記述言語：日本語   出版者・発行元：International Journal of Clinical Oncology  

Background: Primary results from the EPCORE NHL-3 trial (NCT04542824) showed deep, durable responses in Japanese patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with single-agent epcoritamab, a subcutaneous CD3xCD20 bispecific antibody. Here, we report 3-year follow-up of safety and efficacy. Methods: Japanese patients with R/R CD20⁺ DLBCL and ≥ 2 prior systemic therapies received epcoritamab (0.16/0.8-mg step-up doses, then 48-mg full doses) according to the approved label. The primary endpoint was overall response rate per independent review committee. Results: As of July 12, 2024, 36 patients received epcoritamab (median follow-up, 36.7 months). Overall/complete response rates were 56%/47%. Median duration of response was 15.2 months. Median duration of complete response was not reached; an estimated 53% of complete responders remained in complete response at 3 years. Median progression-free/overall survival (PFS/OS) were 4.1/14.9 months overall; neither was reached among complete responders. Three-year PFS/OS estimates were 25%/39% overall and 53%/71% in complete responders. Among 30 evaluable patients, 17 (57%) became minimal residual disease (MRD) negative, which was associated with longer PFS (cycle 3 day 1 landmark analysis). The most common treatment-emergent adverse events (TEAEs) were cytokine release syndrome (83%), injection-site reaction (69%), and neutropenia (39%), consistent with previous reports. No fatal TEAEs occurred. Conclusions: With > 3 years of follow-up, epcoritamab treatment has consistently shown durable responses and high rates of MRD negativity in Japanese patients with R/R DLBCL. Safety was similar to previous reports. These long-term remissions reaffirm encouraging outcomes with epcoritamab for this challenging-to-treat population.

DOI： 10.1007/s10147-025-02788-0

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PubMed

記述言語：日本語   出版者・発行元：Blood  

No standard of care for older patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established. We evaluated the efficacy of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 2 weeks with mogamulizumab (Moga; Moga-CHOP-14) for older patients with untreated ATL. In this multicenter phase 2 trial, patients aged ≥66 years and those aged 56 to 65 years ineligible for transplantation received 6 cycles of Moga-CHOP-14, followed by 2 cycles of Moga monotherapy. The primary end point was 1-year progression-free survival (PFS). Secondary end points were the complete response (CR) rate, overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and safety. We also investigated the impact of CC chemokine receptor 4 (CCR4) mutation and Moga-associated cutaneous adverse events (cAEs) on PFS and OS. The study protocol was amended to allow the dosing interval to be extended to 21 days at the physician's discretion. Among 48 evaluable patients, the 1-year PFS was 36.2% (90% confidence interval, 24.9-47.6), with a median follow-up of 1.6 years. The 1-year OS and EFS were 66.0% and 29.9%, respectively. CR and ORR were 64.6% and 91.7%. No unexpected toxicities were observed. Of 47 patients who received ≥2 cycles of CHOP, 20 (42.6%) received CHOP-14, among whom 12 (25.5%) completed 6 cycles. CCR4 mutation and Moga-associated cAEs were associated with better OS. This study showed that Moga-CHOP significantly improved PFS, although the optimal interval for CHOP remains undetermined. Moga-CHOP is now considered a preferable first-line treatment for this patient population. This trial was registered at https://jrct.mhlw.go.jp/en-top as #jRCTs041180130.

DOI： 10.1182/blood.2024027902

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PubMed

記述言語：日本語   出版者・発行元：Lancet Oncology  

Background: Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas. Methods: This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting. Findings: Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4–17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3–4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6–65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150–250 mg per day. Interpretation: The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting. Funding: Daiichi Sankyo.

DOI： 10.1016/S1470-2045(24)00502-3

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PubMed

記述言語：日本語   出版者・発行元：Lancet Oncology  

Background: Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma. Methods: VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment. Findings: Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0–74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0–73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8–13·8). 52 (44%; 95% CI 35–53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3−4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported. Interpretation: These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile. Funding: Daiichi Sankyo.

DOI： 10.1016/S1470-2045(24)00503-5

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PubMed

記述言語：英語   出版者・発行元：(一社)日本リンパ腫学会  

成熟T細胞性腫瘍の一種であるT細胞前リンパ球性白血病(T-PLL)に対する抗CD52モノクローナル抗体医薬品アレムツズマブの有効性と安全性を後ろ向きに検討した。2015年1月から2023年8月までに5施設でアレムツズマブ治療を受けた日本人T-PLL患者9例(年齢39～78歳)を対象とした。患者2例に治療歴はなく、7例には中央値で1回(範囲1～3回)の前治療歴があった。患者6例は直近の治療に対して難治性であった。患者3例が12週間のアレムツズマブ治療を完了した。全奏効率は78%、完全奏効(CR)率は11%であった。部分奏効を得た患者6例のうち、2例は臨床的CRを得たが、骨髄検査を受けなかった。また、患者1例は臨床的CRを得たが、奏効評価のためのCTおよび骨髄検査を受けなかった。無増悪生存期間の中央値は8.1ヵ月であった。病勢進行後にアレムツズマブ単剤療法の再投与を受けた患者は3例であった。治療関連死はなかった。グレード3または4の非血液学的有害事象は、輸注反応(グレード3;2例)、サイトメガロウイルス再活性化(グレード3;2例)、肺水腫(グレード3;1例)であった。

記述言語：日本語   出版者・発行元：Hematological Oncology  

Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31 weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1–18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%–76.5%) [PTCL, 64.4% (54.0%–73.0%); CTCL, 90.5% (67.0%–97.5%)]. Safety and effectiveness were comparable between patients <70 and ≥ 70 years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.

DOI： 10.1002/hon.3292

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

症例は24歳男性。倦怠感や体重減少の精査のため実施した下部消化管内視鏡検査で回盲部潰瘍を認め,生検でびまん性大細胞型B細胞リンパ腫と診断された。その後の精査中にニューモシスチス肺炎を併発し,後天性免疫不全症候群(AIDS)の合併が判明した。回盲部潰瘍以外に明確な病変はなく,生検組織のin situ hybridization法により腫瘍細胞はEpstein-Barr encoding region(EBER)がびまん性に強陽性であったため,EBV陽性粘膜皮膚潰瘍(EBVMCU)と診断した。免疫再構築により病変が改善することを期待し,抗レトロウイルス療法(ART)を開始した。ART開始79日後には回盲部潰瘍の完全消失を確認し,その後3年以上にわたって寛解を維持している。EBVMUCは種々の免疫抑制状態を背景に発症することが知られておりAIDSもその一つであるが,ARTによる免疫再構築によってEBVMCUが寛解に至った初めての報告である。(著者抄録)

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>症例は24歳男性。倦怠感や体重減少の精査のため実施した下部消化管内視鏡検査で回盲部潰瘍を認め，生検でびまん性大細胞型B細胞リンパ腫と診断された。その後の精査中にニューモシスチス肺炎を併発し，後天性免疫不全症候群（AIDS）の合併が判明した。回盲部潰瘍以外に明確な病変はなく，生検組織の<i>in situ</i> hybridization法により腫瘍細胞はEpstein-Barr encoding region（EBER）がびまん性に強陽性であったため，EBV陽性粘膜皮膚潰瘍（EBVMCU）と診断した。免疫再構築により病変が改善することを期待し，抗レトロウイルス療法（ART）を開始した。ART開始79日後には回盲部潰瘍の完全消失を確認し，その後3年以上にわたって寛解を維持している。EBVMUCは種々の免疫抑制状態を背景に発症することが知られておりAIDSもその一つであるが，ARTによる免疫再構築によってEBVMCUが寛解に至った初めての報告である。</p>

DOI： 10.11406/rinketsu.65.13

PubMed

記述言語：日本語   出版者・発行元：Natural Product Research  

During the screening of novel chemotherapeutic candidates from plants against adult T-cell leukaemia/lymphoma (ATL), we found that extracts of plants in the Solanaceae, Annonaceae, Apocynaceae, and Rutaceae families showed anti-proliferative activity in the MT-1 and MT-2 cell lines. We have isolated active compounds from these plants in the present research because Cupressaceae plants showed potent anti-proliferative activity in the cell lines. We attempted to isolate the active compounds from the leaves of Juniperus rigida. Using activity-guided fractionation, we isolated 22 compounds, including seven terpenoids, three aromatic compounds, two iridoids, five lignans, and five biflavonoids. The anti-proliferative activities of five diterpenoids were moderate, and those of two biflavonoids were stronger. A lignan (compound 13) showed the strongest activity. These compounds are promising candidates for the treatment of ATL.

DOI： 10.1080/14786419.2024.2404655

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PubMed

記述言語：英語   出版者・発行元：一般社団法人 日本リンパ腫学会  

Alemtuzumab is recommended as first-line and second-line therapies for T-cell prolymphocytic leukemia (T-PLL). This study retrospectively evaluated the efficacy and safety of alemtuzumab in nine Japanese patients with T-PLL at five participating institutions who were treated between January 2015 and August 2023. The median age at first administration of alemtuzumab was 72 years (range, 39 to 78). Two patients were treatment naïve, and seven had been treated with a median of one (range, 1 to 3) prior systemic therapy. Six patients were refractory to their most recent therapy. Three patients completed 12 weeks of treatment. The overall response rate and the complete response (CR) rate were 78% and 11%, respectively. Among the six patients who achieved a partial response, two achieved clinical CR but did not undergo bone marrow examination. One patient also achieved clinical CR but did not undergo CT and bone marrow examination for response evaluation. The median progression-free survival time was 8.1 months (95% confidence interval, 0.9 to 18.6). Three patients received readministration of alemtuzumab monotherapy after disease progression. There were no treatment-related deaths. The grade 3 or 4 nonhematologic adverse events included infusion reaction (grade 3, n = 2), cytomegalovirus reactivation (grade 3, n = 2), and pulmonary edema (grade 3, n = 1). One patient experienced Epstein‒Barr virus-positive diffuse large B-cell lymphoma 15 months after the last dose of alemtuzumab. These results confirm that the efficacy and safety of alemtuzumab monotherapy in Japanese patients are comparable to those previously reported.

DOI： 10.3960/jslrt.24028

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PubMed

記述言語：日本語   出版者・発行元：Japanese Journal of Clinical Oncology  

Adult T-cell leukemia–lymphoma is defined as peripheral T-cell lymphoma caused by the human T-cell leukemia virus type I. Adult T-cell leukemia–lymphoma is classified into indolent (favorable chronic or smoldering) or aggressive (acute, lymphoma or unfavorable chronic) types. This review discusses the therapeutic developments for patients with adult T-cell leukemia–lymphoma and unmet issues in treating adult T-cell leukemia–lymphoma. For indolent adult T-cell leukemia–lymphoma, a watchful waiting strategy is recommended until the disease progresses to aggressive adult T-cell leukemia–lymphoma. For aggressive adult T-cell leukemia–lymphoma, multi-agent chemotherapy with or without allogeneic hematopoietic stem cell transplantation has been recommended. However, many patients with adult T-cell leukemia–lymphoma relapse, and their prognosis is poor. Recently, novel agents, including mogamulizumab, lenalidomide, brentuximab vedotin, tucidinostat and valemetostat, have been approved for patients with relapsed or refractory aggressive adult T-cell leukemia–lymphoma, and the combination of mogamulizumab with multi-agent chemotherapy or brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone has been approved for patients with untreated aggressive adult T-cell leukemia–lymphoma in Japan. Importantly, the aging of patients with adult T-cell leukemia–lymphoma has recently been reported, and no standard of care for elderly patients with adult T-cell leukemia–lymphoma has been established. New evidence must be obtained from prospective clinical trials to improve the prognosis of patients with adult T-cell leukemia–lymphoma.

DOI： 10.1093/jjco/hyad108

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PubMed

記述言語：日本語   出版者・発行元：Microbiology Spectrum  

Antibody screening tests for human T-cell leukemia virus type 1 (HTLV-1) are performed based on methods such as chemiluminescent enzyme immunoassay (CLEIA), chemiluminescence immunoassay (CLIA), electrochemiluminescence immunoassay, and particle agglutination (PA). Espline HTLV-III, a commercially available, easy-to-use, and rapid immunochromatographic antibody test (IC), was developed for situations where expensive instruments and laboratory equipment are not available. In this report, we compared the performance of IC with the above existing tests using diverse samples derived from asymptomatic HTLV-1 carriers and patients with HTLV-1-associated diseases in collaboration with 11 Japanese institutes. We found that IC detected HTLV-1 infection in all samples from HTLV-1-associated diseases, including adult T-cell leukemia, HTLV-1-associated myelopathy, and HTLV-1 uveitis (200200). The sensitivity of IC compared with CLIA, CLEIA, and PA was 99.2% (363366), 100% (241241), and 100% (4747), respectively, and the specificity was 99.4% (9941000), 100% (6060), and 100% (4040), respectively. The positive and negative predictive values of IC were 99.7% [95% confidence interval (CI) 99.12–99.92] and 99.5% (95% CI 98.82–99.75), respectively. However, IC had difficulty in correctly judging samples that were diagnosed as seroreactive in other first screening tests but negative by a confirmatory test; for example, of 612 confirmed negative samples that were CLIA seroreactive, 332 samples were IC positive. These results confirmed that IC has sufficient sensitivity and specificity as a screening test for HTLV-1, although, like the other screening tests, it also requires a confirmatory test to determine HTLV-1 infection correctly. IMPORTANCE The World Health Organization estimated that 5–10 million people are infected with human T-cell leukemia virus type 1 (HTLV-1). This number is likely to be underestimated because reliable endemic data are available for only approximately 1.5 billion people worldwide. The point-of-care test is a powerful tool for the easy and quick detection of infections without the requirement for expensive instruments and laboratory equipment. Espline HTLV-III, a newly developed rapid immunochromatographic antibody test that was evaluated in this study, might significantly advance our understanding of the global epidemiology of HTLV-1 infection.

DOI： 10.1128/spectrum.02078-23

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PubMed

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

エプコリタマブ(Epc)はCD3とCD20への二重特異性抗体製剤である。再発/難治性びまん性大細胞型B細胞リンパ腫(R/R DLBCL)に罹患し、2次以上の治療を既に受け、CD20が陽性であった日本人成人患者へのEpc単独療法を評価したI/II相試験(EPCORE NHL-3)の結果を報告した。Epcは28日サイクルで皮下投与し、疾患進行または許容できない毒性が現れるまで継続した。2022年1月31日時点で36名がEpc 48mgでの単独療法を受けた。追跡期間は中央値で8.4ヵ月であり、独立判定委員会による全奏効率は55.6%、完全奏効率は44.4%となった。奏効期間、完全奏効期間、全生存期間はいずれも「到達せず」となった。治療下で発現した、有害事象(全グレード含む)で最も多かったものは、サイトカイン放出症候群(83.3%)、注射部位反応(69.4%)、感染症(44.4%)、好中球数減少(38.9%)、低カリウム血症(27.8%)、リンパ球数減少(25.0%)であった。サイトカイン放出症候群は予測可能であり、グレードが主に1～2と低グレードで、治療中止に至った例は無かった。

記述言語：日本語   出版者・発行元：Cancer Science  

Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL-1. Here, we present results from the similar EPCORE NHL-3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20⁺ B-cell non-Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28-day cycles; once weekly during cycles 1–3, every 2 weeks during cycles 4–9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step-up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow-up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut-off. The most common treatment-emergent adverse events of any grade were CRS (83.3%), injection-site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1–2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines.

DOI： 10.1111/cas.15996

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記述言語：日本語   出版者・発行元：Vaccine  

This prospective observational study aimed to assess the serological response and safety after the third booster shot of SARS-CoV-2 mRNA vaccines in 292 hematopoietic cell transplant (HCT) recipients. In our patients, mild systemic reactions were present in 10–40% and GVHD aggravation in 1.1%. Overall, clinically relevant response (>250 U/mL) was observed in 93.1% of allogeneic (allo)-HCT recipients and 70.6% of autologous (auto)-HCT recipients, respectively. Of note, detectable antibody response with any titer following the first two doses was a powerful predictor for adequate response after booster shot in both cohorts. For such patients, 98.8% of allo- and 92.3% of auto-HCT recipients obtained clinically relevant response after dose 3. In addition, continued systemic steroid and/or calcineurin inhibitors at the booster shot significantly correlated with serological response. These findings highlighted that booster vaccination efficiently improved serological response without safety concerns and thus recommended for the majority of HCT recipients.

DOI： 10.1016/j.vaccine.2023.08.066

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PubMed

記述言語：英語   出版者・発行元：公益社団法人 日本薬学会  

Adult T-cell leukemia/lymphoma (ATL) is a hematopoietic malignancy with a poor prognosis that develops in approximately 5% of human T-cell leukemia virus type 1 (HTLV-1) carriers. Cyclin-dependent kinase 9 (CDK9), together with Cyclin T, forms a transcription elongation factor, positive transcription elongation factor b (P-TEFb). P-TEFb promotes transcriptional elongation by phosphorylating the second serine (Ser2) of the seven amino acid repeat sequence in the C-terminal domain of RNA polymerase II (RNAP II). CDK9 inhibitors suppress cell proliferation by inducing apoptosis in chronic lymphocytic leukemia and breast cancer but there are no reports on autophagy of CDK9 inhibitors. Here, we investigated the effect of LY2857785, a novel CDK9 selective inhibitor, on cell death in ATL-related cell lines in vitro, freshly isolated cells from ATL patients ex vivo, and on ATL tumor xenografts in NOD/SCID mice in vivo. LY2857785 significantly reduced cell viability and induced apoptosis, as shown by annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-3, and suppressed the levels of anti-apoptotic protein myeloid cell leukemia-1 (MCL-1). LY2857785 decreased RNAP II Ser2 phosphorylation and downstream c-Myc protein levels. Interestingly, LY2857785 also increased microtubule-associated proteins 1A/1B light chain 3B (LC3)II binding to autophagosome membranes. Furthermore, LY2857785 decreased the viability of freshly isolated ATL cells and induced apoptosis. Finally, LY2857785 significantly decreased the growth of ATL tumor xenografts. These results suggest that LY2857785 induces cell death of ATL cells by MCL-1-dependent apoptosis and autophagy and has anti-tumor activity.

DOI： 10.1248/bpb.b23-00228

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PubMed

記述言語：日本語   出版者・発行元：Journal of Natural Medicines  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T-lymphocytes caused by human T-cell leukemia virus type I (HTLV-I). There are an estimated 5–20 million HTLV-1-infected individuals worldwide. Conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to patients with ATL, but the therapeutic outcomes of acute and lymphoma-type ATL remain extremely poor. In the course of our screening program for novel chemotherapeutic candidate compounds from plants against two human T-cell leukemia virus I-infected T-cell lines (MT-1 and MT-2), we screened 16 extracts obtained from different parts of 7 Solanaceae plants. We identified that the extracts of Physalis pruinosa and P. philadelphica showed potent anti-proliferative activity in MT-1 and MT-2 cells. In our previous study, we have isolated withanolides from extract of aerial parts of P. pruinosa and examined their structure–activity relationships. In addition, we are also investigating further structure–activity relationships about other withanolides from Solanaceae plants (Withania somnifera, Withania coagulans, Physalis angulate, Nicandra physalodes, Petunia hybrida, and Solanum cilistum). In this study, we attempted to isolate their active compounds against MT-1 and MT-2 from extracts of P. philadelphica. We identified 13 withanolides, including six newly isolated compounds [24R, 25S-4β, 16β, 20R-trihydroxy-1-oxowitha-2-en-5β, 6 β -epoxy-22,26-olide (1), 4β, 7β,20R-trihydroxy-1-oxowitha-2-en-5β, 6β -epoxy-22,26-olide (2), 17β,20 S-dihydroxywithanone (3), 2,3-dihydro-3β-methoxy-23β-hydroxywithaphysacarpin (4), 3-O-(4-rhamnosyl)glucosyl-physalolactone B (5), and 17R, 20R, 22S, 23S, 24R, 25R-4β, 5α, 6β, 20β, 22α -tetrahydroxy-16β, 23-diepoxy-1-oxowitha-2-en-26, 23-olide (6)], from the extract and examined the structure–activity relationships. The 50% effective concentration of withaphysacarpin (compound 7) [MT-1: 0.10 µM and MT-2: 0.04 µM] was comparable to that of etoposide [MT-1: 0.08 µM and MT-2: 0.07 µM]. Therefore, withanolides might be promising candidates for the treatment of ATL.

