Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Hematology  

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin-aldosterone-angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (- 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at - 5.7 (- 6.6, - 4.9) and - 10.1 (- 12.3, - 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.

DOI： 10.1007/s12185-022-03433-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Haematology  

OBJECTIVE: Acute graft-versus-host disease (aGVHD) is a major cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation. Endothelial cell damage may trigger the initiation of aGVHD. METHODS: Endothelial damage and repair were evaluated by counting circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in 17 allogeneic hematopoietic stem cell transplantation patients at pre-conditioning, day 0, day 7, day 14, day 30, and day 60 by multicolor flow cytometry. Von Willebrand factor activity was simultaneously measured. RESULTS: Eight patients developed aGVHD and were compared to non-aGVHD patients. Patients' characteristics were not different, except for previous treatment courses. There was no difference in von Willebrand factor activity between the two groups. Both CEC and EPC counts were decreased on day 7 and day 14 and then increased thereafter. The CEC count on day 7 was significantly lower in the aGVHD group than in the non-aGVHD group (p = .0401). Restoration of the EPC count on day 60 was significantly suppressed in the aGVHD group (p = .0464). The CEC count on day 7 could predict aGVHD development (AUC 0.8214, p = .0372). CONCLUSION: The present results showed that CEC count on day 7 could be a predictor of aGVHD.

DOI： 10.1111/ejh.13781

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Language：English   Publishing type：Research paper (scientific journal)  

Helicobacter pylori causes gastritis, which has been attributed to the development of H. pylori-specific T cells during infection. However, the mechanism underlying innate immune detection leading to the priming of T cells is not fully understood, as H. pylori evades TLR detection. Here, we report that H. pylori metabolites modified from host cholesterol exacerbate gastritis through the interaction with C-type lectin receptors. Cholesteryl acyl α-glucoside (αCAG) and cholesteryl phosphatidyl α-glucoside (αCPG) were identified as noncanonical ligands for Mincle (Clec4e) and DCAR (Clec4b1). During chronic infection, H. pylori-specific T cell responses and gastritis were ameliorated in Mincle-deficient mice, although bacterial burdens remained unchanged. Furthermore, a mutant H. pylori strain lacking αCAG and αCPG exhibited an impaired ability to cause gastritis. Thus H. pylori-specific modification of host cholesterol plays a pathophysiological role that exacerbates gastric inflammation by triggering C-type lectin receptors.

DOI： 10.1084/jem.20200815

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. PATIENTS AND METHODS: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m2/day), doxorubicin (10 mg/m2/day), and vincristine (0.4 mg/m2/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m2/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. RESULTS: In 103 patients, overall response rate and complete response rate were 58&#37; and 25&#37;, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95&#37; confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95&#37; confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation. CONCLUSION: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.

DOI： 10.1016/j.clml.2020.03.008

Language：English   Publishing type：Research paper (scientific journal)  

A case of acquired hemophilia A (AHA) that developed in a patient with autoimmune pancreatitis (AIP) is presented. A 64-year-old woman was diagnosed with AIP in 2007. The symptoms resolved with prednisolone (PSL). Although the dose of PSL was tapered to 7.5 mg/day for maintenance, serum IgG4 levels remained high. She suddenly presented with subcutaneous bleeding in 2015. Her activated partial thromboplastin time was prolonged (80.0 s). A mixing test showed an inhibitor pattern, factor VIII (FVIII) activity was less than 1&#37;, and FVIII inhibitor was 290 BU/mL. She was diagnosed with AHA. Her serum IgG4 was elevated to 133 mg/dL. She was treated first with PSL alone, but she developed bladder tamponade. Cyclophosphamide and activated prothrombin complex concentrate were combined with PSL. She then achieved hemostasis, and FVIII inhibitor disappeared. FVIII inhibitor had been detected since PSL was tapered and AHA recurred two months later. An enzyme-linked immunosorbent assay showed that the inhibitor was mainly IgG4 and IgG1. This case suggests that elevation of IgG4 may be associated with the development of both AHA and AIP.

DOI： 10.1007/s12185-018-2441-3

Language：English   Publishing type：Research paper (scientific journal)  

Although gamma heavy chain disease (γ-HCD) lesions occasionally morphologically resemble angioimmunoblastic T-cell lymphoma (AITL), no association has been described in detail due to the rarity of the disease. In this report, we present a rare manifestation of methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) with AITL-like features accompanied by γ-HCD in a 75-year-old man with rheumatoid arthritis (RA). A biopsy specimen was evaluated using immunohistochemistry, clonal analyses of immunoglobulin VH and T-cell receptor γ gene rearrangements by polymerase chain reaction, and Sanger sequencing for confirmation of the structure of deleted γ-HCD clones. The histological features characterized by proliferation of CD4- and PD-1-positive medium-sized T cells and arborizing high endothelial venules together with numbers of small lymphocytes, eosinophils, plasma cells, and histiocytes in the background mimicked those of AITL, but did not completely fulfill the diagnostic criteria. Clonal analysis demonstrated that the specimen contained multiple LPDs of both B-cell and T-cell lineages. Sequence analysis confirmed the co-existence of a clone responsible for production of the abnormal heavy chain. This report provides new insights into the pathology of γ-HCD. Multiple host-derived factors (e.g., RA and/or use of MTX) may be responsible for the occurrence of LPDs of multiple lineages within a single lymph node.

