CD34+ cells.

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18–9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1–10), lower B2MG (p p

The rare systemic inflammatory disorder ‘adult-onset Still’s disease (AOSD)’ is characterized by recurrent fever, evanescent rash, arthralgia, and leukocytosis with neutrophilia. The Yamaguchi criteria are widely used to diagnose AOSD; these criteria can be used for diagnosis after a wide range of infectious, rheumatic, and neoplastic diseases have been excluded. AOSD generally does not overlap with other rheumatic diseases. We present the rare case of an 80-year-old Japanese woman who presented with arthralgia, fever, and skin rash during treatment for systemic lupus erythematosus (SLE), which was finally diagnosed as an overlap of AOSD. Blood tests revealed leukocytosis with neutrophilia, high C-reactive protein (CRP), and liver dysfunction. Her anti-ds-DNA antibody titer and serum complement titer were at the same level as before and remained stable. We suspected AOSD based on the high serum ferritin level but hesitated to diagnose AOSD because of the patient’s SLE history. We measured serum interleukin (IL)-18; it was extremely high at 161,221 pg/mL, which was strongly suggestive of AOSD. We thus diagnosed AOSD complicated during the course of treatment for SLE. The patient’s arthralgia and high CRP level persisted after we increased her oral prednisolone dose and added oral methotrexate, but her symptoms eventually improved with the addition of intravenous tocilizumab. We note that the presence of autoantibodies or other rheumatic diseases cannot be absolutely ruled out in the diagnosis of AOSD. Although high serum IL-18 levels are not specific for AOSD, the measurement of serum IL-18 may aid in the diagnosis of AOSD in similar rare cases.

Supplemental material, sj-docx-13-tah-10.1177_20406207221142487 for Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide by Yutaka Shimazu, Junya Kanda, Hitomi Kaneko, Kazunori Imada, Ryosuke Yamamura, Satoru Kosugi, Yuji Shimura, Tomoki Ito, Shin-ichi Fuchida, Hitoji Uchiyama, Kentaro Fukushima, Satoshi Yoshihara, Hitoshi Hanamoto, Hirokazu Tanaka, Nobuhiko Uoshima, Kensuke Ohta, Hideo Yagi, Hirohiko Shibayama, Yoshiyuki Onda, Yasuhiro Tanaka, Yoko Adachi, Mitsuhiro Matsuda, Masato Iida, Takashi Miyoshi, Toshimitsu Matsui, Ryoichi Takahashi, Teruhito Takakuwa, Masayuki Hino, Naoki Hosen, Shosaku Nomura, Chihiro Shimazaki, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda in Therapeutic Advances in Hematology

Supplemental material, sj-docx-15-tah-10.1177_20406207221142487 for Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide by Yutaka Shimazu, Junya Kanda, Hitomi Kaneko, Kazunori Imada, Ryosuke Yamamura, Satoru Kosugi, Yuji Shimura, Tomoki Ito, Shin-ichi Fuchida, Hitoji Uchiyama, Kentaro Fukushima, Satoshi Yoshihara, Hitoshi Hanamoto, Hirokazu Tanaka, Nobuhiko Uoshima, Kensuke Ohta, Hideo Yagi, Hirohiko Shibayama, Yoshiyuki Onda, Yasuhiro Tanaka, Yoko Adachi, Mitsuhiro Matsuda, Masato Iida, Takashi Miyoshi, Toshimitsu Matsui, Ryoichi Takahashi, Teruhito Takakuwa, Masayuki Hino, Naoki Hosen, Shosaku Nomura, Chihiro Shimazaki, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda in Therapeutic Advances in Hematology

Supplemental material, sj-docx-14-tah-10.1177_20406207221142487 for Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide by Yutaka Shimazu, Junya Kanda, Hitomi Kaneko, Kazunori Imada, Ryosuke Yamamura, Satoru Kosugi, Yuji Shimura, Tomoki Ito, Shin-ichi Fuchida, Hitoji Uchiyama, Kentaro Fukushima, Satoshi Yoshihara, Hitoshi Hanamoto, Hirokazu Tanaka, Nobuhiko Uoshima, Kensuke Ohta, Hideo Yagi, Hirohiko Shibayama, Yoshiyuki Onda, Yasuhiro Tanaka, Yoko Adachi, Mitsuhiro Matsuda, Masato Iida, Takashi Miyoshi, Toshimitsu Matsui, Ryoichi Takahashi, Teruhito Takakuwa, Masayuki Hino, Naoki Hosen, Shosaku Nomura, Chihiro Shimazaki, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda in Therapeutic Advances in Hematology