DOI： 10.1007/s11418-023-01705-x

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PubMed

記述言語：英語   出版者・発行元：(公社)日本薬学会  

成人T細胞性白血病/リンパ腫(ATL)関連細胞株培養系、ATL患者から分離した細胞の体外培養系、ATLを移植したNOD/SCIDマウスxenograft系での細胞死に対して新規のCDK9選択的阻害薬LY2857785が及ぼす影響を解析した。LY2857785は細胞の生存率を有意に低下させ、アネキシンV陽性細胞、ポリ(ADP-リボース)ポリメラーゼの切断、断片化カスパーゼ3の増加、および抗アポトーシスタンパク質であるMCL-1タンパク質の減少を誘導した。LY2857785は、RNAポリメラーゼII Ser2のリン酸化とシグナル下流のc-Mycタンパク質量を減少し、microtubule-associated proteins 1A/1B light chain 3B-IIのオートファゴソーム膜への結合量を増加し、新規に分離したATL細胞の生存率を低下させた。また、ATL xenograftの成長を有意に抑制した。

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

2種類の成人ヒトT細胞白血病(ATL)ウイルスI感染T細胞株(MT-1、MT-2)に対する植物由来の新規化学療法候補化合物のスクリーニング過程で、7種類のナス科植物から得た16種類のエキスを調査した。その結果、Physalis pruinosa(I)とP.philadelphica(II)のエキスがMT-1とMT-2に強力な抗増殖活性を示すことを確認した。以前の研究では、Iのエキスからwithanolide(WIT)類を単離し、それらの構造活性相関を調査した。別の6種類のナス科植物のWIT類について、更に構造活性相関性を調査した。IIのエキスからMT-1とMT-2に活性を示す化合物を単離した。その結果、既知化合物であるwithaphysacarpinの50%有効濃度はMT-1とMT-2に対してそれぞれ0.10と0.04μMで、参照化合物のエトポシド(0.08μMと0.07μM)に匹敵した。以上より、WIT類はATLの治療に対して有望な候補化合物になりうると考えられた。

記述言語：英語   出版者・発行元：Ferrata Storti Foundation (Haematologica)  

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3).

DOI： 10.3324/haematol.2022.281510

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PubMed

担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Haematology  

Essential thrombocythemia (ET) cases without canonical JAK2, CALR, or MPL mutations, that is, triple-negative (TN) ET, have been found in 10%–20% of ET cases. Owing to the limited number of TN ET cases, its clinical significance remains unclear. This study evaluated TN ET's clinical characteristics and identified novel driver mutations. Among 119 patients with ET, 20 (16.8%) had no canonical JAK2/CALR/MPL mutations. Patients with TN ET tended to be younger and had lower white blood cell counts and lactate dehydrogenase values. We identified putative driver mutations in 7 (35%): MPL S204P, MPL L265F, JAK2 R683G, and JAK2 T875N were previously reported as candidate driver mutations in ET. Moreover, we identified a THPO splicing site mutation, MPL*636Wext*12, and MPL E237K. Four of the seven identified driver mutations were germline. Functional studies on MPL*636Wext*12 and MPL E237K revealed that they are gain-of-function mutants that increase MPL signaling and confer thrombopoietin hypersensitivity with very low efficiency. Patients with TN ET tended to be younger, although this was thought to be due to the inclusion of germline mutations, hereditary thrombocytosis. Accumulating the genetic and clinical characteristics of noncanonical mutations may help future clinical interventions in TN ET and hereditary thrombocytosis.

DOI： 10.1111/ejh.13945

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.15746.

記述言語：日本語   出版者・発行元：Cancer Science  

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3A^R822) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.

DOI： 10.1111/cas.15746

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PubMed

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

標準治療に不適格な再発/難治性急性骨髄性白血病(R/R-AML)患者や新規診断非適応AML患者の臨床的特徴および転帰に関連するゲノム異常を検討するため、パラフィン包埋骨髄クロット標本を用いた多施設共同研究を実施した。AML患者188例が登録され、437遺伝子のDNAと265遺伝子のRNAについてターゲットシーケンシングが行われた。骨髄クロット標本から質の高いDNAとRNAが得られ、177例(97.3%:年齢中央値63歳)で遺伝子変化、41例(23.2%)で融合転写産物が検出された。検査所要期間央値は13日であった。融合遺伝子では、RUNX1-RUX1T1やKMT2Aの再配列のような一般的な融合産物だけでなく、NUP98再配列や稀な融合遺伝子も観察された。患者177例(非適応AML72例、R/R-AML105例)のうち、KITとWT1の変異は全生存率の独立因子であり(ハザード比:それぞれ12.6と8.88)、TP53変異の対立遺伝子頻度が高い(40%以上)患者は予後不良であった。実用的な変異の検出に関しては、患者69例(38%)が治療選択に有用な遺伝子変異(FLT3-ITD/TKD、IDH1/2、DNMT3AR822)を有していた。

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-023-03573-3.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3324/haematol.2022.281435.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-023-01919-3

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Leukemia and Lymphoma  

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type-I (HTLV-1). This study investigated whether the number of newly diagnosed patients with ATL is decreasing in the background of a declining number of individuals infected by HTLV-1 in Kagoshima, Japan, one of the most endemic areas of HTLV-1 in the world. We retrospectively analyzed the number of newly diagnosed patients with ATL between January 2001 and December 2021 in three major hospitals. The number of newly diagnosed patients with B-cell non-Hodgkin lymphoma (B-NHL) in the same period was examined as an internal control. One thousand eighteen and 2,029 patients with ATL and B-NHL were registered, respectively. The age-adjusted incidence of ATL steadily increased between 2001 and 2012, whereas that between 2013 and 2021 decreased. Despite the limitation of its retrospective nature, this is the first report indicating a decrease in ATL patients in Japan.

DOI： 10.1080/10428194.2023.2173524

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PubMed

記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

症例1は29歳のフィリピン人男性で、2年前に来日し、肝脾T細胞リンパ腫と診断されていた。臍帯血移植後の発熱性好中球減少症のためセフェピム、メロペネムを投与され解熱したが、発熱が再発し、汎血球減少が認められ肺炎を発症した。テイコプラニンを追加投与したが発熱は持続した。血液培養でElizabethkingia anophelisが分離された。メロペネムからシプロフロキサシン(CPFX)に変更して支持療法を継続したが発熱は治まらず、呼吸不全により死亡した。症例2は52歳男性で、全身性エリテマトーデスのため他院で免疫抑制療法を受けていたが、意識障害のため当院に移送された。造影CTで前立腺に膿瘍が示唆された。血液と脳脊髄液からE.anophelisが分離された。ミノサイクリンとCPFX、その後はピペラシリン/タゾバクタムに変更して治療したが、発熱が続くため緩和ケア病院へ移送され、その後死亡した。2症例から分離されたE.anophelisの同定はfastANIと164参照株により確認された。コア遺伝子SNPベースの系統樹解析により、症例1由来株は2015～2016年の米国ウィスコンシン州アウトブレイク株、症例2由来株は1982年の米国フロリダ州の患者脳脊髄液からの分離株とそれぞれ密接な関係にあった。2分離株のゲノムには莢膜多糖体合成遺伝子群、カタラーゼーペルオキシダーゼ酵素、VI型分泌系タンパク質だけでなく、いくつかの薬剤耐性関連遺伝子も含まれていた。

記述言語：日本語   出版者・発行元：International Journal of Hematology  

T-cell lymphomas are rare and aggressive tumors, and not only basic research but also the establishment of standard therapies and development of novel drugs for these tumors once lagged behind those for B-cell lymphomas. Now, times have changed. Recent progress in genome-wide analysis made it possible to elucidate the molecular pathophysiology of T-cell lymphomas, and will further facilitate the development of individualized treatment. Japan has a terrible form of virally induced T-cell lymphoma known as adult T-cell leukemia/lymphoma (ATL). Japanese researchers have played significant roles in both basic and clinical research, and finally successfully introduced two brand new drugs from Japan, an anti-CCR4 antibody and an EZH1/2 inhibitor. Large phase 3 trials have now established the addition of brentuximab vedotin to conventional chemotherapy as the standard of care for CD30-positive peripheral T-cell lymphoma (PTCL), including ATL. In contrast, most novel drugs for relapsed/refractory PTCL have been approved on the basis of evidence from small phase 2 trials. Patients still have many unmet needs that we must address. This issue of Progress in Hematology focuses on progress in basic and clinical research on PTCL and ATL.

DOI： 10.1007/s12185-023-03573-3

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記述言語：日本語   出版者・発行元：Journal of Infection and Chemotherapy  

Objective: Elizabethkingia anophelis causes meningitis, bloodstream infections, and respiratory infections in immunocompromised individuals. We examined two E. anophelis strains isolated from the first life-threatening cases caused by this species in Japan to determine the phylogenetic origin and genomic features of them. Methods: We performed whole genome-based analysis to clarify the genetic relationship for the two strains (EK0004 and EK0079) and Elizabethkingia sp. strains isolated from worldwide and to characterize the genomic features such as the prevalence of virulence- and antimicrobial resistance (AMR)-related genes. Patients: A 29-year-old man with hepatosplenic T-cell lymphoma and a 52-year-old man with systemic lupus erythematosus developed fatal bacteremia and meningitis due to E. anophelis, respectively. Results: Two strains, EK0004 and EK0079, were genetically different but most closely related to the strains isolated from the largest outbreak in Wisconsin, USA from 2015 to 2016, and the strain isolated from cerebrospinal fluid of a patient in Florida, USA in 1982, respectively. The two strains contained AMR-related genes such as those encoding for an extended-spectrum β-lactamase and multiple metallo-β-lactamases and several virulence-related genes such as capsular polysaccharide synthesis gene clusters. Conclusions: Although further functional analyses are required to understand the virulence of these clones, these finding suggests that enough caution of E. anophelis infection in immunocompromised patients is required since the number of infections by this species is increasing outside Japan.

DOI： 10.1016/j.jiac.2023.01.005

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PubMed

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本リンパ腫学会  

Several prognostic indices have been reported for peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). The clinical features and prognosis of PTCL differ in a specified pathological diagnosis, whereas those of ATL are more diverse, even in the same clinical subtypes of acute, lymphoma, chronic, and smoldering. The establishment of a prognostic index is important not only for a risk-stratified treatment approach, but also for the preliminary evaluation of therapeutic findings by novel modalities, particularly in rare and aggressive diseases such as ATL. Five prognostic indices for PTCL-not otherwise specified and 6 prognostic indices for ATL are discussed herein. Recent advances in molecular analyses have facilitated prognostication using molecular profiles. In addition to the external validation of these prognostic indices, which are mostly established by clinical information, the development of novel indices by incorporating molecular profiles is warranted to improve the outcomes of patients through the selection of optimal treatments.

DOI： 10.3960/jslrt.22034

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PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood.2022016862.

記述言語：日本語   出版者・発行元：Blood  

Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.

DOI： 10.1182/blood.2022016862

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3324/haematol.2022.280996.

記述言語：日本語   出版者・発行元：Haematologica  

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval: 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

DOI： 10.3324/haematol.2022.280996

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担当区分：最終著者,　責任著者   記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-022-03473-y.

記述言語：日本語   出版者・発行元：International Journal of Hematology  

Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the “iATL-PI,” has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses.

DOI： 10.1007/s12185-022-03473-y

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

症例は35歳女性,22歳時に慢性骨髄性白血病(chronic myeloid leukemia,CML)と診断されBCR::ABL1チロシンキナーゼ阻害薬(tyrosine kinase inhibitors,TKI)治療を受けた。4年間のdeep molecular responseを得てTKI休薬下での自然妊娠を計画した。妊娠時点でMR2.0となったものの,患者背景を考慮しinterferon α治療を開始し,MR3.0～4.0を維持して健常児を出産し,約半年間の授乳後にTKIを再開した。TKIによってCMLの予後は大きく改善した。TKIには流産や催奇形性リスクがあることから,挙児希望のあるCML女性患者の妊娠・出産に対してはtreatment-free remissionを試み,病勢コントロール,患者背景を踏まえた総合的な配慮が必要である。(著者抄録)

記述言語：英語   出版者・発行元：(一社)日本血液学会  

くすぶり型および慢性型成人T細胞白血病リンパ腫(ATL)患者に関する既報データを再検討することにより、可溶性インターロイキン2受容体の値に基づくindolent ATL予後指標(iATL-PI)を検証した。iATL-PIの有効性を評価するため、2010～2011年に診断したくすぶり型または慢性型ATL患者176例(くすぶり型76例[年齢40～89歳]、慢性型100例[年齢36～85歳])のデータと、その後の2016～2017年の予後に関する追跡調査のデータを解析した。ATL診断時の低リスク、中リスク、高リスクのiATL-PI群の割合は、くすぶり型ATLではそれぞれ44.7%、48.7%、5%、良好な慢性ATLでは6.3%、71.9%、21.9%、好ましくない慢性ATLでは5.9%、27.9%、66.2%であった。全体としてくすぶり型または慢性型ATLの患者の生存率は、三つのiATL-PI群によって有意に層別化された。低iATL-PIリスク群の好ましくない慢性型ATL患者の多くは、緩やかな臨床経過をたどった。以上より、iATL-PIは多様な臨床経過を持つくすぶり型および慢性型ATLの予後を予測する有用なツールになり得ることが示された。

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

<p>成人T細胞白血病・リンパ腫（ATL）はヒトT細胞白血病ウイルスI型（HTLV-1）により起こされる末梢性T細胞腫瘍である．indolent ATLとaggressive ATLに分類され，標準治療はindolent ATLに対してはaggressive ATLになるまで無治療経過観察，aggressive ATLに対しては多剤併用化学療法，臓器機能が良好な65歳～70歳以下の症例ではさらに同種造血幹細胞移植を実施することである．同種移植の対象は骨髄非破壊的移植や臍帯血移植，半合致移植が可能になることにより拡大し，予後改善に寄与している．新規薬剤として抗体薬，抗体薬物複合体，免疫調整薬，エピジェネティック薬が日常臨床に導入され，今後さらに本疾患の分子病態に基づいた治療開発が発展することが期待される．</p>

DOI： 10.2169/naika.112.89

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajh.26769.

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：American Journal of Hematology  

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/μL, 1 points), absolute B-cell counts (<100/μL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1–3, and 4–7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

DOI： 10.1002/ajh.26769

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>Enhancer of zeste homolog（EZH）はpolycomb repressive complex 2（PRC2）のサブユニットの一つでヒストンメチル基転移酵素活性を持ち，H3K27メチル化を介して遺伝子発現を制御する。EZHは一部の悪性リンパ腫の病態に大きく関与している。濾胞性リンパ腫（FL）ではEZH2の機能獲得型変異と遺伝子増幅がそれぞれおよそ30，15％に見られる。成人T細胞白血病・リンパ腫（ATL）細胞ではEZH1/2の発現亢進によるH3K27のトリメチル化が特徴的であり，ATL細胞において発現が抑制されている遺伝子の半数以上がH3K27のトリメチル化状態にある。現在EZH2，EZH1/2阻害薬がそれぞれ再発・難治FLとATLに使用可能となっている。悪性リンパ腫におけるEZH標的化治療はまだまだ開始されたばかりであり，今後の展開が期待される。</p>

DOI： 10.11406/rinketsu.64.665

PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>症例は35歳女性，22歳時に慢性骨髄性白血病（chronic myeloid leukemia, CML）と診断されBCR::ABL1チロシンキナーゼ阻害薬（tyrosine kinase inhibitors, TKI）治療を受けた。4年間のdeep molecular responseを得てTKI休薬下での自然妊娠を計画した。妊娠時点でMR2.0となったものの，患者背景を考慮しinterferon α治療を開始し，MR3.0～4.0を維持して健常児を出産し，約半年間の授乳後にTKIを再開した。TKIによってCMLの予後は大きく改善した。TKIには流産や催奇形性リスクがあることから，挙児希望のあるCML女性患者の妊娠・出産に対してはtreatment-free remissionを試み，病勢コントロール，患者背景を踏まえた総合的な配慮が必要である。</p>

DOI： 10.11406/rinketsu.64.102

PubMed

記述言語：日本語   出版者・発行元：BMC Cancer  

Background: Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Methods: We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation. Results: Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines. Conclusions: These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.

DOI： 10.1186/s12885-022-10003-w

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PubMed

担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12885-022-10003-w.

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Leukemia and Lymphoma  

Mogamulizumab (Mog), an anti-C-C motif chemokine receptor 4 (CCR4) antibody, is a therapeutic for adult T-cell leukemia/lymphoma (ATL). Injuries of normal regulatory T cells (Tregs) which express CCR4 by Mog could result in immune-related adverse events including graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we retrospectively analyzed 25 patients among 39 patients with ATL who received allo-HSCT. We found that the risk of grade II to IV GVHD was higher in patients who received Mog before or after allo-HSCT (Mog+) than in those who did not (Mog−). The incidence of severe intestinal GVHD and cytomegalovirus (CMV) enteritis were significantly higher in Mog + patients and resulted in death from GVHD or CMV enteritis. Treg numbers were suppressed until Mog serum concentrations became undetectable. Measuring the concentration of Mog and/or the number of Tregs at the time of allo-HSCT might predict the risk of GVHD.

DOI： 10.1080/10428194.2022.2043300

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FEBS Journal  

Adult T-cell leukemia/lymphoma (ATL) develops after a long period of human T-cell leukemia virus (HTLV)-1 infection and is associated with host aging in addition to genetic abnormalities in HTLV-1 infected cells. SIRT1 is a histone deacetylase involved in cell cycle and apoptosis. We previously showed the high expression of SIRT1 protein in peripheral blood mononuclear cells from patients with ATL. There have been many reports that SIRT1 inhibitors show tumor-suppressive effects. On the other hand, SIRT1 activator SRT1720 induces the cell death of multiple myeloma and breast cancer cells. However, the effect of SRT1720 on ATL is unknown. This study aimed to evaluate the effect of SRT1720 on cell death in leukemic cell lines in vitro and freshly isolated ATL cells ex vivo and in an ATL in vivo mouse model. SRT1720 reduced cell viability in vitro and ex vivo. Additionally, SRT1720 increased the number of apoptotic cells, as shown by annexin V positive cells, cleaved poly (ADP-ribose) polymerase 1, cleaved caspase-3, and fragmented DNA. SRT1720 also induced mitochondrial outer membrane permeabilization with the generation of mitochondrial reactive oxygen species and autophagy. However, SIRT1 knockdown did not attenuate SRT1720-induced cell death in leukemic cell lines. Finally, SRT1720 treatment decreased the growth of human ATL tumor xenografts in immunodeficient mice. Our study shows that while SRT1720 does not target SIRT1, it induces cell death in ATL cells via apoptosis and autophagy and has antitumor activity.

DOI： 10.1111/febs.16353

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PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0267572.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内科学会  

Adult T-cell leukemia/lymphoma (ATL) is a refractory T-cell lymphoma with variable clinical profiles, commonly exhibiting extra-nodal involvement. The myocardial involvement of ATL is often detected at an autopsy; however, the development of a symptomatic cardiac mass due to ATL is extremely rare. We herein report a 65-year-old man with ATL who developed cardiac symptoms due to a rapidly enlarging left ventricular mass soon after the initiation of systemic chemotherapy. We also summarize previously reported cases of symptomatic ATL with cardiac involvement.

DOI： 10.2169/internalmedicine.7925-21

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PubMed

記述言語：日本語   出版者・発行元：Plos One  

Background and aims Immune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach. Methods In this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed. Results Two-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group. Conclusions Patients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.

DOI： 10.1371/journal.pone.0267572

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PubMed

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は65歳男性で、左下腹部痛を認め、造影CT検査で小腸腫瘤が判明した。腹腔鏡下小腸切除術を行い、免疫組織化学的所見はCD4、CD25、CCR4に陽性、TIA-1とEBERに陰性であった。血清HTLV-1抗体が陽性であったことから、急性型成人T細胞白血病/リンパ腫(ATL)と診断した。重度の徐脈が出現し、恒久的ペースメーカー植え込みを行った。冠動脈血管造影で左心房下行動脈の著明な狭窄が判明し、経皮的冠動脈インターベンションを行った。診断の2ヵ月後、ATL治療のために入院した。治療前の経胸壁心エコー検査(TTE)で、心臓腫瘤は検出されなかった。多剤化学療法(VCAP-AMP-VECP)+モガムリズマブの2サイクル目に動悸と労作性息切れが報告され、TTEで左室中隔の中央部に36×25mmの有茎性腫瘤、左室流出路と冠静脈洞の腫瘤が判明した。心臓腫瘤によるATL再燃が疑われた。ゲムシタビン、デキサメタゾン、シスプラチンによる併用化学療法を行うと、心内腫瘤が一過性に縮小したが、3サイクル後に再拡大した。心症状の出現後4ヵ月時、心不全とATL増悪により死亡した。

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/naika.111.566

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood.2021013568.

記述言語：日本語   出版者・発行元：Blood  

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform–specific inactivation of Cic selectively increased CD4⁺CD25⁺Foxp3⁺ T cells in vivo. We also found recurrent (13%) 3′-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell–like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

DOI： 10.1182/blood.2021013568

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjh.17895.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-021-01412-9.