DOI： 10.1111/pin.12703

Language：English   Publishing type：Research paper (scientific journal)  

Aggressive NK-cell leukemia (ANKL) is characterized by systemic infiltration of Epstein-Barr virus (EBV)-associated natural killer cells and poor prognosis. We report a case of ANKL in which EBV-specific cytotoxic T lymphocytes (CTLs) were induced. A 41-year-old male suffered from fever, pancytopenia, and hepatosplenomegaly. The number of abnormal large granular lymphocytes in the bone marrow was increased and the cells were positive for CD56 and EBV-encoded small nuclear RNAs. The patient was diagnosed with ANKL and achieved a complete response following intensive chemotherapy. He then underwent allogeneic peripheral blood stem cell transplantation from his sister. Conditioning therapy consisted of total body irradiation and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. On day 31, complete donor chimerism was achieved and no acute graft-versus-host disease developed. The ANKL relapsed on day 80, and cyclosporine was rapidly tapered and chemotherapy was started. During hematopoietic recovery, the number of atypical lymphocytes increased, but they were donor-derived EBV-specific CTLs. The patient achieved a partial response and EBV viral load decreased to normal range. Unfortunately, ANKL worsen again when the CTLs disappeared from his blood. This is the first case report of ANKL in which induced EBV-specific CTLs may have contributed to disease control.

DOI： 10.1007/s12185-016-2131-y

Language：Japanese   Publishing type：Research paper (scientific journal)  

Light-chain deposition disease (LCDD) is a rare plasma cell neoplasm that secretes an abnormal immunoglobulin light chain, which is deposited in tissues, leading to organ dysfunction. Spontaneous splenic rupture is a rare and life-threatening complication of treatment with granulocyte colony-stimulating factor (G-CSF). Herein, we describe spontaneous splenic rupture after the administration of lenograstim to a patient with LCDD undergoing autologous stem cell transplantation (ASCT). The patient was successfully treated by transcatheter embolization of the splenic artery, and long-term stringent complete remission was attained. Plasma cell neoplasms, including multiple myeloma with amyloidosis, are among the most commonly reported conditions associated with spontaneous splenic rupture in patients undergoing ASCT. This finding suggests that, in addition to the effect of G-CSF on the spleen, a combination of factors, including tissue vulnerability induced by the infiltration of abnormal immunoglobulins, may be involved in the pathogenesis of spontaneous splenic rupture. Notably, splenomegaly is not always evident in these patients. Surgical treatment may not be an option, because of severe myelosuppression, and thus less invasive treatment using transcatheter embolization may be feasible.

DOI： 10.11406/rinketsu.57.754

Language：Japanese  

軽鎖沈着症(LCDD)は単クローン性軽鎖重鎖沈着症の一病型であり,異常軽鎖が諸臓器に沈着する極めて稀な疾患である。一方,脾破裂は稀ではあるが重篤なG-CSF投与の合併症として知られる。我々はLCDDに対する自家末梢血幹細胞移植後,G-CSF投与後に自然脾破裂を合併した症例を経験した。経カテーテル的脾動脈塞栓術により救命でき,長期間病勢コントロールが可能であった。ASCT施行後の骨髄抑制に対しG-CSFを投与した後に自然脾破裂を来した症例報告はmultiple myelomaおよびその類縁疾患が多くみられ,G-CSFによる脾臓の造血巣への影響だけでなく,異常蛋白の血管への沈着に伴う臓器脆弱性などの複合した要素が影響を与えている可能性が示唆され,また必ずしも脾腫を伴わない点も注意が必要である。ASCT直後は外科手術が困難である場合も多く,より侵襲の少ない経カテーテル的脾動脈塞栓術も有効な手段であると考えられる。(著者抄録)

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DOI： 10.1038/bmt.2015.254

Language：Japanese   Publishing type：Research paper (scientific journal)  

CD 20 positive myeloma with small lymphoplasmacytoid morphology is difficult to differentiate from mature B-cell lymphoma. A 71-year-old male was referred to our hospital because of osteolytic vertebral fractures and anemia. Urine was positive for Bence Jones protein, κ type. Bone marrow consisted of approximately 30&#37; small lymphoplasmacytoid cells with scant cytoplasm, and these cells were positive for CD20, CD23 and CD138. FISH analysis revealed t(11;14)(CCND1/IGH). Myeloma with t(11;14) is closely associated with small lymphoplasmacytoid appearance and CD20 and CD23 expressions. The patient was diagnosed as having myeloma based on clinical and cytogenetic findings, and achieved VGPR (very good partial response) after treatment with lenalidomide.