Supplemental material, sj-docx-15-tah-10.1177_20406207221142487 for Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide by Yutaka Shimazu, Junya Kanda, Hitomi Kaneko, Kazunori Imada, Ryosuke Yamamura, Satoru Kosugi, Yuji Shimura, Tomoki Ito, Shin-ichi Fuchida, Hitoji Uchiyama, Kentaro Fukushima, Satoshi Yoshihara, Hitoshi Hanamoto, Hirokazu Tanaka, Nobuhiko Uoshima, Kensuke Ohta, Hideo Yagi, Hirohiko Shibayama, Yoshiyuki Onda, Yasuhiro Tanaka, Yoko Adachi, Mitsuhiro Matsuda, Masato Iida, Takashi Miyoshi, Toshimitsu Matsui, Ryoichi Takahashi, Teruhito Takakuwa, Masayuki Hino, Naoki Hosen, Shosaku Nomura, Chihiro Shimazaki, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda in Therapeutic Advances in Hematology

Supplemental material, sj-docx-14-tah-10.1177_20406207221142487 for Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide by Yutaka Shimazu, Junya Kanda, Hitomi Kaneko, Kazunori Imada, Ryosuke Yamamura, Satoru Kosugi, Yuji Shimura, Tomoki Ito, Shin-ichi Fuchida, Hitoji Uchiyama, Kentaro Fukushima, Satoshi Yoshihara, Hitoshi Hanamoto, Hirokazu Tanaka, Nobuhiko Uoshima, Kensuke Ohta, Hideo Yagi, Hirohiko Shibayama, Yoshiyuki Onda, Yasuhiro Tanaka, Yoko Adachi, Mitsuhiro Matsuda, Masato Iida, Takashi Miyoshi, Toshimitsu Matsui, Ryoichi Takahashi, Teruhito Takakuwa, Masayuki Hino, Naoki Hosen, Shosaku Nomura, Chihiro Shimazaki, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda in Therapeutic Advances in Hematology

This is a plain language summary (PLS) of an article published in a peer-reviewed scientific journal. This PLS is not peer-reviewed. The publisher of the orignial manuscript was not involved in the preparation of this PLS and has neither reviewed not approved its content.

Supplemental material, sj-docx-13-tah-10.1177_20406207221142487 for Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide by Yutaka Shimazu, Junya Kanda, Hitomi Kaneko, Kazunori Imada, Ryosuke Yamamura, Satoru Kosugi, Yuji Shimura, Tomoki Ito, Shin-ichi Fuchida, Hitoji Uchiyama, Kentaro Fukushima, Satoshi Yoshihara, Hitoshi Hanamoto, Hirokazu Tanaka, Nobuhiko Uoshima, Kensuke Ohta, Hideo Yagi, Hirohiko Shibayama, Yoshiyuki Onda, Yasuhiro Tanaka, Yoko Adachi, Mitsuhiro Matsuda, Masato Iida, Takashi Miyoshi, Toshimitsu Matsui, Ryoichi Takahashi, Teruhito Takakuwa, Masayuki Hino, Naoki Hosen, Shosaku Nomura, Chihiro Shimazaki, Itaru Matsumura, Akifumi Takaori-Kondo, Junya Kuroda in Therapeutic Advances in Hematology

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib–lenalidomide–dexamethasone (KRd) and carfilzomib–dexamethasone (Kd). Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database. Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia. Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered.

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for

[Abstract] There has been a belief that the scholastic achievement of students in their course work must have a close relationship with their previous performances in the entrance examination. How-ever, this hypothesis has been insufficiently examined based on a longitudinal study of school records of students at Kindai University Faculty of Medicine. This study was aimed to investigate the correlation between current datasets of the students’ entrance exam scores and the changes in their achievements throughout the curriculum. By calculating and evaluating correlation coefficients between variables, it was concluded that strong correlations existed between IRT standard scores on CBT in the 4th year and graduation ex-amination II (R=0.679) and also between the comprehensive test scores and graduation exam II (R=0.633), while the students’ initial performance in the entrance exams showed a very weak correlation with their course work.

本論稿は、拙論「行為決意の源泉―脳か心か・責任と刑罰に向けてー」駒澤法学第17巻1号および「答責(性)・帰責(属)・責任と意思の自由―脳科学を顧みてー(1)(2)(3)」駒澤法学第19巻2号/第19巻3号/第20巻1号を発表して以来、何か言い足りなさを感じていたことを、補足的に覚書としてまとめたものである。そこで、刑事責任と答責(性)および帰責の概念についてSollenとの関係を補足し、その上で、意思の自由を否定する脳科学者のニューロン決定論とそれに対する批判を再論してみたのである。特に、脳の機能を1元的に重視する脳局在論を批判し、心が脳に従属するという付随併発論も心を脳に還元する還元主義も排斥することをし直した。そのために、動物と同じ脳という器官を有しない植物の機能を垣間見て、この植物が有する知性を考えれば、知性と心は脳に依存するわけではないことを検討してみた。したがって、脳科学者が脳を全ての原因と考える「脳神話論」が1人称視座を無視して全てを物的な3人称視座で説明することの矛盾を追求した。その意味では、意思の自由に関しては、自然科学的アプローチでは説明しえない次元は、「心の科学」ないし「心の哲学」が必要であることを強調した。そして、この心と知性を有する「人」という単位体が、考え思索するのであることを強調した。刑事責任は、このような内心の世界と規範的要請とのかかわりの中で追求し検討しなければないという考えを補筆した次第である。