記述言語：日本語   出版者・発行元：British Journal of Haematology  

‘Monitoring of immune responses following mogamulizumab-containing treatment in patients with adult T-cell leukaemia–lymphoma (ATL)’ (MIMOGA) is a multicentre prospective clinical study (UMIN000008696). In the MIMOGA study, we found that a lower percentage of CD2⁻CD19⁺ B cells in peripheral blood mononuclear cells (PBMC) was a significant unfavourable prognostic factor for overall survival (OS). Accordingly, we then analysed the immunoglobulin G (IgG) heavy-chain repertoire in PBMC by high-throughput sequencing. Of the 101 patients enrolled in the MIMOGA study, for 81 a sufficient amount of PBMC RNA was available for repertoire sequencing analysis. Peripheral IgG B cells in patients with ATL had a restricted repertoire relative to those in healthy individuals. There was a significant positive correlation between the Shannon–Weaver diversity index (SWDI) for the IgG repertoire and proportions of B cells in the PBMC of the patients. Multivariate analysis identified two variables significantly affecting OS: a higher serum soluble interleukin-2 receptor level, and a lower SWDI for the IgG repertoire [hazard ratio, 2·124; 95% confidence interval, 1·114–4·049; n = 44]. The present study documents the importance of humoral immune responses in patients receiving mogamulizumab-containing treatment. Further investigation of strategies to enhance humoral immune responses in patients with ATL is warranted.

DOI： 10.1111/bjh.17895

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本臨床薬理学会  

<p>【目的】モガムリズマブ (Mog) は日本発の抗CCR4モノクローナル抗体であり、成人T細胞白血病リンパ腫 (ATL) 等の患者に対する治療薬である。本剤での治療に際し、Stevens-Johnson症候群や中毒性表皮壊死症 (SJS/TEN) 等の重篤な有害事象が報告されており、これらの発症リスクを予測するバイオマーカーの同定は喫緊の課題である。一方、アロプリノール等の低分子医薬品により発症するSJS/TENについては、特定のHLAアリルの関連が示されている。これらより、本研究ではMog投与による皮膚障害発症に関連するゲノムマーカー (HLA) の探索を目的とした。【方法】複数の研究連携施設においてMogの投与を受けたATL患者を対象とし、後方視的解析を行った。CTCAE v5.0でGrade 2以上の皮膚及び皮下組織障害を認めた患者を発症群、Grade 1以下の患者を対照群とした。患者ゲノムDNAを用いて<i>HLA-A, B, C, DPB1, DQB1, DRB1</i>アリルを同定し、発症群に関連するアリルをFisherの正確検定にて探索した。探索したアリルに加えて患者背景因子を説明変数とした多変量ロジスティック回帰分析を行った。本研究は名古屋市立大学大学院医学研究科及び各参加医療機関での研究倫理委員会の承認を得た。また、全ての解析対象患者から文書による同意を得て実施した。【結果・考察】男性74、女性61、合計135人のATL患者を対象とした。年齢中央値は67歳(範囲: 37- 87歳、年齢情報1人欠損)、急性型95、リンパ腫型20、慢性型14、くすぶり型3人であった(病型情報3人欠損)。単変量解析の結果、<i>DRB1^*14:05</i>(+)(n＝8)のみが発症群66/135人と関連する可能性が示された(オッズ比[OR]: 7.97, 95%信頼区間[CI]: 1.05-181.69)。次に<i>DRB1^*14:05</i>(+)、性別、年齢(＞ 70 vs ≦ 70 歳)、臨床病型を変数とした多変量ロジスティック回帰分析を行った(n＝131)。結果、<i>DRB1^*14:05</i>(+)(OR: 10.48, 95%CI: 1.13-97.14)及び、非リンパ腫型(OR: 4.74, 95%CI: 1.43-15.72)が有意に発症群と関連した。つまり患者背景因子を平準化した解析で、<i>DRB1^*14:05</i>アリルの有無は、Mog投与による、grade 2以上の皮膚関連有害事象発症の、独立した有意なリスク因子であることが示された。【結論】<i>DRB1^*14:05</i>アリルを有する患者は、Mog関連の皮膚障害発症にリスクを有する可能性が示唆された。より多数例での検証的解析、及び他の本剤対象疾患での解析が望まれる。</p>

DOI： 10.50993/jsptsuppl.43.0_1-c-o02-3

DOI： 10.3390/molecules26247619.

記述言語：日本語   出版者・発行元：Molecules  

During the screening of novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, we identified that the extracts of Thuja occidentalis (Cupressaceae) showed potent anti-proliferative activity in MT-1 and MT-2 cells. Therefore, we attempted to isolate the active components from this plant. We isolated and identified 32 compounds (1–32; eight lignans, 18 terpenoids, and six flavonoids) from the extracts of the leaves and cones. Their structures were determined by spectroscopic analysis. Several of the isolated compounds inhibited the growth of both cell lines. Lignans showed more potent activity than other classes of compounds. A comparison of the activities of compounds 1–8 revealed that the presence of a trans-lactone (linkage of C-6 to C-7) correlated with increased activity. Diterpenes showed moderate activity, and the presence of a ketone moiety at the C-7 position correlated with increased activity in compounds 12–21. In addition, biflavones showed moderate activity, and the presence of methoxy functions appeared to influence the activity of these compounds. Several lignans were lead compound of anti-cancer reagent (etoposide). In conclusion, not only lignans, but also diterpenes and/or biflavones, may be promising candidates for the treatment of adult T-cell leukemia/lymphoma.

DOI： 10.3390/molecules26247619

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Adult T-cell leukemia-lymphoma (ATL) is a T-cell malignancy that is endemic to Japan. In this latest nationwide study of ATL, we collected the data from 4 nationwide registries of patients diagnosed in 2012-2013; the Hematology Blood Disease, the Skin Cancer Society, the Hospital-Based Cancer Registries, and information from the hospitals that participated in the Japanese nationwide survey of ATL in 2010-2011. In the present study, 2614 patients with ATL were diagnosed based on the registries, and 117 departments registered 1042 patients. Among these patients, 984 were eligible for analysis. The median age at diagnosis was 69 y. A larger proportion of patients with ATL older than 70 y was diagnosed with the lymphoma subtype, and more than half of the patients with ATL in the metropolitan areas were born in the human T-cell leukemia virus type I (HTLV-1)-endemic areas of Kyushu/Okinawa, which are almost identical to the findings in our 2010-2011 study. Additionally, we identified that patients with ATL migrated from the endemic areas for HTLV-1 to the non-endemic metropolitan areas. The present study was able to reduce the burden of searching each hospital and to update the clinico-epidemiological characteristics of a large number of patients with ATL in Japan, suggesting the usefulness and feasibility of the novel data collection method. The establishment of a more sophisticated database management system for ATL is necessary for future continuous surveys.

DOI： 10.1111/cas.15097

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PubMed

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

2012～2013年に新たに成人T細胞白血病・リンパ腫(ATL)と診断された患者の全国調査を実施した。日本の三つの全国登録システム(血液疾患、皮膚がん学会、院内がん登録)のデータおよび2010年から2011年までのATLの日本全国調査に参加した病院からのデータを収集した。それらの登録に基づき2614名のATL患者が診断され、117診療科で1042名の患者が登録されていた。解析対象とした患者984名の診断時の年齢中央値は69歳であった。70歳以上のATL患者ではリンパ腫亜型の割合が多く、大都市圏のATL患者の半数以上は九州・沖縄のヒトT細胞白血病ウイルスI型(HTLV-1)流行地域で生まれており、2010から2011年までの調査結果とほぼ同様であった。さらに、ATL患者がHTLV-1の流行地域から非流行地域である大都市圏に移動していることも確認された。以上より、新しいデータ収集方法を用いることにより日本におけるATL患者の臨床疫学的特徴を更新することができた。

出版者・発行元：南江堂  

DOI： 10.15106/j_naika128_261

記述言語：日本語   出版者・発行元：Seminars in Hematology  

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1). Between 3% and 5% of HTLV-1-infected individuals develop ATL after a long latency. Confirmation of seropositivity of anti-HTLV-1 antibody, and clonal proliferation of CD4 and CD25 positive lymphocytes with nuclear pleomorphism in patients suspicious of malignant lymphoma or chronic lymphocytic leukemia is crucial for the diagnosis of ATL. The clinical course of ATL is very heterogeneous, and divided into acute, lymphoma, chronic, and smoldering types. The chronic type is further subclassified into the favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL, and favorable chronic and smoldering type ATL are defined as aggressive and indolent ATL, respectively. Recently identified prognostic indices based on clinical parameters and/or genetic predictors of outcomes need to be confirmed and incorporated for more stratified therapeutic interventions. The standard of care for aggressive ATL is multiagent chemotherapy followed by allogeneic hematopoietic stem cell transplantation if possible, while that for indolent ATL is watchful waiting until progression to aggressive ATL. The combination of interferon-α and zidovudine is also standard for leukemic type ATL. In addition, mogamulizumab, lenalidomide, and brentuximab vedotin have been incorporated into clinical practices in Japan. Furthermore, several novel drugs are currently undergoing clinical trials.

DOI： 10.1053/j.seminhematol.2021.02.005

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PubMed

記述言語：日本語   出版者・発行元：European Journal of Haematology  

Objectives: Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy caused by long-term infection with human T-cell leukemia virus type-1 (HTLV-1). While ATL pathogenesis has been associated with HTLV-1-derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined. Methods: To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL. Results: We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11-0.68). Despite being reported in cutaneous T-cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF-κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-κB activity and significantly increased IL-2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax. Conclusions: We identified, and functionally validated, a novel gain-of-function mutation in patients with aggressive ATL. During TCR activation by Tax or gain-of-function mutations, RLTPR Q575E selectively upregulates NF-κB signaling and may exert oncogenic effects on ATL pathogenesis.

DOI： 10.1111/ejh.13540

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>成人T細胞白血病・リンパ腫（ATL）はヒトT細胞白血病ウイルスI型が原因の末梢性T細胞腫瘍で，aggressive ATLとindolent ATLに二分し治療が行われてきた。70歳以下のaggressive ATLに対してはVCAP-AMP-VECP療法が標準治療とされ，さらに可能な限り同種造血幹細胞移植が実施されている。新規薬剤としてmogamulizumab，lenalidomide，brentuximab vedotinが導入され，再発・難治例に対しHDAC阻害薬が承認申請中，EZH1/EZH2阻害薬は第II相試験の登録が終了している。Indolent ATLに対しては無治療経過観察が行われてきたが，海外で頻用されるinterferon-αとzidovudineの併用療法について，本邦で前向き臨床試験を実施している。今後ATL患者は高齢化が進むことから，未だ全く決定されていない高齢者に対する標準治療の開発が重要になる。</p>

DOI： 10.11406/rinketsu.62.766

PubMed

記述言語：日本語   出版者・発行元：Cancer Science  

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.

DOI： 10.1111/cas.14658

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PubMed

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

2010～2011年に成人T細胞白血病/リンパ腫(ATL)と診断され、2016～2017年まで登録された患者の予後を臨床的サブタイプ別および治療法別に評価するための観察的多施設共同病院ベースの後方視的研究を行った。対象の患者770例のうち、391例が急性型、192例がリンパ腫型、106例が慢性型、81例がくすぶり型であった。急性型患者391例のうち、343例が化学療法を受けた。その化学療法レジメンの内訳は、161例がVCAP-AMP-VECP様レジメン、132例がCHOP様レジメン、残りがその他のレジメンであった。急性型ATL患者62例が同種造血幹細胞移植を受けた。最終の観察時点で、患者770例のうち243例が生存した。全ATL患者の4年後の生存率は24.8%で、サブタイプ別では、急性型、リンパ腫型、好ましくない慢性型、好ましい慢性型、くすぶり型の4年生存率(生存期間の中央値)は、それぞれ16.8%(252日)、19.6%(305日)、26.6%(572日)、62.1%(1937日)、59.8%(1851日)であった。急性型とリンパ腫型ATLの4年生存率は、1991年の報告に比べて改善したが、慢性型とくすぶり型ATLの4年生存率は改善しなかった。

記述言語：日本語   出版者・発行元：Blood Advances  

Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696). Mogamulizumab-naive patients were enrolled (n 5 102), of whom 101 received mogamulizumab-containing treatment (68 acute, 18 lymphoma, 12 chronic, and 3 smoldering subtypes). At enrollment, there was a significant inverse correlation between serum soluble interleukin-2 receptor (sIL-2R) levels and percentages of Tax-specific cytotoxic T lymphocytes (Tax-CTLs) in the entire lymphocyte population or in the CD8¹ T cell subset, but there was not a correlation with cytomegalovirus pp65–specific cytotoxic T lymphocytes (CMV-CTLs). The overall response rate was 65%, and median progression-free survival and overall survival (OS) were 7.4 and 16.0 months, respectively. A higher percentage of Tax-CTLs, but not CMV-CTLs, within the entire lymphocyte population or in the CD8¹ T cell subset was significantly associated with longer survival. Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD2²CD19¹ B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS. This indicates that a higher percentage of B cells might reflect some aspect of a favorable immune status leading to a good outcome with mogamulizumab treatment. In conclusion, the MIMOGA study has demonstrated that mogamulizumab exerts clinically meaningful antitumor activity in ATL. The patient’s immunological status before mogamulizumab was significantly associated with treatment outcome. Further time series immunological analyses, in addition to comprehensive genomic analyses, are warranted.

DOI： 10.1182/BLOODADVANCES.2020003053

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PubMed

記述言語：英語   出版者・発行元：(公社)日本薬学会  

Asclepias curassavicaの抽出物から活性成分として17のカルデノリドを単離した。殆どのカルデノリドが両方の腫瘍細胞系の増殖を抑制した。最も活性の高い成分のカロトロビン(CT)のMT-2細胞に対するEC50値は、ドキソルビシンの効力に匹敵した。正常な末梢血単核細胞に対するCTの細胞毒性効果は、MT-1およびMT-2細胞に対する増殖阻害の誘発に使用されるよりも6～12倍高い濃度で認められた。CTで72時間処理した後のアネキシンV陽性細胞の割合は増加し、MT-1およびMT-2細胞でアポトーシスが濃度依存的に誘発された。細胞周期実験では、CTによりMT-1およびMT-2細胞がG2/M期に停止することが示された。したがって、CTは成人T細胞白血病/リンパ腫の治療の有望な候補になり得ると考えられた。

記述言語：日本語   出版者・発行元：FEBS Journal  

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm with poor prognosis that develops after chronic infection with human T-cell leukemia virus type 1 (HTLV-1). Although AMP-activated protein kinase (AMPK) is a critical cellular energy sensor, it has recently become clear that AMPK can act as a tumor regulator. Here, we assessed the expression of AMPK in primary ATL cells and the effects of dorsomorphin, an AMPK inhibitor, on primary ATL cells and HTLV-1-infected T-cell lines. AMPK expression in acute and chronic ATL patients was significantly higher than in asymptomatic HTLV-1 carriers and healthy donors. Dorsomorphin induced apoptosis in peripheral blood mononuclear cells from ATL patients. Dorsomorphin also induced dose- and time-dependent apoptosis in HTLV-1-infected T-cell lines. Dorsomorphin increased the production of intracellular reactive oxygen species (ROS) and induced ataxia telangiectasia-mutated Ser1981 phosphorylation and p53 accumulation. These results indicated that dorsomorphin induces apoptosis via ROS-mediated DNA damage in HTLV-1-infected T-cell lines. Furthermore, dorsomorphin suppressed the growth of human ATL tumor xenografts in NOD/SCID mice. Together, these data suggest that AMPK could be a candidate therapeutic target for ATL and that dorsomorphin could be a therapeutic agent for ATL.

DOI： 10.1111/febs.15239

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PubMed

記述言語：日本語   出版者・発行元：Retrovirology  

Background: The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. Results: Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. Conclusions: Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.

DOI： 10.1186/s12977-020-00534-0

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PubMed

記述言語：日本語   出版者・発行元：Cancer Medicine  

Background: Human T-lymphotropic virus-1 (HTLV-1)⁺ Hodgkin lymphoma (HL) is difficult to differentiate from adult T-cell leukemia/lymphoma (ATLL) with HL-like histology (HL-like ATLL). Methods: Cytological and immunohistological features, HTLV-1 proviral DNA integration, and rearrangements of the T-cell receptor (TCR) Cβ1 gene were examined in 11 HTLV-1⁺ patients with HL-like disease. Results: Six patients were classified as HTLV-1⁺ HL and five as HL-like ATLL in accordance with genetic findings of HTLV-1 proviral DNA integration and rearrangements of the TCR Cβ1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV-1⁺ HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL-like ATLL specimens, small- and medium-sized atypical lymphocytes with indented and irregular-shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30⁺ and CD15⁺ Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein-Barr virus infection. The 50% overall survival period was significantly longer for the HTLV-1⁺ HL group (180 months) than for the HL-like ATLL group (7.8 months; P =.004). Conclusions: HTLV-1⁺ HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25⁺ and CCR4⁺ lymphocytes. In HTLV-1 endemic areas, distinguishing HTLV-1⁺ HL from HL-like ATLL is important because of their differing treatment strategies and prognoses.

DOI： 10.1002/cam4.3139

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：Anticancer Research  

Background/Aim: Adult T-cell leukemia (ATL) is a hematological malignancy caused by infection with human Tcell leukemia virus type 1 (HTLV-1). Chemotherapy, antibody therapy, and bone marrow transplantation are used to treat this disease, however, median survival time has not been significantly improved. Our aim was to develop and evaluate a novel antibody-drug conjugate (ADC) with regards to cell cytotoxicity and target specificity. Materials and Methods: In this study, we have constructed a novel ADC, which is composed of an anti-CD70 single chain Fv-Fc antibody conjugated with the anticancer agent emtansine using a novel antibody modification method. Cell cytotoxicity and target specificity were assessed using a cell proliferation assay. Results: The anti-CD70 ADC selectively killed HTLV-1-infected cells and ATL cells without affecting other cells. Conclusion: The anti-CD70 ADC offers some chemotherapeutic potential for the treatment of ATL.

DOI： 10.21873/anticanres.14452

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PubMed

出版者・発行元：(一社)日本血液学会-東京事務局  

成人T細胞白血病・リンパ腫(ATL)はヒトTリンパ球向性ウイルスI型が原因となり発症する予後不良な末梢性T細胞腫瘍である。腫瘍浸潤による肝障害のため殺細胞性抗がん剤による化学療法が困難な状況をmogamulizumab(Moga)で救援し,長期寛解が得られている急性型ATLを報告する。症例は66歳男性,ATLの肝浸潤に伴う全身状態悪化のため減量化学療法を開始したが効果に乏しく,高ビリルビン血症,低アルブミン血症のため継続困難であった。Moga投与後,末梢血異常リンパ球は急速に減少,肝障害は改善し,通常量の化学療法が施行可能となった。抗体薬のMogaは体内薬物動態への肝代謝能や血清アルブミン値の影響が少ないと考えられ,肝浸潤による高ビリルビン血症や低アルブミン血症のため通常の殺細胞性抗がん剤を投与しにくい状態のATL患者の救援治療としても有望な選択肢である。(著者抄録)

記述言語：日本語   出版者・発行元：International Journal of Hematology  

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm associated with the human T-cell leukemia virus type-I (HTLV-1); prognosis still remains very poor. We retrospectively reviewed the treatment of 198 patients with acute-, lymphoma- and unfavorable chronic-type ATL (aggressive ATL) diagnosed from 2005 to 2014 in a hospital located in an area of Japan in which HTLV-1 is highly endemic. One-hundred forty-three, and 35 patients were treated using OPEC/MPEC and VCAP-AMP-VECP, respectively. OPEC/MPEC was mainly used until around 2010, and gradually switched to VCAP-AMP-VECP, especially for younger patients. The 2-year overall survival for patients treated by VCAP-AMP-VECP was significantly higher than that using OPEC/MPEC for patients < 70 years old (y.o.), but not for patients ≥ 70 y.o. A less intensive chemotherapy OPEC/MPEC could be performed without reducing dose intensity, even in elderly patients, and its therapeutic outcome is not inferior to that of VCAP-AMP-VECP. It is difficult to draw definite conclusion from this small retrospective study; however, OPEC/MPEC may represent an alternative option for elderly patients with aggressive ATL.