DOI： 10.11406/rinketsu.56.335

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症例は71歳男性で、重いものを持った際の腰痛で近医にて第4腰椎圧迫骨折を指摘され、その後も同様腰痛を繰り返し、軽度貧血を認めて多発性骨髄腫疑いで紹介受診した。検査で軽度貧血、免疫グロブリンの低値を認めた。尿でκ型のベンスジョーンズ蛋白を認め、M蛋白の増加を認めた。骨髄検査では小～中型のリンパ形質細胞様細胞を約30&#37;に認め、CD20が陽性で、免疫染色ではκ鎖が陽性であった。CTで胸腰椎を中心に多発骨融解や圧迫骨折を認めた。骨髄腫細胞のFISH検査で小型のCD20陽性骨髄腫の関連深いCCND1/IgH融合遺伝子を認め、多発性骨髄腫(ベンスジョーンズ型)と診断した。VMP療法で尿M蛋白量は改善したが、便秘、倦怠感が強く3サイクルで中止し、Rd療法でvery good partial responseを得た。しかし認容性が低く、下痢や倦怠感で定期的投与ができず、間欠的Rd療法を行ったが、徐々に病状が悪化して緩和ケア病院に転院した。

Language：English   Publishing type：Research paper (scientific journal)  

This retrospective study analyzes the results of radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan in 94 Japanese patients with relapsed or refractory low-grade B cell non-Hodgkin lymphoma at a single institution. All patients had previously been administered with 1-8 (median 1) regimens of rituximab alone or combined with other chemotherapeutic regimens at a mean age of 64 years. The overall response rate was 90 &#37; and the complete response (CR) rate was 69 &#37;. The median overall survival was not reached and progression-free survival (PFS) was 26 months, respectively, for the early phase 50 patients during a median follow-up period of 46.5 months. In this cohort, the PFS rates for the 50 early phase patients who had undergone ≤2 and ≥3 previous regimens, and for those who achieved CR compared with those who did not (partial response, PR; stable disease, SD; progressive disease, PD) were 38 and 11 months, respectively. Multivariate analysis showed that these two factors were statistically significant (p = 0.0011 and p <0.0001, respectively). The overall incidence of grade ≥3 non-hematological toxicity was 9 &#37;. Two patients died of treatment-related deteriorating hepatitis C. A second malignancy developed in two patients at 10.5 and 3.5 months after treatment. We recommend administering (90)Y-ibritumomab tiuxetan as early in the disease course as possible, and at the latest as a third-line therapy to maximize the benefits of RIT, which should improve the quality of life for patients.

DOI： 10.1007/s12185-014-1636-5

Language：Japanese   Publishing type：Research paper (scientific journal)  

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma, characterized by human herpes virus 8 (HHV8) infection and serous effusions without detectable tumor masses. However, cases with HHV8 unrelated PEL have also been reported, mainly in Japan, and these are referred to as PEL-like lymphoma (PEL-LL). We describe a 70-year-old man with cardiac comorbidity who developed PEL-LL with pleural effusion. The patient achieved a complete response (CR) after treatment with oral low-dose sobuzoxane and etoposide combined with rituximab. To date, the patient has been in CR for about 7 months without chemotherapy. PEL-LL reportedly has a better prognosis than PEL. Because PEL-LL is positive for CD20, unlike PEL, combination therapy including rituximab may be effective. PEL-LL mainly affects elderly people, so that further investigation of tolerable and effective regimens is required.

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Primary effusion lymphoma(PEL)は体腔液中に限局して腫瘍細胞が増殖する稀なB細胞性リンパ腫であり,原則的に明らかな腫瘤形成は認められないとされ,human herpes virus 8(HHV8)感染が陽性である。しかしながら本邦を中心にHHV8感染が認められないPEL類似の症例も報告されており,これらをPEL-like lymphoma(PEL-LL)とする疾患群も提唱されている。今回我々は胸水貯留で発症したPEL-LLを経験した。心疾患を有する70歳男性であり,リツキシマブ併用経口ソブゾキサン,エトポシド少量療法にて7ヵ月間完全奏効を維持している。PEL-LLはPELと比較し,予後良好であることが報告されており,CD20抗原が陽性であることからリツキシマブの追加効果が期待されている。PEL-LLは高齢者に多い疾患であり,より忍容性のある有効な治療法の開発が期待される。(著者抄録)

Event date： 2023.4

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Event date： 2022.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岐阜グランドホテル   Country：Japan  

Event date： 2022

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Event date： 2019.12

Language：English   Presentation type：Oral presentation (general)  

Venue：アクトシティ浜松   Country：Japan  

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Language：Japanese   Publisher：(公財)大和証券ヘルス財団  

Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本骨髄腫学会  

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Language：Japanese