本論稿は、(1)編では、拙著『自由意思と刑事責任―脳科学を顧みて』(八千代出版2017年)において論究が不充分であった、(刑事)責任(Schuld)に対する答責と答責性(Verantwortung und Verantwortlichkeit)・帰責と帰属(Zurechnung und Zuschreibung)の関係性とこれらの概念内容を探求し、(2)編において再び、意思の自由を否定する脳科学者のニューロン決定論とそれに対する批判を垣間見て、特に、脳科学者Gerhard Rothとそれに呼応する哲学者Michael Pauenが主張するニューロン決定論を批判的に検討した。そして、「心」が「脳」に付随併発するのではなくて、両者の同時併発と表裏一体性を主張した。(3)編においては、従来の通説である「責任=非難」論に疑問を呈し、責任は非難ではなくて非難の前提条件であることを主張し、「心」の「脳」への還元論と付随併発論のいずれをも否定し、更に、システム理論に基づく「脳」と「心」と「身体」の統合的な単位体としての「人」の意思決定を説いた。そして、この単位体しての「人」が主体的な自由意思に基づいて自己改善を図らなければならないことを強調した。

本論稿は、拙著『自由意思と刑事責任―脳科学を顧みて』(八千代出版2017年)において論究が不充分であった、(刑事)責任(Schuld)に対する答責と答責性(Verantwortung und Verantwortlichkeit)・帰責と帰属(Zurechnung und Zuschreibung)の関係性とこれらの概念内容を探求し、その上で再び、意思の自由を否定する脳科学者のニューロン決定論とそれに対する批判を垣間見て、特に、脳科学者Gerhard Rothとそれに呼応する哲学者Michael Pauenが主張するニューロン決定論と自由の両立可能性論が、本当に一元的な物理学的決定論とは異質なのかどうかという疑問を提起して、彼らを批判しながら、「心」が「脳」に付随併発するのではなくて、両者の同時併発と表裏一体性を主張した。更に、個別具体的な行為に関する意思の自由の証明不可能性は認めつつ、自律性・起動者性・選好性・熟慮性に基づく意思の自由の想定が不可欠であること、自由意思は1人称視座に基づく心理的な現象であり、「行為決意の源泉」と「自己改善の源泉」は「心」でなければならないこと、しかし決定要因は否定できないことを説き、責任概念と意思の自由の関係、責任と非難(可能性)の関係、精神医学と脳障害そして視座の相違について言及した。

[Abstract] Interleukin (IL)-18 has important roles in the pathogenesis of organ failure caused by endotoxemia. To determine whether IL-18 receptor(R)αsignaling ameliorates or deteriorates the renal function in lipopolysaccharide (LPS)-induced acute kidney injury(AKI), we compared IL-18Rα knockout (KO) mice with wild-type (WT) mice following LPS injection. As the results, IL-18Rα deficiency ameliorated the renal function and reduced the serum level of pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interferon-gamma (IFN-γ), and IL-18. The renal suppressor of cytokine signaling 1(SOCS1) mRNA expression was also significantly reduced in IL-18Rα KO mice compared with WT mice. In addition, the adoptivetransfer of splenocytes from WT mice into IL-18Rα KO mice increased their serum pro-inflammatory cytokine levels and deteriorated the renal function In conclusion, IL-18Rα deficiency ameliorated the release of systemic pro-inflammatory cytokines and renal function in mice with LPS-induced AKI. Thus, IL-18Rα affects renal injury through the pro-inflammatory cytokine signaling pathway in the pathogenesis of LPS-induced AKI.