DOI： 10.1007/s12185-019-02769-w

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

ヒトT細胞白血病ウイルスI型(HTLV-1)蔓延地域である鹿児島に位置する一病院において、2005〜2014年に急性型、リンパ腫型、予後不良因子を有する慢性型のアグレッシブ成人T細胞白血病/リンパ腫(ATL)と診断された患者191例(男性105例、女性86例、年齢中央値72歳)の治療について後ろ向きに分析した。138例がOPEC/MPEC、33例がVCAP-AMP-VECPで治療された。2010年頃まではOPEC/MPECが主に使用されていたが、徐々にVCAP-AMP-VECPに切り替えられ、特に若年患者に対する使用が増えた。VCAP-AMP-VECPで治療された患者の2年全生存率は、70歳未満の患者ではOPEC/MPECよりも有意に高かったが、70歳以上の患者では有意差は示されなかった。これらの結果から、OPEC/MPECによる治療は、高齢者であっても治療強度を低下させずに行うことができ、VCAP-AMP-VECPと比較して劣っておらず、高齢のアグレッシブATL患者の代替療法の一つの選択肢となる可能性が示された。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>成人T細胞白血病・リンパ腫（ATL）はヒトTリンパ球向性ウイルスI型が原因となり発症する予後不良な末梢性T細胞腫瘍である。腫瘍浸潤による肝障害のため殺細胞性抗がん剤による化学療法が困難な状況をmogamulizumab（Moga）で救援し，長期寛解が得られている急性型ATLを報告する。症例は66歳男性，ATLの肝浸潤に伴う全身状態悪化のため減量化学療法を開始したが効果に乏しく，高ビリルビン血症，低アルブミン血症のため継続困難であった。Moga投与後，末梢血異常リンパ球は急速に減少，肝障害は改善し，通常量の化学療法が施行可能となった。抗体薬のMogaは体内薬物動態への肝代謝能や血清アルブミン値の影響が少ないと考えられ，肝浸潤による高ビリルビン血症や低アルブミン血症のため通常の殺細胞性抗がん剤を投与しにくい状態のATL患者の救援治療としても有望な選択肢である。</p>

DOI： 10.11406/rinketsu.61.612

PubMed

記述言語：英語   出版者・発行元：公益社団法人 日本薬学会  

<p>In the course of our screening program for novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, the extracts of <i>Asclepias curassavica</i> L. showed potent activity against MT-1 and MT-2 cells. Therefore, we attempted to isolate their active components. We identified a new cardenolide, 19-dihydrocalactinic acid methyl ester (<b>1</b>), along with 16 known cardenolides (<b>2</b>–<b>17</b>). Their structures were determined on the basis of spectroscopic data. Almost all of the isolated cardenolides inhibited the growth of both tumor cell lines. All the doubly linked cardenolides (<b>11</b>–<b>17</b>) except for <b>14</b> showed more potent activity than the other cardenolides. A comparison of the activities of <b>11</b>, <b>14</b> and <b>16</b> revealed that the presence of hydroxy or acetoxy functional groups at C-16 led to a decrease in the activity. The 50% effective concentration (EC₅₀) value of calotropin (<b>11</b>) against MT-2 cells was comparable to the potency of the clinical antineoplastic drug doxorubicin. The cytotoxic effect of <b>11</b> toward normal mononuclear cells obtained from the peripheral blood (PB-MNCs) was observed at a concentration 6 to 12 times higher than that used to induce growth inhibition against MT-1 and MT-2 cells. The proportions of annexin V-positive cells after 72 h of treatment with <b>11</b> were increased, indicating that it significantly induced apoptosis in MT-1 and MT-2 cells in a concentration-dependent manner. Cell cycle experiments demonstrated that <b>11</b> arrested MT-1 and MT-2 cells at the G2/M phase. Therefore, compound <b>11</b> may be a promising candidate for the treatment of adult T-cell leukemia/lymphoma.</p>

DOI： 10.1248/bpb.b20-00465

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PubMed

記述言語：日本語   出版者・発行元：European Journal of Pharmacology  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus-1 and has a poor outcome. New molecular targets for the prevention and treatment of ATL are needed urgently. We previously reported high expression of Sirtuin 1, a nicotinamide adenine dinucleotide (NAD⁺)-dependent histone/protein deacetylase, in primary acute-type ATL cells. NAD⁺ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) modulates Sirtuin 1 activity. Here, we examined the expression and effects of inhibiting NAMPT, a rate-limiting enzyme in NAD⁺ biosynthesis, in ATL cells. We found that peripheral blood mononuclear cells from patients with acute-type ATL expressed significantly higher levels of NAMPT protein than cells from healthy subjects. FK866, a NAMPT inhibitor, induced apoptosis of freshly isolated ATL cells ex vivo and HTLV-1-infected T-cell lines in vitro, which was accompanied by activation of caspases, DNA fragmentation, and disruption of mitochondrial transmembrane potential. However, a pan-caspase inhibitor failed to prevent this FK866-induced cell death, while FK866 increased the caspase-independent cell death mediator endonuclease G. Intriguingly, FK866 also activated autophagy, as demonstrated by increases in protein levels of autophagosome marker LC3-II. Thus, FK866 simultaneously activated apoptosis and autophagy. Finally, FK866 treatment markedly decreased the growth of human ATL tumor xenografts in immunodeficient mice. We showed that NAMPT is highly expressed in primary ATL cells ex vivo, and that FK866 induces autophagy and caspase-dependent and -independent cell death pathways in vitro and has an anti-tumor activity in vivo. These results suggest a novel therapeutic strategy for patients with this fatal disease.

DOI： 10.1016/j.ejphar.2019.172738

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PubMed

記述言語：日本語   出版者・発行元：International Journal of Hematology  

The aim of this study was to elucidate the role of a non-canonical JAK2 mutation JAK2-T875N, which was identified by exome sequencing in a patient with essential thrombocytosis (ET) who had a family history of suspecting ET. Whole exome sequencing was performed on peripheral blood mononuclear cells and buccal swab-derived genomic DNA. Sanger sequencing was performed to confirm the variant. We evaluated the function of the mutation on JAK2 activity and downstream signaling (Erk, STATs) using JAK2-T875N-transfected or transduced cell lines. 293T cells transfected with JAK2 cDNA carrying V617F or T875N mutations showed increased levels of phosphorylated JAK2 and Erk. Enhanced STAT3 and STAT5 activity was confirmed by promoter assay. JAK2-T875N-transduced Ba/F3 cells showed increased cellular growth without IL-3 stimulation. To our knowledge, this is the first case of ET caused by JAK2-T875N mutation with a family history of thrombocytosis and cerebral infarction.

DOI： 10.1007/s12185-019-02725-8

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

出版者・発行元：(一社)日本血液学会  

症例は46歳女性で、18年間にわたり血小板増加が続いており、本態性血小板増加症(ET)と診断された。末梢血単球のゲノムDNAを用いたエクソーム解析で、エクソン18におけるヌクレオチド2623でのJAK2 C-to-A変異c2623aによってposition 875におけるトレオニンからアスパラギンへのアミノ酸置換がもたらされたことが明らかになった。変異は頬側スワブ由来ゲノムDNAとCD3陽性リンパ球由来ゲノムDNAを用いた標的配列決定によって確認した。父親に血小板増加症と脳卒中の病歴があった。JAK2活性と細胞外シグナル制御キナーゼ(Erk)およびシグナル伝達性転写因子(STAT)といった下流シグナル伝達に対する変異機能を、JAK2-T875N遺伝子導入または形質導入細胞株を用いて評価した。V617FまたはT875N変異を有するJAK2相補DNAを遺伝子導入した293T細胞により、リン酸化JAK2およびErkの増加が示された。プロモーターアッセイによってSTAT3およびSTAT5活性の強化を確認した。JAK2-T875N遺伝子導入Ba/F3細胞では、インターロイキン-3刺激なしで細胞増殖の亢進が認められた。

記述言語：日本語   出版者・発行元：Bone Marrow Transplantation  

Currently, allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative modality for patients with adult T-cell leukemia–lymphoma (ATL). When used in conjunction with posttransplantation cyclophosphamide (PTCY) for graft-versus-host disease prophylaxis, allo-HCT from an HLA haplo-identical donor yields promising outcomes for many diseases other than ATL. However, appropriate comparisons with other donor sources, especially cord blood and conventional HLA haplo-identical donors, are needed to validate the safety and efficacy of this modality. In this study, we retrospectively evaluated the outcome of allo-HCT without PTCY in patients with ATL registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database between 1985 and 2015. During that period, 46 patients received allo-HCT without PTCY and survivors were followed for a median of 2316.5 days (range: 220–3884 days). Although the estimated 1- and 5-year overall survival rates of the entire cohort were 34.5% and 17.7%, respectively, the cumulative 1- and 5-year non-ATL mortality rates of 41.3% and 55.8%, respectively, were high. The results of our study will serve as a platform for discussions of the safety and efficacy of haplo-HCT for future clinical trials in patients with ATL.

DOI： 10.1038/s41409-018-0400-5

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：British Journal of Haematology  

JCOG9801, a randomized phase III trial, reported that vincristine, cyclophosphamide, doxorubicin and prednisone (VCAP); doxorubicin, ranimustine and prednisone (AMP); and vindesine, etoposide, carboplatin and prednisone (VECP) (VCAP-AMP-VECP; mLSG15) showed superior clinical outcomes when compared to cyclophosphamide, doxorubicin, vincristine and prednisone every 2 weeks (CHOP-14; mLSG19) in patients with untreated aggressive adult T-cell leukaemia-lymphoma (ATL). To identify patients who require VCAP-AMP-VECP, we conducted a supplementary analysis of JCOG9801. Overall, 105 patients were included and categorized into low- (n = 44), intermediate- (n = 54) and high-risk (n = 7) groups according to the age-adjusted ATL prognostic index (ATL-PI). We excluded the high-risk group due to small numbers of patients. VCAP-AMP-VECP did not show any superior trend for overall survival (OS) in the low-risk group (hazard ratio: 1·04; 95% confidence interval: 0·54–2·04). Better OS was observed in the intermediate-risk group treated with VCAP-AMP-VECP (hazard ratio: 0·65; 95% confidence interval: 0·36–1·19). In the intermediate-risk group, the VCAP-AMP-VECP arm showed higher complete response rates than the CHOP-14 arm (44·0% vs. 13·8%). The VCAP-AMP-VECP arm in both risk groups exhibited grade 4 thrombocytopenia, while grade 4 neutropenia was only observed in the intermediate-risk group. VCAP-AMP-VECP remains suitable for the intermediate-risk group, whereas its benefits appear modest in the low-risk group.

DOI： 10.1111/bjh.15950

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PubMed

記述言語：日本語   出版者・発行元：BMC Cancer  

Background: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival. Methods: We tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection. Results: Strong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs. Conclusions: This is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.

DOI： 10.1186/s12885-019-5730-1

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PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ejh.13220.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：European Journal of Haematology  

Objective: This prospective, observational, postmarketing surveillance was conducted to evaluate the safety and effectiveness of mogamulizumab, an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, in patients with CCR4-positive, relapsed or refractory (r/r) adult T-cell leukemia-lymphoma (ATL) in Japan. Method: All patients were scheduled to receive intravenous infusions of mogamulizumab 1.0 mg/kg once weekly for 8 weeks, alone or in combination with other modalities. Results: In the safety analysis population comprising 572 patients, mogamulizumab therapy was started between May 29, 2012, and April 30, 2013, and adverse drug reactions (ADRs) were reported in 73.4% (38.6% serious cases) of patients. The most common ADRs were skin disorders (33.2% [10.8% serious cases]), infusion-related reactions (30.1% [4.7% serious cases]), and infections (22.0% [14.7% serious cases]). In the effectiveness analysis population comprising 523 patients, the best overall response rate and the response rate at the end of therapy were 57.9% and 42.0%, respectively. The median overall survival was 5.5 months. Safety and effectiveness results were similar between patients aged ≥70 and <70 years. Conclusion: This postmarketing surveillance confirmed the safety and effectiveness of mogamulizumab for the treatment of patients with r/r ATL, including elderly patients, in clinical practice.

DOI： 10.1111/ejh.13220

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1200/JCO.18.00501.

記述言語：日本語   出版者・発行元：Journal of Clinical Oncology  

PURPOSE Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches. METHODS Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology—Human T-Lymphotropic Virus and Related Retroviruses—in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents. RESULTS As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (. 90% agreement). CONCLUSION This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL

DOI： 10.1200/JCO.18.00501

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PubMed

記述言語：日本語   出版者・発行元：Journal of Epidemiology  

Background: The aims of the present report were to estimate the prevalence of congenital anomalies (CAs) among infants in Japan using data from the Japan Environment and Children’s Study (JECS) and to evaluate the validity of CA classification within JECS. Methods: Data on CAs were collected at delivery and at age 1 month from the medical records of 101,825 infants at 15 regional centers. The analyses focused on 61 CAs, selected on the basis of reported associations with environmental exposure. Prevalence per 10,000 pregnancies (including miscarriages, stillbirths, and live births) was stratified according to four reporting patterns (at delivery, at age 1 month, at either, and at both). To evaluate the accuracy of observed CA prevalence, the medical records of 179 cases from a single JECS regional center underwent independent, retrospective re-evaluation. Results: The prevalence of major CAs in four reporting patterns (at delivery, at age 1 month, at either, and at both) was 2.4, 2.6, 3.5, and 1.4 for myelomeningocele=spina bifida; 4.3, 4.2, 5.3, and 3.2 for cleft palate; 18.1, 17.4, 19.5, and 15.1 for cleft lip with or without cleft palate; 73.4, 100.3, 120.8, and 52.8 for congenital heart disease; and 10.5, 14.1, 15.0, and 9.6 for Down’s syndrome, respectively. In the subsample re-evaluation, CA diagnoses were confirmed for 92.7%, 93.3%, 90.5%, and 97.8% of cases in the four reporting patterns (at delivery, at age 1 month, at either, and at both), respectively. Conclusions: The present report generated reliable data concerning the prevalence of major CAs in JECS.

DOI： 10.2188/jea.JE20180014

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出版者・発行元：Clinical Neurology  

DOI： 10.5692/clinicalneurol.cn-001318

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

ヒトT細胞白血病ウイルス1型(HTLV-1)定量的PCRの標準化を目的として、基準試料を開発したので報告した。Jurkat細胞で希釈したTL-Om1細胞の凍結乾燥細胞基準試料を調製し、HTLV-1定量的PCRに対する一時的基準として品質を評価した。基準試料のプロウイルス量(PVL)に割り当てる数値をデジタルPCRで判定した。HTLV-1定量的PCR標的シーケンスと内部標準遺伝子標的シーケンスを混合したテスト検体を測定して、デジタルPCR結果の精度を確認した。デジタルPCR結果が絶対値に極めて近いことを確認した。基準試料のPVLを2.71copy/100細胞と判定した。九つの協力機関に対して、それぞれの機関の方法を用いて基準試料のPVLの測定を依頼した。結果は1.08〜3.49copy/100細胞で、機関間の最大差が3.23倍となり、幾何平均は2.23copy/100細胞であった。基準試料の付与値を組み込んだ式を用いてこれらのPVLを修正することで矛盾を最小化しなければならなかった。別機関で臨床検体のPVLを測定したところ、修正後にほとんどの臨床検体で研究室間の幾何変動係数が小さかった。基準試料の値を組み入れた式を用いた修正によって、研究室間の差異を最小化できることが示された。

記述言語：日本語   出版者・発行元：Microbiology and Immunology  

Quantitative PCR (qPCR) of human T-cell leukemia virus type 1 (HTLV-1) provirus is used for HTLV-1 testing and for assessment of risk of HTLV-1-related diseases. In this study, a reference material was developed for standardizing HTLV-1 qPCR. Freeze-dried TL-Om1 cells diluted with Jurkat cells were prepared and an assigned value for proviral load (PVL) of 2.71 copies/100 cells was determined by digital PCR. Nine Japanese laboratories using their own methods evaluated the PVLs of this reference material as 1.08–3.49 copies/100 cells. The maximum difference between laboratories was 3.2-fold. Correcting measured PVLs by using a formula incorporating the assigned value of this reference material should minimize such discrepancies.

DOI： 10.1111/1348-0421.12644

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PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.cn-001170.

記述言語：日本語   出版者・発行元：Oncotarget  

Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required. STF-62247 induces autophagy and selectively kills renal cell carcinoma without apoptotic cell death. Here, we demonstrate that STF-62247 reduced cell viability and resulted in autophagosome accumulation and autophagy in leukemic cell lines (S1T, MT-2, and Jurkat). Interestingly, STF-62247 induced apoptosis in HTLV-1-infected cell lines (S1T and MT-2), as indicated by DNA fragmentation and caspase activation, but not in non-HTLV-1-infected Jurkat cells; a caspase inhibitor did not prevent this caspase-associated cell death. STF-62247 also increased nuclear endonuclease G levels. Furthermore, STF-62247 reduced cell viability and increased the number of apoptotic cells in peripheral blood mononuclear cells collected from patients with acute ATL, which has a poor prognosis. Therefore, STF-62247 may have novel therapeutic potential for ATL. This is the first evidence to demonstrate the cell growth-inhibitory effect of an autophagy inducer by caspase-dependent apoptosis and caspase-independent cell death via autophagy and endonuclease G in leukemic cells.

DOI： 10.18632/oncotarget.25291

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PubMed

担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

出版者・発行元：(一社)日本血液学会-東京事務局  

54歳女。易疲労感を主訴とした。甲状腺がんの術後経過観察中に肝脾腫を認め、近医婦人科で子宮筋腫と貧血を指摘された。紹介受診時の各種検査で多発ニューロパチー、血清VEGF上昇、IgA-λ型M蛋白、肝脾腫、下肢浮腫、内分泌異常、皮膚の色素沈着を認めたことからpolyneuropathy、organomegaly、endocrinopathy、M-protein and skin changes症候群と診断した。当初、大量化学療法併用自家造血幹細胞移植を計画していたが、治療前に肺高血圧症が判明した。lenalidomide・dexamethazone療法を先行し、3コース施行後の右心カテーテル検査で肺高血圧症の改善を確認してから大量化学療法併用自家造血幹細胞移植を行った。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1182/blood-2017-01-761874.

記述言語：日本語   出版者・発行元：Blood  

Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis.We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/ smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, andCDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

DOI： 10.1182/blood-2017-01-761874

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>POEMS syndrome is often complicated by pulmonary hypertension. The standard therapy for patients with POEMS syndrome is high-dose chemotherapy followed by autologous stem cell transplantation. However, the safety of high-dose chemotherapy for patients complicated with pulmonary hypertension remains unclear, and the optimal therapy for these patients is yet to be establishment. Herein, we report the case of a 54-year-old woman with POEMS syndrome accompanied by pulmonary hypertension. We successfully and safely performed lenalidomide and dexamethasone (Ld) therapy followed by high-dose chemotherapy and autologous stem cell transplantation, which improved her pulmonary hypertension. Thus, Ld can be considered as safe and effective for pulmonary hypertension with POEMS syndrome.</p>

DOI： 10.11406/rinketsu.59.489

PubMed

記述言語：日本語   出版者・発行元：Cancer Science  

Adult T-cell leukemia–lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60–75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu–Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed.

DOI： 10.1111/cas.13398

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PubMed

出版者・発行元：John Wiley & Sons Australia, Ltd  

日本における成人T細胞白血病(ATL)の最近の疫学的特徴を把握するため、全国的なATL調査を行い、ATLの疫学的および臨床的特徴が、時間とともにどのように変化したのかを評価した。2010年から2011年の間に126病院から新規にATLと診断された患者996名のうち922名(男487名、女435名、年齢中央値68歳)を対象とした。その結果、67.2%は九州-沖縄地方で診断されていた。サブタイプは急性型の49.5%が最も多く、リンパ腫型(25.7%)、慢性型(14.2%)と続いた。リンパ腫型は男性、慢性型は女性で多く罹患している傾向が認められた。リンパ腫型の約半数は70歳以上で、慢性型と診断された患者の3分の1は60歳以下であった。これらの特徴は1980年代および1990年代に行った全国調査の結果とは異なっていた。以上より、最近のATL患者の約半数は集中的な細胞傷害性療法ができない68歳以上で、高齢者のための新しい毒性の低い薬剤やATLの発症を予防する更なる戦略が必要と考えられた。

記述言語：日本語   出版者・発行元：International Journal of Hematology  

We present the interim results of a postmarketing all-case surveillance study in patients with C–C chemokine receptor 4 (CCR4)-positive, relapsed or refractory adult T-cell leukemia–lymphoma (ATL) treated with the anti-CCR4 monoclonal antibody mogamulizumab since its 2012 launch in Japan. The safety and efficacy analysis populations comprised 484 and 442 patients, respectively. The ATL subtype was acute in 58.9% and lymphoma in 34.2% of patients. All patients were scheduled to receive intravenous infusions of mogamulizumab (1.0 mg/kg) once weekly for eight weeks, alone or in combination with other modalities. Adverse drug reactions (ADRs) were reported in 74.0% of patients, of which 35.7% were serious and 6.2% were fatal. The priority survey items of infusion-related reaction, skin disorder, infection, immune disorder, and tumor lysis syndrome were reported in 29.3, 34.3, 22.1, 3.5, and 2.5% of patients, respectively. Graft-versus-host disease was reported in 25/42 patients who received mogamulizumab before allogeneic hematopoietic stem cell transplantation. The best overall response rate was 57.7% overall, 57.5% in patients treated with mogamulizumab alone, and 58.2% in patients treated with combination therapy. This surveillance indicates that mogamulizumab shows acceptable tolerability in practice; however, because of the risk of serious/fatal ADRs, patients administered mogamulizumab should be carefully monitored.

DOI： 10.1007/s12185-017-2270-9

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PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

出版者・発行元：(一社)日本血液学会  

モガムリズマブ(MO)で治療されたC-Cケモカイン受容体4(CCR4)陽性の再発/難治性成人T細胞白血病/リンパ腫(ATL)患者の市販後調査を行い、有効性を484名(男258名、女226名)、安全性を442名で調べた。ATL亜型は急性が58.9%、リンパ腫が34.2%であった。患者全例にMO 1.0mg/kgを週に1回、単独または他の治療と併用して8週間点滴した。薬物有害反応(ADR)は患者の74.0%で報告され、そのうち35.7%が重篤、6.2%が致死的であった。点滴関連反応は29.3%、皮膚障害は34.3%、感染症は22.1%、免疫障害は3.5%、腫瘍溶解症候群は2.5%で認められた。移植片対宿主病は同種造血幹細胞移植の前にMOを投与された患者42名(男30名、女12名)中25名で報告された。全奏効率は57.7%で、単独治療群が57.5%、併用治療群が58.2%であった。MOの忍容性は許容できるが、重篤なADRのリスクがあるため注意深く監視すべきと考えられた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：Blood  

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log<inf>10</inf>(soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log<inf>10</inf>(sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) 5 1.51 3 log<inf>10</inf>(sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively (P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively (P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach. (Blood. 2017;130(1):39-47)

DOI： 10.1182/blood-2017-01-757542

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PubMed

出版者・発行元：Adult T-cell Leukemia/Lymphoma  

DOI： 10.1007/978-4-431-56523-9_9

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）  

出版者・発行元：九州リウマチ学会  

68歳男性。1991年関節リウマチ(RA)と診断、メトトレキサート(MTX)を開始、2004年インフリキシマブ(IFX)が追加された。2013年に縦隔・腹腔内にリンパ節腫大を認め医原性免疫不全関連リンパ増殖性疾患(OIIA-LPD)を疑い、MTXとIFXを中止し自然退縮した。RAの悪化を認め、免疫抑制剤が追加されたが副作用で中止となり、2014年1月アバタセプト(ABT)単独療法開始、2年後、sIL-2Rの上昇と縦隔リンパ節腫大からOIIA-LPDと診断した。ABTの中止のみでLPDは退縮したが、消化管大量出血による出血性ショックと播種性血管内凝固症候群のため死亡した。病理解剖で残存していた縦隔リンパ節はEBV陽性ホジキンリンパ腫と診断された。OIIA-LPD寛解後のRAの治療においてABTは比較的安全との症例報告が散見されるが、ABTでもLPDを誘発する可能性があり、注意が必要である。(著者抄録)

出版者・発行元：南江堂  

DOI： 10.15106/j03022.2017162737

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：BMC Cancer  

Background: BK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration. Methods: Eleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route. The dose was escalated (1.0, 2.0, 3.3, and 5.0mg/m²) using a 3+3 design. Results: Eight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0mg/m²) and 2 (2.0mg/m²). Grade 3 transient hypotension as an adverse event (defined as a DLT in the present study) was observed in two of four patients at dose level 3 (3.3mg/m²). Treatment with BK-UM was associated with decreases in HB-EGF levels in serum and abdominal fluid in seven of 11 patients and five of eight patients, respectively. Clinical outcomes included a partial response in one patient, stable disease in five patients, and progressive disease in five patients. Conclusions: BK-UM was well tolerated at doses of 1.0 and 2.0mg/m², with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0mg/m² BK-UM is recommended for subsequent clinical trials. Trial registration: This trial was prospectively performed as an investigator-initiated clinical trial. The trial numbers are UMIN000001002and UMIN000001001, with registration dates of 1/30/2008 and 2/4/2008, respectively. UMIN000001001 was registered as a trial for the continuous administration of BK-UM after UMIN000001002.

DOI： 10.1186/s12885-017-3071-5

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PubMed

記述言語：日本語   出版者・発行元：Journal of Natural Medicines  

During the course of our studies towards the identification of promising chemotherapeutic candidates from plants against two human T-cell lymphotropic virus type I-infected T-cell lines (MT-1 and MT-2), we screened 17 extracts from 9 rutaceous plants against MT-1 and MT-2 cells. The extracts from the aerial parts and roots of Boenninghausenia japonica, as well as the leaves and roots of Ruta graveolens showed potent antiproliferative effects. After activity-guided fractionation, we isolated 44 compounds from two rutaceous plants, including three new compounds (1–3), which were classified into 26 coumarin analogs (13 coumarins, 8 furanocoumarins, 4 dihydrofuranocoumarins and one dihydropyranocoumarin), 15 alkaloid analogs (7 quinolone alkaloids, 4 acridone alkaloids, 3 furanoquinoline alkaloids and one tetrahydroacridone alkaloid) and 3 flavonoid glycosides. Structure–activity relationship studies were also evaluated. The coumarin compounds (2, 3 and 7–9) bearing a 3-dimethylallyl moiety showed potent activity. Similarly, of all the furanocoumarins evaluated in the current study, compound 17 bearing a 3-dimethylallyl group also showed potent activity. A dihydrofuranocoumarin (27) bearing a 3-dimethylallyl moiety showed the most potent activity. Following 27, compound 28 showed potent activity. These results therefore suggested that the presence of a 3-dimethylallyl moiety was important to the antiproliferative activity of these coumarin analogs.

DOI： 10.1007/s11418-016-1046-5

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

During the course of our studies towards the identification of promising chemotherapeutic candidates from plants against two human T-cell lymphotropic virus type I-infected T-cell lines (MT-1 and MT-2), we screened 17 extracts from 9 rutaceous plants against MT-1 and MT-2 cells. The extracts from the aerial parts and roots of Boenninghausenia japonica, as well as the leaves and roots of Ruta graveolens showed potent antiproliferative effects. After activity-guided fractionation, we isolated 44 compounds from two rutaceous plants, including three new compounds (1-3), which were classified into 26 coumarin analogs (13 coumarins, 8 furanocoumarins, 4 dihydrofuranocoumarins and one dihydropyranocoumarin), 15 alkaloid analogs (7 quinolone alkaloids, 4 acridone alkaloids, 3 furanoquinoline alkaloids and one tetrahydroacridone alkaloid) and 3 flavonoid glycosides. Structure-activity relationship studies were also evaluated. The coumarin compounds (2, 3 and 7-9) bearing a 3-dimethylallyl moiety showed potent activity. Similarly, of all the furanocoumarins evaluated in the current study, compound 17 bearing a 3-dimethylallyl group also showed potent activity. A dihydrofuranocoumarin (27) bearing a 3-dimethylallyl moiety showed the most potent activity. Following 27, compound 28 showed potent activity. These results therefore suggested that the presence of a 3-dimethylallyl moiety was important to the antiproliferative activity of these coumarin analogs.

出版者・発行元：シュプリンガー・ジャパン(株)  

ミカン科植物の17種類の抽出物を対象に、2種類のヒトTリンパ球向性ウイルス1型株(MT-1とMT-2)に対する抗増殖活性をスクリーニングした。Boenninghausenia japonicaの地上部と根、およびRuta graveolensの葉と根の抽出物が強い抗増殖活性を示した。これらの抽出物について活性ガイド分画を行い、3種類の新規化合物を含む44種類の化合物を得た。うち26種類はクマリンアナログ、15種類はアルカロイドアナログ、3種類はフラボノイドグリコシドであった。構造活性相関を解析したところ、3-ジメチルアリル部分を持つクマリン化合物とジヒドロフラノクマリン、および3-ジメチルアリル基を持つフラノクマリンが強い抑制活性を示した。これらのクマリンアナログの抗増殖活性には、3-ジメチルアリル部分の存在が重要であると考えられた。

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

<p>成人T細胞白血病（adult T-cell leukemia：ATL）は，ヒトT細胞白血病ウイルス1型（human T-cell leukemia virus type 1：HTLV-1）によって発生する予後不良な末梢性T細胞腫瘍である．多様な病態・臨床経過から，急性型，リンパ腫型，慢性型，くすぶり型の4病型に分けられる．急性型・リンパ腫型ならびに予後不良因子を有する慢性型ATLはaggressive ATL，予後不良因子を有さない慢性型・くすぶり型ATLはindolent ATLと分類され，治療方針が決定される．Aggressive ATLでは，急速な経過を辿る症例が多く，適切な診断と治療が必要である．</p>

DOI： 10.2169/naika.106.1397

記述言語：英語   出版者・発行元：日本リンパ網内系学会  

<p>A classification for adult T-cell leukemia-lymphoma (ATL) based on clinical features was proposed in 1991: acute, lymphoma, chronic, and smoldering types, and their median survival times (MSTs) were reported to be 6.2, 10.2, 24.3 months, and not reached, respectively. Several new therapies for ATL have since been developed, i.e. dose-intensity multi-agent chemotherapies, allogeneic hematopoietic stem cell transplantation (allo-HSCT), monoclonal antibodies, and anti-viral therapy. The monoclonal antibody to CCR4, mogamulizumab, clearly improved response rates in patients with treatment-naïve and relapsed aggressive ATL, and has the potential to provide a survival advantage. The outcomes of allo-HSCT have been reported since the early 2000s. High treatment-related mortality was initially the crucial issue associated with this treatment approach; however, reduced intensity conditioning regimens have decreased the risk of treatment-related mortality. The introduction of allo- HSCT has had a positive impact on the prognosis of and potential curability with treatments for ATL. A meta-analysis of a treatment with interferon-α and zidovudine (IFN/AZT) revealed a survival benefit in patients with the leukemic subtype. A phase 3 study comparing IFN/AZT with watchful waiting in patients with indolent ATL is ongoing in Japan. Several clinical trials on novel agents are currently being conducted, such as the histone deacetylase inhibitors, alemtuzumab, brentuximab vedotin, nivolumab, and an EZH1/2 dual inhibitor.</p>

DOI： 10.3960/jslrt.17008

PubMed

記述言語：日本語   出版者・発行元：American Journal of Surgical Pathology  

Smoldering-type and chronic-type adult T-cell leukemia/lymphomas (ATLL) patients have relatively indolent clinical courses, but often progress into aggressive lymphoma-type and acute-type disease. We examined the roles of transcription factor C-MYC and its ubiquitin ligase FBXW7 in tumor tissues from 137 patients with ATLL. Immunohistochemical tests showed ≥50% of lymphoma cells in 78.7% (48/61) of lymphoma-type, and 64.9% (24/37) of acute-type samples expressed C-MYC, significantly higher than was seen in smoldering-type (3.6%) and chronic-type (9.1%) samples (P<0.01). Real-time polymerase chain reaction showed C-MYC mRNA expression in lymphoma-type and acute-type samples were significantly higher than in smoldering-type (P<0.01). C-MYC expression was highly correlated with its mRNA levels (ρ=0.65, P<0.0001), chromosomal amplification and duplication (ρ=0.3, P=0.045) and MIB1 labeling index (ρ=0.69, P<0.0001). Expression of FBXW7 protein and mRNA in lymphoma-type samples were significantly lower than those of smoldering-type (P<0.01 for each), and both were inversely correlated with C-MYC (protein: ρ=-0.4, P=0.0002; mRNA: ρ=-0.31, P=0.015). Seven patients with smoldering-type or chronic-type ATLL converted to acute-type, in 4 of whom C-MYC expression increased from <50% to ≥50%. Patients with ≥50% C-MYC or MIB1 had significantly worse prognosis than those with <50% C-MYC (P=0.0004) or MIB1 (P<0.0001), as did those with ≥7.5 C-MYC mRNA scores (P=0.033); whereas significantly better prognosis was associated with ≥50% FBXW7 protein (P=0.0006) or ≥0.17 FBXW7 mRNA (P=0.016). C-MYC and FBXW7 affect ATLL proliferation and progression, and low FBXW7 may increase C-MYC expression. C-MYC was a critical prognostic factor in ATLL patients.

DOI： 10.1097/PAS.0000000000000871

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>成人T細胞白血病・リンパ腫（ATL）はヒトTリンパ球向性ウイルスI型（HTLV-1）によって引き起こされる予後不良な末梢性T細胞腫瘍である。主として母乳によって成立したHTLV-1感染者の3～5％がATLを発症する。現在の本邦の標準治療は，aggressive ATL（急性型，リンパ腫型と予後不良因子を有する慢性型）に対しては多剤併用化学療法，さらに可能な症例では同種造血幹細胞移植を実施すること，indolent ATL（くすぶり型と予後不良因子のない慢性型）に対してはaggressive ATLとなるまで無治療経過観察することである。近年はATL細胞の表面抗原を標的とする抗体療法，ATL細胞の分子異常を標的とする治療，免疫環境を修飾する治療の開発が試みられており，そのうち抗CCR4抗体モガムリズマブと，免疫調整薬レナリドミドはすでに日常臨床に導入されている。</p>

DOI： 10.11406/rinketsu.58.676

PubMed

記述言語：日本語   出版者・発行元：日本皮膚悪性腫瘍学会  

DOI： 10.5227/skincancer.31.209

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>成人T細胞白血病・リンパ腫（ATL）はヒトTリンパ球向性ウイルスI型（HTLV-1）によって引き起こされる末梢性T細胞腫瘍である。HTLV-1感染リンパ球は，TaxやHTLV-1 bZIP factorなどによって不死化され，やがてクローナルな増殖を始める。ATLの分子病態の特徴は，ATL細胞が多くのゲノム異常を持ち，しかもそれらのほとんどがいくつかの標的経路に収束すること，ヒストンH3リジン27のトリメチル化に特徴づけられるゲノム全域にわたるエピジェネティックな異常によって機能的microRNAや腫瘍抑制因子の発現が抑制され，腫瘍の発生と維持に関わっていることである。これらATLに特徴的な分子病態のなかで，CCR4を標的とする治療は既に抗体薬として日常診療に導入されたほか，Taxを標的とする免疫療法，免疫チェックポイント阻害薬による治療，EZH1/2を標的とする治療の開発が進んでいる。</p>

DOI： 10.11406/rinketsu.58.2004

PubMed

出版者・発行元：(一社)日本肝臓学会  

症例は66歳、男性。全身倦怠感、発熱、腹痛、食思不振で近医を受診し、血小板減少、肝腎機能障害を認め、当院へ緊急入院となった。腹部超音波検査、CT検査で著明な肝脾腫と脾内占拠性病変、脾出血を認めた。急速に肝不全が進行、播種性血管内凝固症候群(disseminated intravascular coagulation:DIC)も合併し、全身状態は増悪した。第3病日には腹腔内出血を来し、第5病日に死亡した。家族の同意を得て、剖検を行った。肝腫大、著明な脾腫大を認め、脾臓は被膜の破綻、出血を伴い脾破裂をきたしていた。肝臓、脾臓には腫瘍細胞がびまん性に増殖しており、免疫染色にて悪性リンパ腫(diffuse large B-cell lymphoma:DLBCL)と診断した。今回、我々は脾破裂を伴い急性肝不全様の急激な経過を呈した悪性リンパ腫の一例を経験したので文献的考察を含めて報告する。(著者抄録)

記述言語：日本語   出版者・発行元：BMC Neurology  

Background: Volume isotropic turbo spin-echo acquisition (VISTA) is a new method similar to the 3D black-blood imaging method that enables visualization of a intramural hematoma. T1-VISTA has recently been applied in the diagnosis of intracranial arterial dissection. However, the identification of an intramural hematoma in posterior inferior cerebellar dissection (PICA-D) by T1-VISTA has only rarely been reported. Case presentation: We herein report two patients who suffered from PICA-D complicated with ischemic stroke. Initial magnetic resonance arteriography was not informative, however, T1-VISTA depicted high-intensity signal areas suggesting an intramural hematoma of PICA-D in both cases. The high-intensity signal areas gradually reduced and finally disappeared at 4 months and 5 months after the onset, respectively. Conclusion: Our cases demonstrate that T1-VISTA was able to assist in the diagnosis and follow-up of PICA-D.

DOI： 10.1186/s12883-016-0637-9

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記述言語：日本語   出版者・発行元：Histopathology  

Aims: Forkhead box protein 3-positive (FoxP3⁺) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV-1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics. Methods and results: We describe here 11 cases of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and two cases of mycosis fingoides (MF) which were positive for FoxP3. The median age of the 11 PTCL-NOS cases was 65 years (range: 48-80 years), and all the patients were male. Eight patients (80%) showed stages III/IV disease, and six (60%) were categorized as high-intermediate/high-risk groups according to the International Prognostic Index. Two cases of MF were 57- and 59-year-old males. Both cases were categorized as stage IA, according to International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) classification. Immunohistochemically, all the cases were negative for cytotoxic molecule marker, and nine (75%) were αβ T cell type. Scattered Epstein-Barr virus (EBV)-infected cells were detected in four cases of PTCL-NOS, implying the reactivation of EBV caused by the immunodeficient status of the patients. Conclusions: FoxP3⁺ PTCL-NOS constitute a minor phenotypical subtype with poor prognosis and EBV reactivation in some. Conversely, two cases of MF showed an indolent clinical course which was different from previously reported cutaneous T cell lymphoma (CTCL) cases.

DOI： 10.1111/his.12885

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：American Journal of Surgical Pathology  

We investigated the expression of the aEb7 integrin (CD103)-intestinal homing receptor of T-intraepithelial lymphocytes (IELs) in 130 cases of adult T-cell leukemia/lymphoma (ATLL). We detected CD103⁺ lymphoma cells in 55% (31/56) of mainly gastrointestinal (GI)-involved ATLL cases. Among them, lymphoma cells of 18 cases located in other involved organs had similar CD103 expression patterns. Histologically, we found (a) increased reactive IELs in non-neoplastic mucosal layers in 28% (5/18) of surgical and mucosal resection cases, (b) preserved epithelial glands, and (c) numerous small intraepithelial ATLL nests in involved lesions in 36 (69%) and 21 (40%), respectively, of the 52 examined cases. These 3 patterns were common in intestinal type II enteropathy-associated T-cell lymphoma but were rare in intestinal EBV⁺ nasal-type/like T/natural killer (NK)-cell lymphoma. We detected CD103⁺ tumor cells in 41% (16/39) of lymph node-involved ATLL, in 31% (11/35) of skin-involved ATLL, in 68% (21/31) of type II CD4⁺ enteropathy-associated T-cell lymphoma cases, in 36% (8/22) of primary gastric T/NK-cell lymphomas, and in 77% (7/9) of CD8⁺ epidermotropic mycosis fungoides. CD103⁺ ATLL prefers involving the GI tract over the skin (P<0.05). CD103 expression in GI-involved and/or total ATLL cases was significantly higher than in other 9 T/NK-cell lymphoma groups (P<0.05 or 0.01). Only ATLL cases were commonly CD103⁺ in CD4⁺ T/NK-cell lymphoma groups (P<0.05 or 0.01). Human T-lymphotropic virus-1-infected CD103⁺ T-IELs and mucosal T cells may be important sources of ATLL.

DOI： 10.1097/PAS.0000000000000597

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人　日本肝臓学会  

<p>症例は66歳，男性．全身倦怠感，発熱，腹痛，食思不振で近医を受診し，血小板減少，肝腎機能障害を認め，当院へ緊急入院となった．腹部超音波検査，CT検査で著明な肝脾腫と脾内占拠性病変，脾出血を認めた．急速に肝不全が進行，播種性血管内凝固症候群（disseminated intravascular coagulation：DIC）も合併し，全身状態は増悪した．第3病日には腹腔内出血を来し，第5病日に死亡した．家族の同意を得て，剖検を行った．肝腫大，著明な脾腫大を認め，脾臓は被膜の破綻，出血を伴い脾破裂をきたしていた．肝臓，脾臓には腫瘍細胞がびまん性に増殖しており，免疫染色にて悪性リンパ腫（diffuse large B-cell lymphoma：DLBCL）と診断した．今回，我々は脾破裂を伴い急性肝不全様の急激な経過を呈した悪性リンパ腫の一例を経験したので文献的考察を含めて報告する．</p>

DOI： 10.2957/kanzo.57.674

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the expression of the αEβ7 integrin (CD103)-intestinal homing receptor of T-intraepithelial lymphocytes (IELs) in 130 cases of adult T-cell leukemia/lymphoma (ATLL). We detected CD103 lymphoma cells in 55% (31/56) of mainly gastrointestinal (GI)-involved ATLL cases. Among them, lymphoma cells of 18 cases located in other involved organs had similar CD103 expression patterns. Histologically, we found (a) increased reactive IELs in non-neoplastic mucosal layers in 28% (5/18) of surgical and mucosal resection cases, (b) preserved epithelial glands, and (c) numerous small intraepithelial ATLL nests in involved lesions in 36 (69%) and 21 (40%), respectively, of the 52 examined cases. These 3 patterns were common in intestinal type II enteropathy-associated T-cell lymphoma but were rare in intestinal EBV nasal-type/like T/natural killer (NK)-cell lymphoma. We detected CD103 tumor cells in 41% (16/39) of lymph node-involved ATLL, in 31% (11/35) of skin-involved ATLL, in 68% (21/31) of type II CD4 enteropathy-associated T-cell lymphoma cases, in 36% (8/22) of primary gastric T/NK-cell lymphomas, and in 77% (7/9) of CD8 epidermotropic mycosis fungoides. CD103 ATLL prefers involving the GI tract over the skin (P<0.05). CD103 expression in GI-involved and/or total ATLL cases was significantly higher than in other 9 T/NK-cell lymphoma groups (P<0.05 or 0.01). Only ATLL cases were commonly CD103 in CD4 T/NK-cell lymphoma groups (P<0.05 or 0.01). Human T-lymphotropic virus-1-infected CD103 T-IELs and mucosal T cells may be important sources of ATLL.