[Abstract] Background :Overexpression of Tribbles homolog 1 (Tribl) and Tribbles homolog 2 (Trib2) in hematopoietic stem/progenitor cells evokes acute myeloid leukemia (AML) in murine transplantation models. Degradation of CCAAT-enhancer-binding-protein α (C/EBPα) plays a crucial role in Trib1 or Trib2-induced AML. However, because C/EBPα knockout mice do not develop AML, it is likely that Trib1 and Trib2 influence other signaling pathways besides C/EBPα. Elevated Akt phosphorylation is considered to contribute to the development of AML. In contrast, two groups recently reported that reduced Akt activity is involved in the pathogenesis of leukemia. We performed this study to reveal the role of Akt signaling in Trib family-induced AML.Methods : G-CSF-induced granulocytic differentiation of 32D cells was assessed morphologically and phenotypically. G-CSF-induced signaling wasassessed by Westernblotting. Results : Overexpression of Trib1 or Trib2 inhibited GCSF-induced granulocytic differentiation of 32D cells, which was accompanied by reduced Akt phosphorylation. Also, an Akt inhibitor API-2 blocked G-CSF-induced granulocytic differentiation independently of C/EBPα degradation. Furthermore, retroviral C/EBPα restoration did not completely abolish the differentiation block caused by Trib1 and Trib2. Conclusion :Trib1 and Trib2 block granulocytic differentiation, at least partially, by suppressing Akt phosphorylation.

[Abstract] Bacterial or fungal sepsis is one of the leading causes of death in patients with hematological disease. Neutropenia occurs depending on the dose of chemotherapy or radiotherapy and is considered to be an important predictive factor for the incidence and severity of infection in chemotherapy patients. Approximately 40％ to 60％ of febrile patients who receive chemotherapy are clinically or microbiologically diagnosed with infection, while the remaining patients are diagnosed with fever of unknown origin and treated as such. Along with the routine use of carbapenem antibiotics (which mainly target Gram-negative bacteria) in recent years, multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), have evolved and have become a serious clinical and social problem, however, no specific strategy for infection control has yet been established. For patients with hematological disease who had fever caused by an unknown pathogen, including febrile neutropenic patients, we performed antimicrobial cycling and assessed changes over time in the isolation rates of MRSA, Pseudomonas aeruginosa, etc. For 448 patients admitted to our hospital, the use of carbapenem, penicillin, fluoroquinolone, and cephem antibiotics (all of which were injectable preparations) was rotated in this order at 3-month intervals over a two-year period (antimicrobial cycling). We concluded that cycling of the four classes of antibiotics used in this study was effective in patients with fever of unknown origin, including febrile neutropenic (FN) patients, since it could decrease the isolation rates of MRSA and P. aeruginosa.

[Abstract] Acute myeloid leukemia (AML) is a clonal disorder that is caused by acquired somatic mutations in hematopoietic stem/progenitors. These mutations mainly include chromosomal translocations and point mutations, which were divided into two major groups called Class I and Class II mutations. Class I mutations including those of FLT3, KIT, and RAS, which primarily promote the growth and survival of hematopoietic cells without significant effects on differentiation. Class II mutations include those of CBF, RARA, CEBPA, and MLL, which cause differentiation arrest or are involved in self-renewal of hematopoietic cells, while they hardly affect the growth and survival of hematopoietic cells. Thus, the cooperation between class I mutation and class II mutation is supposed to be required to develop AML. The screening of these genetic mutations is now performed to diagnose AML in daily clinical practice. In addition, because these abnormalities crucially influence biologic properties of AML cells, they are the most important prognostic factors for AML and utilized to classify AML in the WHO classification. Furthermore, recent advances in the understanding of the genetic basis have enabled us to construct novel therapeutic approaches, and some of which are already in clinical trials or applied to daily clinical practice.

[Abstract] Monoclonal antibodies have markedly changed the treatment possibilities for patients with indolent B-cell lymphoma. ^Y-Ibritumomab tiuxetan (Zevalin) is the first radioimmunotherapy (RIT) agent approved for the treatment of relapsed and refractory indolent lymphoma patients. In most cases, the maximum clinical response were observed two to three months after RIT. Treatment with ^Y-ibritumomab tiuxetan may have potential late effects in some cases of relapsed follicular lymphomas, and we must be careful to start the next treatment after RIT.

Background: Detection and quantitation of BCR-ABL1 transcripts are crucial for managing patients with chronic myeloid leukemia (CML). Although real-time quantitative polymerase chain reaction (RT-qPCR) can be measured on an International Scale (IS), this has not become fully universal. By using a WHO international standard panel established for calibrating secondary standards based on the IS, we have previously developed an RT-qPCR kit, ODK-1201, for quantification of major BCR-ABL1. Results: In this study, the reliability of kit-specific conversion factor 1.12 was validated by exchanging patients’ samples between three local clinical laboratories and a reference laboratory. The mean bias of the local method after IS conversion was 1.6 fold lower than the reference method. The clinically-useful sensitivity of the kit was further evaluated for monitoring patients with deep molecular response. Based on the correlation of the IS values between ODK-1201 and the reference laboratory method, the detection level of the kit was estimated as 0.0032 % BCR-ABL1IS. Conclusions: ODK-1201 is a highly sensitive one-step RT-qPCR system for detecting BCR-ABL1 on the IS in 2 h after RNA extraction, thus contributing to standardization of molecular monitoring in CML. Refereed/Peer-reviewed