記述言語：日本語   出版者・発行元：Blood  

Adult T-cell leukemia/lymphoma (ATL) is amalignancy ofmature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stemcell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features andmanagement of ATL in Japan. The clinical data were collected retrospectively fromthemedical records of patientsdiagnosedwithATLbetween 2000 and2009, anda total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, andsmoldering types, respectively, remained. Themedian survival timeswere 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stemcell transplantation was 227, and their median survival timeandOSat 4 years after allogeneic hematopoietic stemcell transplantationwas 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatmentmodalities, but an improvement of 4-year OS was observed in comparisonwith the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected.

DOI： 10.1182/blood-2015-03-632489

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PubMed

記述言語：日本語   出版者・発行元：International Journal of Hematology  

A 57-year-old male with acute-type adult T cell leukemia–lymphoma (ATL) developed persistent watery, non-bloody diarrhea at a volume of 2–3 L/day following the administration of the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab. An extensive examination revealed the absence of any pathogenic bacteria or parasites in his stool. Biopsied specimens from the colonic mucosa contained many small nests of apoptotic bodies in the colonic glands, which mimicked acute-colonic graft-versus-host disease. Activation of the auto-reactive immune system due to the depletion of regulatory T-cells by mogamulizumab was suspected as causative. Special attention should be paid to the risk of unique immune-related adverse events induced by mogamulizumab.

DOI： 10.1007/s12185-015-1811-3

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PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

症例は57歳男性で、急性成人T細胞白血病リンパ腫(ATL)と診断された。患者が同種幹細胞移植を拒絶したためTHP-COP療法を開始した。その後は部分寛解に達したが、THP-COP療法終了直後にリンパ節と皮膚のATL病変が増大したため、当院に紹介となった。末梢血中のATL細胞において抗CCケモカイン受容体4(CCR4)が強力に発現していたため、day1、8、15、22に4回のモガムリズマブ投与を行った。その後、ゲムシタビン、カルボプラチン、デキサメサゾンによる併用化学療法を開始した。モガムリズマブの投与後に2〜3L/日の持続する水様性非血性下痢が出現したが、便中から病原性細菌や寄生虫は検出されなかった。大腸粘膜の生検検体では、結腸腺に多数のアポトーシス小体の小さい巣が認められ、これは急性大腸性移植片対宿主病とよく似ていた。この原因として、モガムリズマブによる制御性T細胞の欠乏による自己反応性免疫系の活性化が疑われた。

記述言語：日本語   出版者・発行元：Cancer Science  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

DOI： 10.1111/cas.12735

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PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

少なくとも1レジメンの化学療法を施行された再発/難治性成人T細胞白血病/リンパ腫(ATL)患者15名(男10名、女5名、49〜73歳)を対象に、ボルテゾミブ単剤療法の有効性と安全性を評価する臨床第II相試験を行った。主要評価項目は全奏効率(ORR)、副次評価項目は安全性、病変での最良効果、無増悪生存期間(PFS)であった。全奏効率として部分寛解(PR)が1名、安定が5名で認められ、ORRは6.7%であった。部位別の効果は末梢血の完全寛解が1名、測定可能な標的病変のPRが2名、皮膚病変のPRが2名で、PFRは38日であった。全ての患者で有害事象(AE)が1回以上認められ、80%でグレード3/4のAEが1回以上みられたが、新しい安全性所見はなかった。ボルテゾミブは単独でこのコホートの患者に対し非常に有望とは思われなかったため、この試験の終了を決定した。

記述言語：日本語   出版者・発行元：Journal of Natural Medicines  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). There are an estimated 5 million to 20 million HTLV-1-infected individuals worldwide; their lifetime risk of developing ATL is 3-5 %, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Although conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to ATL patients, the prognosis is often poor. In previous studies, we screened 459 extracts from 344 plants to isolate components exhibiting antiproliferative activity against HTLV-1-infected T-cell lines (MT-1 and MT-2). In our continuing search for potential anti-HTLV-1 natural products, 15 extracts of Asclepiadaceae plants were further tested against MT-1 and MT-2 cells. The MeOH extract of aerial parts of Tylophora tanakae showed antiproliferative activity. Activity-guided fractionation resulted in the isolation of 6 phenanthroindolizidine alkaloids (including a new compound), and we examined their antiproliferative activity against MT-1 and MT-2 cells. The EC<inf>50</inf> value of some of the alkaloids was in the low nanomolar range, comparable to that of the clinically used antineoplastic drug doxorubicin. Structure-activity relationship analyses suggested that a 14β-hydroxy moiety is essential for activity against HTLV-1-infected T cells. In contrast, the presence of a 2-methoxy moiety, a 7-methoxy moiety, or an N-oxide moiety appears to reduce the potency of the antiproliferative activity against HTLV-1-infected T cells.

DOI： 10.1007/s11418-015-0906-8

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出版者・発行元：シュプリンガー・ジャパン(株)  

ガガイモ科植物の15種の抽出物の、ヒトTリンパ球向性ウイルス1型(HTLV-1)感染T細胞系(MT-1およびMT-2)に対する作用を検討した。Tylophora tanakaeの地上部のメタノール抽出物が抗増殖効果を示した。activity-guided fractionationを行ったところ、6種のフェナンスロインドリジジンアルカロイド(1種の新規化合物を含む)が単離された。MT-1およびMT-2細胞に対する抗増殖活性を測定した結果、一部の化合物のEC50は低いナノモル濃度を示し、抗癌薬ドキソルビシンに匹敵した。構造活性相関では、14β-ヒドロキシ基が必須であった。一方、2-メトキシ基、7-メトキシ基、N-オキシド基は抗増殖活性を低下させるようであった。

記述言語：日本語   出版者・発行元：British Journal of Haematology  

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

DOI： 10.1111/bjh.13338

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PubMed

担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Human T-lymphotropic virus type-I(HTLV-1)は成人T細胞白血病・リンパ腫(ATL),HTLV-1関連脊髄症/熱帯性痙性脊髄麻痺などの原因ウイルスで,主に授乳や性交渉によって感染が成立する。本研究では国内4施設におけるHTLV-1感染者(キャリア)対応の実態を調べた。キャリア外来標榜施設では,献血時もしくは妊娠時の検査でHTLV-1感染を知り,HTLV-1関連疾患発症の有無についての検査やHTLV-1感染に伴う不安への説明や相談,関連疾患に対する説明を希望し受診する場合が多かった。受診者の約半数はHTLV-1感染を2年以上前に告知されており,近年のHTLV-1やキャリア外来への社会での認知から,キャリア自身の意識が変わったことが受診につながったものと考えられる。一方で,HTLV-1高度浸淫地域においてはかかりつけ医によって十分な対応がなされている可能性が高いと考えられた。HTLV-1非浸淫地域にある2施設ではHTLV-1キャリアと診断された受診者の50%以上が両親とも出生地は九州以外であり,HTLV-1キャリアは九州出身者に多いとされてきた事実の変貌が明らかになった。今後HTLV-1キャリア数は減少するものの,居住地の偏在は少なくなると考えられ,医療ニーズに適切かつ効率よく対応する体制の構築が重要である。

出版者・発行元：(一社)日本血液学会-東京事務局  

Human T-lymphotropic virus type-I(HTLV-1)は成人T細胞白血病・リンパ腫(ATL),HTLV-1関連脊髄症/熱帯性痙性脊髄麻痺などの原因ウイルスで,主に授乳や性交渉によって感染が成立する。本研究では国内4施設におけるHTLV-1感染者(キャリア)対応の実態を調べた。キャリア外来標榜施設では,献血時もしくは妊娠時の検査でHTLV-1感染を知り,HTLV-1関連疾患発症の有無についての検査やHTLV-1感染に伴う不安への説明や相談,関連疾患に対する説明を希望し受診する場合が多かった。受診者の約半数はHTLV-1感染を2年以上前に告知されており,近年のHTLV-1やキャリア外来への社会での認知から,キャリア自身の意識が変わったことが受診につながったものと考えられる。一方で,HTLV-1高度浸淫地域においてはかかりつけ医によって十分な対応がなされている可能性が高いと考えられた。HTLV-1非浸淫地域にある2施設ではHTLV-1キャリアと診断された受診者の50%以上が両親とも出生地は九州以外であり,HTLV-1キャリアは九州出身者に多いとされてきた事実の変貌が明らかになった。今後HTLV-1キャリア数は減少するものの,居住地の偏在は少なくなると考えられ,医療ニーズに適切かつ効率よく対応する体制の構築が重要である。(著者抄録)

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

Human T-lymphotropic virus type-I (HTLV-1)は成人T細胞白血病・リンパ腫(ATL)，HTLV-1関連脊髄症/熱帯性痙性脊髄麻痺などの原因ウイルスで，主に授乳や性交渉によって感染が成立する。本研究では国内4施設におけるHTLV-1感染者（キャリア）対応の実態を調べた。キャリア外来標榜施設では，献血時もしくは妊娠時の検査でHTLV-1感染を知り，HTLV-1関連疾患発症の有無についての検査やHTLV-1感染に伴う不安への説明や相談，関連疾患に対する説明を希望し受診する場合が多かった。受診者の約半数はHTLV-1感染を2年以上前に告知されており，近年のHTLV-1やキャリア外来への社会での認知から，キャリア自身の意識が変わったことが受診につながったものと考えられる。一方で，HTLV-1高度浸淫地域においてはかかりつけ医によって十分な対応がなされている可能性が高いと考えられた。HTLV-1非浸淫地域にある2施設ではHTLV-1キャリアと診断された受診者の50%以上が両親とも出生地は九州以外であり，HTLV-1キャリアは九州出身者に多いとされてきた事実の変貌が明らかになった。今後HTLV-1キャリア数は減少するものの，居住地の偏在は少なくなると考えられ，医療ニーズに適切かつ効率よく対応する体制の構築が重要である。

DOI： 10.11406/rinketsu.56.666

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PubMed

出版者・発行元：(一社)日本核医学会  

治療前にFDG-PET/CT検査を受けた体の悪性リンパ腫患者30名(瀰漫性B細胞リンパ腫16名およびその他のリンパ腫14名)を対象とし、局所脳グルコース代謝をレトロスペクティブに評価した。局所脳グルコース代謝は両側性前頭および頭頂葉皮質において糖分解体積の増加に伴い減少することが示された。化学療法後の統計的画像解析により、良好なレスポンダーでは両側性前頭および後頭皮質の局所脳グルコース代謝の回復が認められたが、低レスポンダーでは治療前後の局所脳グルコース代謝変化は認められなかった。さらに、健常人との比較により、治療前の悪性リンパ腫患者では頭頂-後頭皮質において局所脳グルコース代謝が低下していることが示された。本検討により、悪性リンパ腫患者では脳の機能的変化および/または無症候性の脳の損傷を生じていることが示唆された。

記述言語：日本語   出版者・発行元：Annals of Nuclear Medicine  

Methods: The subjects consisted of 30 patients, including 16 patients with diffuse large B-cell lymphoma and 14 patients with other types of lymphoma. Patients with primary cerebral lymphoma were excluded from this study. All patients underwent CT and whole-body FDG-PET scans, including 4-min brain scans using a dedicated PET/CT scanner during both the pre- and post-treatment periods. The whole-body scans started 60 min after the administration of 185 MBq of FDG, after which the brain data were extracted from whole-body data. The degree of regional cerebral glucose metabolism was evaluated on a voxel-by-voxel basis using statistical parametric mapping (SPM). The total tumor glycolytic volume of the body was measured using a separate workstation. The normal control subjects were 12 persons who underwent medical check with FDG-PET/CT and had no lesions suggesting malignant tumor.Results: The level of regional cerebral glucose metabolism decreased in association with an increase in the total glycolytic volume in the bilateral frontal and parietal cortices. After chemotherapy, the statistical image analysis demonstrated an interval recovery of the cerebral glucose metabolism of the bilateral parietal and occipital cortices in the good responders, whereas there were no significant differences observed in regional cerebral glucose metabolism between the pre- and post-treatment images in the poor responders. Comparison between normal control subjects and patients with pre-treatment lymphoma also showed that the regional cerebral glucose metabolism decreased in the parieto-occipital cortices in patients with lymphoma compared to normal control subjects.Objectives: The aim of this study was to clarify the characteristics of regional cerebral glucose metabolic abnormalities in patients with malignant lymphoma of the body using statistical image analyses. Post-therapeutic changes in cerebral glucose metabolism were also evaluated.Conclusions: We demonstrated that patients with malignant lymphoma of the body exhibited abnormal regional cerebral glucose metabolism, which improves after chemotherapy. Although the mechanism underlying the reduction of cerebral glucose metabolism remains unclear, our findings indicate the functional alternation and/or subclinical damage of the brain in patients with malignant lymphoma.

DOI： 10.1007/s12149-014-0890-1

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記述言語：日本語   出版者・発行元：The Lancet Oncology  

Adult T-cell leukaemia-lymphoma (ATL) is a malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1), and its prognosis is poor. There are an estimated 5 million to 20 million HTLV-1 infected individuals worldwide; their lifetime risk of developing ATL is 3-5%, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Recent advances in the treatment of ATL are the introduction of treatment targeted against CC chemokine receptor 4 (CCR4), which is abundantly expressed on most ATL cells, and allogeneic haemopoietic stem-cell transplantation for aggressive ATL. Promising outcomes are also reported with early intervention for indolent ATL with interferon α and zidovudine. Clinical trials should incorporate a validated prognostic index to assess the results, because of the difficulties associated with undertaking large-scale trials and significant diversity of clinical features with ATL, even in the same clinical subtypes (acute, lymphoma, chronic, and smoldering).

DOI： 10.1016/S1470-2045(14)70202-5

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PubMed

記述言語：日本語   出版者・発行元：Anticancer Research  

Background: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes and its prognosis still remains very poor. Materials and Methods: The potential of combining the Bcl-2 homology 3 mimetic ABT-737, which blocks Bcl-2, Bcl-X<inf>L</inf>, and Bcl-w, with either the proteasome inhibitor bortezomib or histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) to inhibit the growth of human T-lymphotropic virus type-I (HTLV-1) infected T-cell lines and its mechanism was further evaluated. Results: ABT-737 synergistically induced apoptosis when combined with either bortezomib or SAHA in HTLV-1 infected T-cell lines and fresh ATL cells. Bortezomib increased the expression of Noxa, which subsequently enhanced the formation of Mcl-1-Noxa complexes, resulting in the functional neutralization of Mcl-1, an inducer of resistance to ABT-737. On the other hand, SAHA reduced the expression of survivin, an anti-apoptotic molecule that confers drug resistance on ATL cells. Conclusion: The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL.

Scopus

PubMed

記述言語：日本語   出版者・発行元：British Journal of Haematology  

This study evaluated the clinical features of 276 patients with aggressive adult T-cell leukaemia-lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long-term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG-PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease-related deaths in 10 patients with lymphoma-type were observed in contrast to the 10 ATL-related deaths in other types. In multivariate analysis of 193 patients, the JCOG-PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG-PI was reproducible in an external validation. Patients with lymphoma-type who survived >5 years might have been cured. The JCOG-PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies. © 2014 John Wiley & Sons Ltd.

DOI： 10.1111/bjh.12962

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PubMed

記述言語：日本語   出版者・発行元：Supportive Care in Cancer  

Purpose: The aims of this study were to evaluate the safety, efficacy, and pharmacokinetics of repeated doses of palonosetron 0.75 mg on days 1 and 3 in Japanese patients who received highly or moderately emetogenic chemotherapy. Methods: Twenty- six patients received palonosetron 0.75 mg intravenously before chemotherapy on days 1 and 3 plus dexamethasone (12-16 mg before chemotherapy on day 1 and 4-8 mg on days 2 and 3). The primary endpoints were safety and pharmacokinetics. Pharmacokinetics were evaluated in a subset of patients (n=6). Complete response and complete protection were evaluated as secondary endpoints. Results: The accumulation ratios for C<inf>max</inf> and AUC <inf>last</inf> after the second dose on day 3 were 1.42 and 1.37, respectively. These values were consistent with the theoretical values expected from the half-life of palonosetron on day 1. Almost all of the patients had no nausea or vomiting in the acute phase (complete response (CR) rate, 96.2 % [25/26]; CP rate, 92.3 % [24/26]). In the delayed phase (24-192 h post-chemotherapy), the complete response and complete protection rates were 76.9 % (20/26) and 61.5 % (16/26), respectively. Treatment was well tolerated. Conclusions: This is the first study to report the pharmacokinetics of multiple doses of palonosetron 0.75 mg, given on days 1 and 3, in Japanese patients. Repeated treatment with palonosetron was safe and well tolerated by patients who received highly or moderately emetogenic anticancer chemotherapy. © 2014 Springer-Verlag.

DOI： 10.1007/s00520-014-2179-2

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PubMed

記述言語：日本語   出版者・発行元：Cancer Science  

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[-]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n = 20/25] versus EBV[-]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E. © 2014 The Authors.

DOI： 10.1111/cas.12389

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PubMed

出版者・発行元：John Wiley & Sons Australia, Ltd  

ヒトオリゴヌクレオチドマイクロアレイ分析を用いて、高齢者のEpstein-Barrウイルス(EBV)陽性びまん性大細胞型B細胞リンパ腫(EBV(+)DLBCL-E)5つとEBV(-)DLBCL7つの遺伝子発現プロファイリングを行い、EBV(+)DLBCL-Eにおける経路の特徴を調べた。遺伝子セット濃縮解析や遺伝子オントロジー解析から、EBV(+)DLBCL-EではJanusキナーゼシグナルトランスデューサー-転写活性化因子(JAK-STAT)と核因子κB経路が豊富であった。これはin vitro分析でも確かめられ、DLBCL細胞株にEBVを感染させるとJAK-STATとNF-κB経路の高活性化が誘導された。ウェスタンブロット分析ではEBV感染細胞株でリン酸化STAT3蛋白質の発現レベル上昇を認めた。免疫組織化学により、EBV(+)DLBCL-E臨床試料のリンパ腫細胞でリン酸化STATS3蛋白質の発現をしばしば認められた。JAK-STATとNF-κB経路を標的とする治療はEBV(+)DLBCL-Eの臨床転帰を改善する可能性があると考えた。

記述言語：日本語   出版者・発行元：Hypertension  

The relationship between the poststroke blood pressure (BP) and functional outcomes in patients with acute ischemic stroke is still controversial. The aim of the present study was to elucidate the impact of the poststroke BP on the clinical outcomes of acute ischemic stroke. Among the patients in the Fukuoka Stroke Registry, 1874 patients with first-ever acute ischemic stroke (within 24 hours of onset) who had been functionally independent before onset were prospectively enrolled in the present study. The poststroke BP levels were defined as the average values during the 48 hours after onset. The study outcomes were a good neurological recovery, neurological deterioration, and a poor functional outcome. The higher poststroke BP levels were significantly associated with a lower probability of a good neurological recovery and elevated risks of neurological deterioration and a poor functional outcome after adjusting for potential confounding factors. The multivariate-adjusted odds ratios (95% confidence interval) in the highest quintile of systolic BP (versus the lowest quintile as a reference) were 0.51 (0.37-0.71) for a good neurological recovery, 1.92 (1.15-3.27) for neurological deterioration, and 2.51 (1.69-3.74) for a poor functional outcome. Similar associations were observed when we applied the poststroke diastolic BP or pulse pressure. No evidence of the J-curve phenomenon was observed for each association. These results suggest that a high poststroke BP was significantly associated with unfavorable clinical outcomes in patients with acute ischemic stroke. There was no evidence of the J-curve phenomenon between the poststroke BP levels and the clinical outcomes. © 2013 American Heart Association, Inc.

DOI： 10.1161/HYPERTENSIONAHA.113.02189

Scopus

出版者・発行元：一般社団法人 日本血液学会  

DOI： 10.11406/rinketsu.54.1817

PubMed

記述言語：日本語   出版者・発行元：Journal of Natural Medicines  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T lymphocytes caused by human T-cell lymphotropic virus type I (HTLV-I). In our previous paper, 214 extracts from 162 plants were screened to elucidate the anti-proliferative principles against HTLV-I-infected T-cell lines. In this study, 245 extracts from 182 plants belonging to 61 families were further tested against two HTLV-I-infected T-cell lines (MT-1 and MT-2). Potent anti-proliferative effects were exhibited against MT-1 and MT-2 cells by 52 and 60 of the 245 extracts tested, respectively. Of these, two extracts showed strong inhibitory activity (EC<inf>50</inf> values 0.1-1 μg/mL; +++) against both cells, 7 extracts showed moderate inhibitory activity (EC<inf>50</inf> values 1-10 μg/mL; ++), and 43 extracts showed weak inhibitory activity (EC<inf>50</inf> values 10-100 μg/mL; +), whereas the remaining extracts did not show any activity (EC<inf>50</inf> values >100 μg/mL; -) against MT-1 cells. On the other hand, 10 extracts showed moderate inhibitory activit and, 48 extracts showed weak inhibitory activity, whereas the remaining extracts did not show any activity against MT-2 cells. Extracts from the aerial parts of Annona reticulata and A. squamosa showed the most potent inhibitory activity and three aporphine alkaloids were isolated from their extracts as the active principles by activity-guided fractionation. © 2013 The Japanese Society of Pharmacognosy and Springer Japan.

DOI： 10.1007/s11418-013-0747-2

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PubMed

出版者・発行元：(一社)日本消化器外科学会  

症例は59歳の女性で,幼少時より鼻出血を繰り返し,数回の赤血球輸血を受けていた.9年前より慢性C型肝炎を指摘され近医で経過観察されていた.今回,肝S6に径4cm大の腫瘍を指摘され当科紹介となった.家族歴と血液検査結果よりvon Willebrand病(von Willebrand disease;以下,vWDと略記)患者に発生した肝細胞癌と診断した.凝固因子補充療法のガイドラインに従い,activated partial thromboplastin time(APTT)を指標として血液凝固第VIII因子(blood clotting factor VIII;以下,F VIIIと略記)製剤の投与後に肝部分切除術を施行した.術後第1病日より8日間のF VIII製剤の補充を行い,術後経過良好にて第13病日に退院となった.vWD病患者においてもF VIII製剤の補充を行うことで安全に肝切除を施行した症例を報告する.(著者抄録)

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

ヒト成人T細胞白血病/リンパ腫(ATL)に対する有望な化学療法薬候補を検討するため、植物のスクリーニングを行った。61属182種類の植物から調製した245の抽出物について、2種類のヒトT細胞白血病ウイルスI型(HTLV-I)感染T細胞株(MT-1、MT-2)に対する活性を評価した。245の抽出物のうち、MT-1細胞に強力な抗増殖作用を示したのは52、MT-2細胞に強力な抗増殖作用を示したのは60であった。そのうち、いずれの細胞に対しても強力な阻害活性を示したのは2つ(EC50 0.1〜1μg/mL、+++)、中等度の阻害活性を示したのは7つ(EC50 1〜10μg/mL、++)、弱い阻害活性を示したのは43で(EC50 10〜100μg/mL、+)、残りの抽出物はMT-1細胞に活性を示さなかった(EC50>100μg/mL、-)。MT-2細胞に対しては、10の抽出物が中等度の阻害活性、48の抽出物が弱い阻害活性を示し、残りは活性を示さなかった。Annona reticulataとA. squamosaの地上部の抽出物は阻害活性が最も強力で、それら抽出物から活性成分として、3つのアポルフィンアルカロイドが分離された。

記述言語：日本語   出版者・発行元：Journal of Natural Medicines  

Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure-activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4β-hydroxy group as well as a 5β,6β-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death. © 2012 The Japanese Society of Pharmacognosy and Springer.

DOI： 10.1007/s11418-012-0700-9

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PubMed

出版者・発行元：シュプリンガー・ジャパン(株)  

著者等は以前に、162種の植物からの214種の抽出物について、ヒト成人T細胞白血病/リンパ腫(ATL)細胞株に対する抗増殖成分のスクリーニングを行い、数種のウィタノリドを単離し、その構造活性相関(SAR)について検討した。今回更にSARについての研究範囲を広げて、ナス科の植物から既に単離していた31種のウィタノリドを用いてATL細胞株に対する抗増殖活性を調べた。活性発現には、5β、6β-エポキシ基と共に4β-ヒドロキシ基が必須であると推測された。3-と27-位のどちらかの位置の糖の存在により、逆に活性が低下した。更に24,25-ジヒドロウィタノリドDが最も強い阻害物質であり、アポトーシス性細胞死を誘導してATL細胞株に対する選択毒性を示すことが示された。

記述言語：日本語   出版者・発行元：一般社団法人 日本消化器外科学会  

症例は59歳の女性で，幼少時より鼻出血を繰り返し，数回の赤血球輸血を受けていた．9年前より慢性C型肝炎を指摘され近医で経過観察されていた．今回，肝S6に径4 cm大の腫瘍を指摘され当科紹介となった．家族歴と血液検査結果よりvon Willebrand病（von Willebrand disease；以下，vWDと略記）患者に発生した肝細胞癌と診断した．凝固因子補充療法のガイドラインに従い，activated partial thromboplastin time（APTT）を指標として血液凝固第VIII因子（blood clotting factor VIII；以下，F VIIIと略記）製剤の投与後に肝部分切除術を施行した．術後第1病日より8日間のF VIII製剤の補充を行い，術後経過良好にて第13病日に退院となった．v WD病患者においてもF VIII製剤の補充を行うことで安全に肝切除を施行した症例を報告する．

DOI： 10.5833/jjgs.2012.0320

Scopus

記述言語：英語  

記述言語：日本語   出版者・発行元：Journal of Clinical Oncology  

Purpose: The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI). Patients and Methods: In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model. Results: Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor [sIL-2R]) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ ² = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ ² = 74.2, 2 df; log-rank test). Conclusion: The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks. © 2012 by American Society of Clinical Oncology.

DOI： 10.1200/JCO.2011.38.2101

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PubMed

記述言語：日本語   出版者・発行元：Cancer Letters  

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). ABT-737, a small molecule inhibitor of Bcl-2, Bcl-X <inf>L</inf>, and Bcl-w, significantly induced apoptosis in HTLV-1 infected T-cell lines as well as in fresh ATLL cells, and synergistically enhanced the cytotoxicity and apoptosis induced by conventional cytotoxic drugs. Moreover, ABT-737 significantly inhibited the in vivo tumor growth of an ATLL mouse model. These results suggest that the use of an agent targeting anti-apoptotic bcl-2 family proteins, either alone or in combination with other conventional drugs, represents a novel promising approach for ATLL. © 2011 Elsevier Ireland Ltd.

DOI： 10.1016/j.canlet.2011.11.030

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PubMed

記述言語：日本語   出版者・発行元：Journal of Clinical Oncology  

Purpose: Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL. Patients and Methods: A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg. Results: Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases. Conclusion: KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted. © 2012 by American Society of Clinical Oncology.

DOI： 10.1200/JCO.2011.37.3472

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PubMed

記述言語：日本語   出版者・発行元：Current Neurovascular Research  

Platelet derived growth factor (PDGF)-B plays a neuroprotective role in brain damages, including ischemic stroke. It has been suggested recently that PDGF receptor β (PDGFRβ) expressed in brain pericytes as well as in neurons and astrocytes may mediate the neuroprotective role of PDGF-B. The aims of this study were to elucidate the roles of PDGFRβ signaling in brain pericytes after ischemic stroke. In a rat middle cerebral artery occlusion (MCAO) model, PDGFRβ expression was induced specifically in the pericytes in peri-infarct areas and its level was gradually increased. PDGF-B induced marked phosphorylation of Akt in cultured brain pericytes. Consistently, PDGF-B was upregulated in endothelial cells in per-infarct areas and Akt was strongly phosphorylated in the PDGFRβ-expressing pericytes in periinfarct areas after MCAO. In the cultured pericytes, PDGF-B induced cell growth and anti-apoptotic responses through Akt. Furthermore, PDGF-B significantly increased the expression of nerve growth factor (NGF) and neurotrophin-3 (NT-3) through Akt in the pericytes. Thus, the PDGFRβ-Akt signaling in brain pericytes may play various important roles leading to neuroprotection after ischemic stroke. © 2012 Bentham Science Publishers.

DOI： 10.2174/156720212799297100

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記述言語：日本語   出版者・発行元：Drugs of Today  

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I, and its clinical subtypes are categorized into smoldering, chronic, lymphoma and acute types. The standard care for patients with the acute, lymphoma and unfavorable chronic types (aggressive ATL) consists of intensive chemotherapy with or without subsequent allogeneic hematopoietic stem cell transplant, or a combination of interferon alfa and an antiretroviral agent, while that for the chronic type without unfavorable prognostic factors and the smoldering type (indolent ATL) is watchful waiting. Recently, early intervention for indolent ATL employing interferon alfa and an antiretroviral agent has been reported to lead to a marked benefit in a retrospective study. This modality should be evaluated in larger clinical trials, since patients with indolent ATL show a median survival time of as short as 4-5 years. Copyright © 2011 Prous Science, S.A.U. or its licensors. All rights reserved.

DOI： 10.1358/dot.2011.47.8.1590785

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PubMed

出版者・発行元：Springer Japan  

記述言語：日本語   出版者・発行元：Anticancer Research  

The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CRM197 plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL.

Scopus

記述言語：日本語   出版者・発行元：Journal of Natural Medicines  

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I (HTLV-1). Clinical manifestations of ATL range from smoldering to chronic, lymphoma and acute subtypes. Patients with acute and lymphoma-type ATL require therapeutic intervention. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATL patients, but the therapeutic outcomes of acute and lymphoma-type ATL remain very poor. In this study, 214 extracts from 162 plants belonging to 65 families were screened for the purpose of elucidating the anti-proliferative effect against HTLV-1-infected T-cell lines. Extracts from aerial parts of Physalis pruinosa showed potent inhibitory effect. We isolated five withanolides from the extracts by activity-guided fractionation and examined the structure-activity relationships. The presence of a 5β,6β-epoxy function is suggested to be essential for the activity, and the most active principle showed selective toxicity to HTLV-1-infected T-cell lines. © 2011 The Japanese Society of Pharmacognosy and Springer.

DOI： 10.1007/s11418-011-0543-9

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PubMed

出版者・発行元：シュプリンガー・ジャパン(株)  

ATL(adult T-cell leukemia)はHTLV-1により引き起こされる疾患で,急性期に有効な治療法は存在しない.新たな化学療法薬探索の目的で,抗ATL活性を指標に162種214個の植物エキスライブラリーのスクリーニングを行い,ショクヨウホオズキ地上部エキスが顕著な活性を示すことを明らかとした.生物活性を指標に分離精製を行った結果,5種のwithanolidesを得た.また,活性測定の結果,B環にエポキシ基をもつ化合物が最も強い活性を示すことを明らかにするとともに,正常細胞に対する選択的毒性があることも明らかとした.(著者抄録)

PubMed

記述言語：英語  

記述言語：日本語   出版者・発行元：International Journal of Hematology  

Combination therapy with interferon-α and zidovudine (IFN/AZT) has been regarded as standard care for acute and indolent (i.e., chronic and smouldering) ATL based on reports involving a limited number of patients. This treatment approach has not been evaluated in Japan, a major endemic area of this disease in the world. This is the first Japanese report of IFN/AZT for ATL. It is impossible to draw any definitive conclusion from this small study; however, IFN/AZT showed clear anti-ATL effects for refractory/relapsed ATL patients. This report would contribute for developing future ATL treatment in Japan. © 2010 The Japanese Society of Hematology.

DOI： 10.1007/s12185-010-0717-3

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PubMed

出版者・発行元：(一社)日本血液学会  

インターフェロン-αとジドブジン(IFN/AZT)の日本での評価はまだなされていない。IFN/AZTを成人T細胞白血病/リンパ腫(ATL)の3症例(63歳男性、62歳女性、48歳男性)に用いた。63歳男性は修正EPOCH療法で完全緩解を得たが、斑状皮膚病巣からATL細胞浸潤が認められIFN/AZTを開始し、急速に皮膚症状が消え1ヵ月以内にWBCが減少した。62歳女性は無治療で4年間くすぶっていたATLが発症し、THP-COPで治療し部分緩解となった。2ヵ月後病状が悪化しINF/AZTを開始した。反応は明確ではなかったが、病状は抑えることができた。48歳男性は急性ATLと診断されCHOPとVCAP、AMP、VECPで治療したが効果はなく、この処方は重篤な骨髄抑制を示した。IFN/AZTを開始したが、効果は見られず22日間で中止した。同種幹細胞移植に備えての骨髄機能を廃絶する処方でもATL症状を根絶することはできなかった。

出版者・発行元：福岡大学研究推進部  

出版者・発行元：「臨床血液」編集部  

PubMed

記述言語：日本語   出版者・発行元：[Rinshō ketsueki] The Japanese journal of clinical hematology  

A 72-year-old man with extranodal natural killer cell lymphoma (ENKL) presented with a painless swelling of the left forearm. He was initially diagnosed as having a bacterial cellulitis and received antimicrobial therapy. However, his left arm became increasingly swollen in association with fever and redness of the lesion. Therefore, he underwent focal dissection. Because of persistent swelling, the left arm was rebiopsied 9 months later, and a diagnosis of ENKL developing in the subcutis was established. He was treated with focal radiation therapy in combination with dexamethasone, etoposide, ifosfamide, methotrexate and L-asparaginase. The lesion was significantly reduced in size but did not disappear completely. Two months later the lesion became necrotic, although swelling of the forearm lesion, left axillary and cervical lymph nodes were kept under control. We then performed amputation of the left forearm since it could not be saved medically. The patient currently remains alive and well without progression 2 years after amputation. When evaluating panniculitis, which is difficult to cure, ENKL should be considered in the differential diagnosis and treated appropriately.

Scopus

出版者・発行元：(一社)日本血液学会-東京事務局  

72歳男性。左前腕部に腫脹を生じ蜂窩織炎の診断で抗菌剤治療を受けたが改善しなかった。7ヵ月後に疼痛,発熱を伴い腫脹が増大したため病巣掻爬術と抗菌剤含有セメント挿入術を施行された。2ヵ月後にさらに腫脹が増大したため組織検査を再検し,壊死組織とその辺縁に中型異型リンパ球の増殖を認めた。異型リンパ球はCD3,CD56,CD30,TIA1,granzymeB,EBERが陽性,CD4,CD8,CD25,CD79a,CD20が陰性で節外性NK/T細胞リンパ腫(ENKL)と診断,臨床病期はIIB期だった。左前腕腫瘤の放射線療法と多剤併用化学療法を行い病変は縮小したが,掻爬部の壊死と腐敗が進行し左上肢を切断した。現在まで約2年無増悪生存している。治療に反応しない蜂窩織炎様病変の鑑別診断にはENKLも考慮し,適切な診断と治療を行うことが肝要である。(著者抄録)

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1416100649

出版者・発行元：(株)医学書院  

症例は46歳女性で、右足底部の異常感覚(ジンジン感)が出現し、右下腿、大腿後面と広がった。その後、しびれ感が出現し、下肢脱力のためバスの乗り降りなどが困難となり尿意を感じなくなった。意識清明、脳神経に異常を認めず、両下肢遠位筋は軽度の筋力低下を認めた。右大腿・下腿後面、両足底部および臀部に表在覚低下と異常感覚を認めた。深部腱反射右膝蓋腱反射が低下し、両アキレス腱反射が消失し、病的反射は認めなかった。責任病巣は下位腰髄から円錐上部と推測されるもの画像所見から異常を認めず、骨髄穿刺で血管内リンパ腫(IVL)と診断した。円錐上部症候群で発症したIVLで、亜急性進行性で原因不明の下位腰髄・円錐上部障害や上行性脊髄症をみた場合、IVLの可能性を考えることが重要と思われた。

記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

72歳男性。左前腕部に腫脹を生じ蜂窩織炎の診断で抗菌剤治療を受けたが改善しなかった。7ヵ月後に疼痛，発熱を伴い腫脹が増大したため病巣掻爬術と抗菌剤含有セメント挿入術を施行された。2ヵ月後にさらに腫脹が増大したため組織検査を再検し，壊死組織とその辺縁に中型異型リンパ球の増殖を認めた。異型リンパ球はCD3, CD56, CD30, TIA1, granzymeB, EBERが陽性，CD4, CD8, CD25, CD79a, CD20が陰性で節外性NK/T細胞リンパ腫(ENKL)と診断，臨床病期はIIB期だった。左前腕腫瘤の放射線療法と多剤併用化学療法を行い病変は縮小したが，掻爬部の壊死と腐敗が進行し左上肢を切断した。現在まで約2年無増悪生存している。治療に反応しない蜂窩織炎様病変の鑑別診断にはENKLも考慮し，適切な診断と治療を行うことが肝要である。

DOI： 10.11406/rinketsu.51.422

記述言語：英語   出版者・発行元：日本リンパ網内系学会  

Cladribine is approved to be used in 24-hour continuous infusion for the treatment of low-grade lymphoma by the Ministry of Health, Labor and Welfare in Japan. Pharmacokinetic studies showed that the antitumor activity of cladribine by 2-hour infusion should be comparable to that given by continuous infusion. The safety and anti-tumor activity of short infusion of cladribine was shown in hairy cell leukemia, chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma in Europe. We therefore underwent a pilot study to confirm the safety and efficacy of cladribine given by 2-hour infusion for Japanese patients with relapsed or refractory indolent B-cell lymphoma. Cladribine at a dose of 0.09 mg/kg was administered in 2-hour intravenous infusion for 5 consecutive days. The treatment was repeated at a 28-day interval for at least 2 cycles, and its efficacy and toxicity were investigated. Fourteen patients were entered into this study. Eight patients (57%) responded to cladribine, including 2 (14%) complete response (CR) and 6 (43%) partial response (PR). The median duration of response was 20+ and 21+ months for CR, and 12 months ranging from 3 to 34 months for PR, respectively. Grade 3 or 4 neutropenia and lymphocytopenia occurred in 43% and 71% of patients, respectively, but there was no febrile neutropenia or opportunistic infection associated with cladribine treatment. No other adverse events greater than grade 3 were encountered. The tumor response and degree of toxicity were comparable with those observed in cladribine treatment given by continuous infusion at a same dose. Cladribine can be administered in 2-hour infusion in an outpatient clinic and is therefore quite convenient for patients. [<I>J Clin Exp Hematopathol 49(2) : 69-75, 2009</I>]

DOI： 10.3960/jslrt.49.69

Scopus

PubMed

記述言語：英語   出版者・発行元：(一社)日本リンパ網内系学会  

再発性および難治性の緩慢性B細胞リンパ腫の日本人患者に対して、クラドリビンを2時間静脈内注入し、安全性と有効性を調べる試験的研究を行った。14名の患者を対象として0.09mg/kgのクラドリビンの静脈内注入を1日2時間、5日間行った。投与は28日間隔で最低2サイクル行い、有効性と毒性を評価した。クラドリビン投与に対し2名は完全緩解(CR)、6名は部分緩解(PR)を達成した。反応継続期間はCRで20+と21+ヶ月、PRで3〜34ヵ月であった。第3〜4度の好中球減少とリンパ球減少がそれぞれ43%、71%の患者で生じた。発熱性好中球減少や、クラドリビン投与に関連した日和見感染はみられなかった。第3度以上の有害事象は生じなかった。腫瘍反応と毒性の程度はクラドリビンを持続注入した際と同程度であった。クラドリビン治療は外来診察室での2時間の静脈内注入で行うことが可能である。

記述言語：日本語   出版者・発行元：Leukemia and Lymphoma  

There are a few reports suggesting that rituximab (RTX) might be a risk for interstitial pneumonitis (IP). We also experienced such patients in the era of RTX. Here, we reviewed all the patients with non-Hodgkin lymphoma who were treated with RTX-CHOP-like regimen (R-CHOP) to determine the risk of developing IP. One of 59 (1.7) patients who received CHOP alone and 8 of 129 (6.2) patients who were treated with R-CHOP experienced IP (p0.28). Furthermore, three of eight patients who have had IP during R-CHOP were confirmed having Pneumocystis jirovecii pneumonia (PCP). PCP occurred during the fourth, sixth, and seventh cycle of chemotherapy, respectively. Among the patients treated by R-CHOP, 3 of 32 (9) patients whose lymphocyte counts were <1000/μL before chemotherapy developed PCP, while 70 patients whose lymphocyte counts were >1000/μL did not (p0.03). In four of eight patients, IP occurred during the administration of granulocyte-colony stimulating factor. RTX seems to have a certain risk to induce IP including PCP. Patients with lymphoma who were treated by R-CHOP regimen, might be considered as PCP prophylactic, especially if the number of lymphocytes is low at the beginning of chemotherapy. © 2009 Informa Healthcare USA, Inc.

DOI： 10.3109/10428190903258780

Scopus

PubMed

記述言語：英語  

記述言語：日本語   出版者・発行元：Journal of Infection and Chemotherapy  

Bacillus cereus is known as a serious bacterial pathogen in neutropenic patients. B. cereus is often resistant to β-lactams, including penicillins and cephalosporins. We report a case of fatal pneumonia caused by B. cereus in a patient with newly diagnosed acute myeloid leukemia (AML) during remission induction therapy. Cefepime was started for febrile neutropenia (FN) initially and was switched to panipem/betamipron, when fulminant pneumonia supervened. The isolated strain was resistant not only to cefepime but also to panipenem/betamipron. This is the first report of fulminant infection caused by carbapenem-resistant B. cereus in a neutropenic patient. B. cereus should be kept in mind as a target of empirical treatment when neutropenic patients develop pneumonia © 2009 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

DOI： 10.1007/s10156-008-0654-8

Scopus

PubMed

出版者・発行元：エルゼビア・ジャパン(株)  

症例は末梢血に芽細胞を認めた60歳の男性で、急性骨髄性白血病と診断された。入院9日目に白血球減少状態となり、14日目に発熱を認めたため、セフェピムの投与を開始した。24日目に再びスパイク熱を発症したことから、セフェピムからパニペネム/ベタミプロンに切り替えた。28日後に咳嗽、左側胸膜痛及び下痢を認めたため、翌日CT検査を行ったところ、左側肺全体に広がる融合性の浸潤物を認め、同日死亡した。血液及び喀痰からセレウス菌が検出された。抗生物質感受性試験を行ったところ、セフェピムのみならずパニペネム/ベタミプロンに耐性を示した。本症例は好中球減少症患者におけるカルバペネム耐性セレウス菌を原因とする劇症型感染症の最初の症例である。好中球減少症患者が肺炎を発症した際にはセレウス菌感染を念頭に置くべきである。

記述言語：日本語   出版者・発行元：European Journal of Haematology  

We describe a 44-yr-old Japanese woman with persistent polyclonal T-cell proliferation and recalcitrant clinical course of haemophagocytic syndrome (HPS). T cells bearing αβ T-cell receptors (TCR) expressed increased amounts of CD95 and of CD45RO, which are phenotypically memory T cells. The TCR repertoire was broad and diverse. Regardless of CD95 expression, these cells were resistant to CD95-mediated apoptosis. Aggressive natural killer cell leukaemia (ANKL) without an association with Epstein-Barr virus was detected 1 month after therapeutic splenectomy that followed 3 yr of immunosuppressive therapy against HPS. The immunophenotype of these leukaemia cells was CD56, CD16^dim, CD7, CD45RA and they expressed some CD2, CD8 and HLA-DR. Moreover, hyperdiploid clones with complex chromosomal abnormalities were also detected. Latent NK-cell malignancy seemed to cause the CD95-resistant memory T-cell proliferation and splenectomy resulted in overt ANKL progression. There should be careful consideration of the risks versus benefits of splenectomy in HPS, in light of the possibility of fatal leukaemia/lymphoma progression. © 2008 The Authors.

DOI： 10.1111/j.1600-0609.2008.01097.x

Scopus

PubMed

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1402103468

記述言語：日本語   出版者・発行元：British Journal of Haematology  

The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment induces proliferation and survival of MM cells, as well as osteoclastogenesis. This study investigated the therapeutic potential of novel p38 mitogen-activated protein kinase (p38MAPK) inhibitor LY2228820 (LY) in MM. Although cytotoxicity against MM cell lines was modest, LY significantly enhanced the toxicity of bortezomib by down-regulating bortezomib-induced heat shock protein 27 phosphorylation. LY inhibited interleukin-6 secretion from long term cultured-BM stromal cells and BM mononuclear cells (BMMNCs) derived from MM patients in remission. LY also inhibited macrophage inflammatory protein-1α secretion from patient MM cells and BMMNCs as well as normal CD14 positive osteoclast precursor cells. Moreover, LY significantly inhibited in vitro osteoclastogenesis from CD14 positive cells induced by macrophage-colony stimulating factor and soluble receptor activator of nuclear factor-κB ligand. Finally, LY also inhibited in vivo osteoclatogenesis in a severe combined immunodeficiency mouse model of human MM. These results suggest that LY represents a promising novel targeted approach to improve MM patient outcome both by enhancing the effect of bortezomib and by reducing osteoskeletal events. © 2008 The Authors.

DOI： 10.1111/j.1365-2141.2008.07044.x

Scopus

PubMed

記述言語：日本語   出版者・発行元：European Journal of Haematology  

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell lymphotrophic virus type I. Clinical manifestations of ATLL range from smoldering to chronic, lymphoma and acute. Patients with acute and lymphoma type ATLL require therapeutic intervention. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATLL patients, but the therapeutic outcomes of acute and lymphoma type ATLL remain very poor. Promising results of allogeneic stem cell transplantation (SCT) for ATLL patients have recently been reported and the treatment outcome might be improved for some ATLL patients. Besides conventional chemotherapy and SCT, interferon, zidovudine, arsenic trioxide, targeted therapy against surface molecule on ATLL cells, retinoid derivatives, and bortezomib have been administered to ATLL patients in pilot or phase I/II studies. Further studies are required to confirm the clinical benefits of these novel therapeutics. This article reviews the current status and future directions of ATLL treatment. © 2008 The Authors.

DOI： 10.1111/j.1600-0609.2007.01016.x

Scopus

PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

傍腫瘍性辺縁系脳炎（paraneoplastic limbic encephalitis，PLE）は，悪性腫瘍に伴う自己免疫機序を介して生じる傍腫瘍性神経症候群の1つで，記憶障害や情動変化，痙攣など多彩な症状を呈する．原疾患としては肺小細胞癌や精巣腫瘍，乳癌などが多く^1），成人T細胞白血病（adult T cell leukemia/lymphoma，ATLL）での合併は報告されていない．我々はPLEを合併したATLLの症例を経験したので報告する．<br>

DOI： 10.2169/naika.97.410

Scopus

PubMed

出版者・発行元：(一社)日本内科学会  

58歳女。右頸部腫瘤と全身倦怠感、その後に傾眠傾向が出現し近医受診したところ、頸部リンパ節腫大の指摘で紹介入院となった。会話を止めると2、3秒で眠る状態で、扁桃生検よりMalignant lymphoma、diffuse、pleomorphic、T-cell typeと判断した。MRI、FLAIR像では両側扁桃体、海馬、海馬傍回、視床下部、尾状核頭部で高信号を呈していた。以上の検査結果から、急性型成人T細胞白血病(ATLL)と診断した。また、突発性睡眠は傍腫瘍性辺縁系脳炎(PLE)と考えた。ATLLに対しLSG15プロトコールによる化学療法を行ったところ、右頸部リンパ節、右扁桃腺は縮小し、突発性睡眠も消失、異常所見もほぼ消失した。

記述言語：日本語  

出版者・発行元：(一社)日本病理学会  

症例は70歳男性。尿閉を主訴に来院した。直腸診で、前立腺はやや弾性硬で中等度に肥大しており、prostate specific antigen(PSA)は10.4ng/mlと高値を示した。前立腺癌を疑い経直腸的生検と経尿道的切除術(TUR-P)を行った。組織学的には生検、TUR-Pともに小型から中型のcentrocyte-like cells(CCL細胞)の間質へのびまん性浸潤がみられ、上皮内にリンパ球が浸潤したlymphoepithelial lesion(LEL)がみられた。浸潤しているCCL細胞はCD20,CD79a陽性であったが、IgGκ,λに偏りはなく形質細胞分化はみられなかった。MIB-1陽性率は約20%であった。CT検査にて、前立腺以外の臓器に病変は認められなかった。前立腺原発の節外性粘膜関連濾胞辺縁帯リンパ腫(MALTリンパ腫)は報告が少なく、まれな症例と考えた。(著者抄録)

記述言語：日本語   出版者・発行元：一般社団法人 日本医療薬学会  

DOI： 10.20825/amjsphcs.18.0_301_1

出版者・発行元：南江堂  

DOI： 10.15106/j00974.2008061396

DOI： 10.1182/blood-2007-05-093294

PubMed

DOI： 10.1182/blood-2006-10-052845

PubMed

DOI： 10.1158/1535-7163.MCT-07-0010

PubMed

記述言語：日本語   出版者・発行元：Haematologica  

Arsenic trioxide (A <inf>s</inf>2O <inf>3</inf>) with or without interferon-α (IFN) was given to 4 patients with relapsed/refractory adult T-cell leukemia/lymphoma (ATLL). Treatment with A <inf>s</inf>2O <inf>3</inf> and IFN showed an encouraging response in two moderately-aggressive ATLL patients, while A <inf>s</inf>2O <inf>3</inf> alone was ineffective in two patients with very aggressive and rapidly progressing ATLL. Further studies are needed to clarify the role of A <inf>s</inf>2O <inf>3</inf> and its usefulness when combined with IFN for the treatment of ATLL.

DOI： 10.3324/haematol.10703

Scopus

PubMed

DOI： 10.1111/j.1365-2141.2006.06443.x

PubMed

DOI： 10.1073/pnas.0609329103

PubMed

DOI： 10.1158/1078-0432.CCR-05-2501

PubMed

DOI： 10.1111/j.1365-2141.2006.06122.x

PubMed

DOI： 10.1182/blood-2005-08-3434

PubMed

DOI： 10.1111/j.1365-2141.2005.05946.x

PubMed

DOI： 10.1158/0008-5472.CAN-05-1195

PubMed

DOI： 10.1182/blood-2005-01-0346

PubMed

記述言語：日本語   出版者・発行元：Oncogene  

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme required for the de novo synthesis of guanine nucleotides from IMP. VX-944 (Vertex Pharmaceuticals, Cambridge, MA, USA) is a small-molecule, selective, noncompetitive inhibitor directed against human IMPDH. In this report, we show that VX-944 inhibits in vitro growth of human multiple myeloma (MM) cell lines via induction of apoptosis. Interleukin-6, insulin-like growth factor-1, or co-culture with bone marrow stromal cells (BMSCs) do not protect against VX-944-induced MM cell growth inhibition. VX-944 induced apoptosis in MM cell lines with only modest activation of caspases 3, 8, and 9. Furthermore, the pan-caspase inhibitor z-VAD-fmk did not inhibit VX-944-induced apoptosis and cell death. During VX-944-induced apoptosis, expressions of Bax and Bak were enhanced, and both apoptosis-inducing factor (AIF) and endonuclease G (Endo G) were released from the mitochondria to cytosol, suggesting that VX-944 triggers apoptosis in MM cells primarily via a caspase-independent, Bax/AIF/Endo G pathway. Importantly, VX-944 augments the cytotoxicity of doxorubicin and melphalan even in the presence of BMSCs. Taken together, our data demonstrate a primarily non-caspase-dependent apoptotic pathway triggered by VX-944, thereby providing a rationale to enhance MM cell cytotoxicity by combining this agent with conventional agents which trigger caspase activation. © 2005 Nature Publishing Group. All rights reserved.

DOI： 10.1038/sj.onc.1208739

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PubMed

DOI： 10.1158/0008-5472.CAN-05-0850

PubMed

DOI： 10.1182/blood-2005-01-0320

PubMed

DOI： 10.1182/blood-2005-02-0838

PubMed

DOI： 10.1182/blood-2004-09-3794

PubMed

DOI： 10.1038/sj.onc.1208522

PubMed

DOI： 10.1182/blood-2004-06-2281

PubMed

DOI： 10.1038/sj.onc.1208118

PubMed

DOI： 10.1158/1078-0432.CCR-04-0632

PubMed

DOI： 10.1182/blood-2004-05-1760

PubMed

DOI： 10.1158/0008-5472.CAN-04-0124

PubMed

記述言語：日本語   出版者・発行元：一般社団法人日本医療薬学会  

Arsenic trioxide (As<SUB>2</SUB>O<SUB>3</SUB>) chemotherapy is now used for the treatment of relapsed patients with acute promyelocytic leukemia (APL) and adult T-cell leukemia (ATL) in the First Internal Medicine Department of Fukuoka University Hospital. In order to adjust the dosage, we studied the pharmacokinetics of As<SUB>2</SUB>O<SUB>3</SUB> when administered intravenously to patients with APL and ATL. Plasma arsenic concentrations were measured by gas-chromatograph/mass-spectrometry (GC/MS). The maximum arsenic concentration (C<SUB>max</SUB>) and area under the curve (AUC) were 8.3&plusmn;0.8 (&mu;M) and 61.7&plusmn;4.2 (&mu;M&middot;hr) on the first day and 8.6&plusmn;0.7 (&mu;M) and 63.5&plusmn;6.6 (&mu;M&middot;hr) on the twentieth day of treatment, respectively. Apparent distribution volume and total body clearance were 0.14&plusmn;0.02 (L/kg) (range 0.12-0.18) and 0.036&plusmn;0.004 (L/hr/kg) (range 0.030-0.039), respectively. From these results, we conclude that the pharmacokinetic behavior of As<SUB>2</SUB>O<SUB>3</SUB> did not alter in continuous administration, and the variation in pharmacokinetic parameters was extremely small among the patients.

DOI： 10.5649/jjphcs.30.492

記述言語：日本語   出版者・発行元：(一社)日本医療薬学会  

福岡大学倫理審査委員会の承認を得て,第一内科で実施した再発・治療抵抗性造血器腫瘍患者に対する亜ヒ酸療法施行時の体内動態について検討を行った.亜ヒ酸療法を目的として入院した急性前骨髄性白血病(APL)2例と成人T細胞性白血病リンパ腫(ATL)3例を対象とした.日内および日間変動係数(CV%)は2.1〜5.4%で,血清中からの回収率は95〜98%であった.定量限界(S/N)は0.05μMで,0.1-10μMの範囲内で良好な相関関係が得られた.血漿中ヒ素濃度は点滴静脈内投与終了時に最高値を示した後,速やかに低下し,24時間後にはほぼ投与前レベルに達した.連続投与によるヒ素体内動態の変動および血漿中におけるヒ素の蓄積性はほとんどないことが示唆された

DOI： 10.1158/0008-5472.can-03-3630

PubMed

記述言語：日本語   出版者・発行元：European Journal of Haematology  

Arsenic trioxide (As<inf>2</inf>O<inf>3</inf>) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 × 10 ³/μl increased to 134 × 10³/μl following the administration of As<inf>2</inf>O<inf>3</inf>. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 × 10 ³/μl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (C<inf>pmax</inf>) and a half-life time (t^1/2) of 6.9 μM and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As<inf>2</inf>O <inf>3</inf> therapy. © Blackwell Munksgaard 2004.

DOI： 10.1111/j.0902-4441.2003.00206.x

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PubMed

出版者・発行元：一般社団法人 日本血液学会  

九州血液疾患治療グループ(K-HOT)は九州内22施設の血液内科で組織される。造血器腫瘍治療時の感染症対策の現状を把握するため，2001年11月から2002年4月にグループ内アンケート調査を行った。回収率は一次調査86%（22施設中19施設），一次調査回答施設を対象にした二次調査89%（19施設中17施設）であった。成人T細胞白血病/リンパ腫ではスルファメトキサゾール・トリメトプリム(ST)合剤や結核既往例での抗結核薬の予防投与が広く行われ，顆粒球コロニー刺激因子の投与タイミングが他疾患より早い特徴があった。自家造血幹細胞移植（自家SCT）時のアシクロビル，免疫グロブリン製剤(Ig)やST合剤投与は簡略化が見られた。一方，同種SCT時のIg総投与量は施設間で大きく異なっていた。本調査は，支持療法の現状を把握する上で非常に有用である。

DOI： 10.11406/rinketsu.44.483

PubMed

記述言語：日本語   出版者・発行元：[Rinshō ketsueki] The Japanese journal of clinical hematology  

The Kyushu Hematology Organization for Treatment Study Group (K-HOT) consisted of 22 institutions specializing in hematology in Kyushu. This study is aimed at reviewing the daily practice of infection control for the treatment of hematological malignancies in our group. Nominal questionnaires were mailed to the hematology department in each institution from November 2001 to April 2002. For the first general surveys, 19 of 22 (86%) institutions responded. The second survey was mailed to the 19 respondents and 17 answered the detailed questionnaires with a response rate of 89%. Prophylactic use of trimethoprim-sulfamethoxazole (ST) against Pneumocystis carinii and anti-mycobacterial drugs in patients who had a history of tuberculosis was routine especially for patients with adult T-cell leukemia/lymphoma (ATL). Furthermore, the neutrophil counts to start a granulocyte-colony stimulating factor appeared to be high in ATL as compared with other hematological malignancies. In the setting of autologous stem cell transplantation (SCT), prophylactic use of acyclovir, immunoglobulin and ST was not routine and was reduced in duration, if used at all, as compared with allogeneic SCT. For allogeneic SCT, the cumulative dose of immunoglobulin significantly varied from institutions to institutions. The benefit of this study is the ability to recognize practical management patterns for infection control.

Scopus

出版者・発行元：(一社)日本血液学会-東京事務局  

九州の22施設の血液内科で構成された九州血液疾患治療グループ(K-HOT)を対象に,造血器腫瘍治療時の感染症対策の現状把握を目的とした記名式アンケート調査を行った.一次調査は19施設より回答を得,その19施設を対象に二次調査を行った.その結果,病室の環境,医療従事者のガウン・マスクの使用,食事の管理は,原疾患や造血幹細胞移植(SCT)の方法によって異なった.感染症対策として,スルファトキサゾール・トリメトプリム(ST)合剤,ニューキノロン系薬剤,フルコナゾールの経口投与が多く使用されていたが,自家SCTでは簡素化されていた.成人T細胞白血病リンパ腫に対しては,予防投薬としてST合剤や結核既往患者に対する抗結核薬を使用する施設が多く,顆粒球コロニー刺激因子投与の開始時期も他の疾患より早かった

記述言語：日本語   出版者・発行元：Cancer Letters  

Arsenic trioxide (As<inf>2</inf>O<inf>3</inf>) has been shown to be effective for treatment of patients with refractory or relapsed acute promyelocytic leukemia and a variety of other malignant hematopoetic disorders. We studied the effect of this agent on proliferation of human hepatoma-derived cell lines (SK-Hep-1, HepG2, and HuH7). In HuH7 cells, As<inf>2</inf>O<inf>3</inf> reduced proliferation time- and dose-dependently at 1 and 2 μM, while in SK-Hep-1 and HepG2 cells, As<inf>2</inf>O<inf>3</inf> inhibited proliferation at 2 and 4 μM respectively. Cell cycle analysis by flow cytometry showed that As<inf>2</inf>O<inf>3</inf> induced apoptosis in these hepatoma-derived cells as confirmed by appearance of sub-G<inf>1</inf> cells. Sensitivity of hepatoma-derived cells to As<inf>2</inf>O<inf>3</inf> was inversely related to their intracellular glutathione (GSH) and intensity of GSH synthesis. Arsenic sensitivity was restored to relatively resistant cell lines when GSH was depleted by L-buthionine sulfoximine (BSO). These results indicate that As<inf>2</inf>O<inf>3</inf> may have therapeutic potential for treatment of hepatocellular carcinoma. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3835(01)00800-X

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PubMed

PubMed

記述言語：日本語   出版者・発行元：[Rinshō ketsueki] The Japanese journal of clinical hematology  

A 75-year-old man visited our hospital complaining of heartburn in November 1997. Gastroscopical examination revealed ulcerous protruding extended from the gastric antrum to body and a flat, elevated lesion in the greater curvature of the stomach. Biopsy specimens revealed a CD4-positive malignant lymphoma. The serum anti-human T-lymphotrophic virus type I (HTLV-I) antibody test was positive. He was diagnosed as having primary gastric adult T-cell leukemia/lymphoma (ATLL; acute type). Complete remission was achieved with chemotherapy. In December 1998, the patient experienced a relapse. The lesions were limited to the region between the upper gastric body and the fornix and disappeared with radiation therapy. A second relapse was detected in the gastric greater curvature and descending portion of the duodenum in May 1999 but spontaneously disappeared in 5 months. The third relapse in May 2000 was systemic. Monoclonal integration of the HTLV-I provirus was observed in DNA extracted from ascitic lymphocytes. Chemotherapy was resumed, but the response was poor. The patient subsequently died of respiratory failure as a result of pneumonia. Although gastrointestinal involvement is frequent in ATLL, this appears to be a rare case of an idolent clinical course with lesions limited to the stomach and duodenum for 30 months.

Scopus

出版者・発行元：(一社)日本血液学会-東京事務局  

75歳男.胸焼けを主訴とした.上部消化管内視鏡検査にて胃前庭部大弯に平盤状隆起性病変,前庭部から体部の広範囲にわたり潰瘍を伴う隆起性病変がみられ,生検にて悪性リンパ腫と診断され,免疫染色にて腫瘍細胞はCD4陽性であり,可溶性IL-2レセプターの軽度上昇,血清抗HTLV-I抗体陽性であったことから胃原発急性型成人T細胞白血病/リンパ腫(ATLL)と診断した.多剤併用化学療法を施行し完全寛解となった.胃体上部から穹窿部の後壁に再発がみられたが放射線療法施行にて病変は消失し,胃体部大彎と十二指腸下行脚に2回目の再発を来たしたものの自然消失した.その後,全身性に再発し,多剤併用化学療法を行ったが無効で,肺炎を併発し呼吸不全にて死亡した.以上より,本症例は胃に初発後2年6ヵ月間病変が消化管に限局し緩慢な経過をとった点で極めて稀な症例であると考えられた

記述言語：日本語   出版者・発行元：Biochemical and Biophysical Research Communications  

An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity partially prevented hypoxia-induced apoptosis. 2-Deoxy-D-ribose inhibits a number of components of the caspase-mediated hypoxia-induced apoptotic pathway. It inhibits hypoxia-induced caspase 3 activation, mitochondrial cytochrome c release, downregulation of Bcl-2 and Bcl-x<inf>L</inf>, upregulation of hypoxia-inducible factor (HIF)-1α, and loss of mitochondrial transmembrane potential in human leukemia HL-60 cell line. These findings suggest a molecular mechanism by which 2-deoxy-D-ribose confers the resistance to apoptosis. Thus 2-deoxy-D-ribose-modulated suppression of HIF-1α expression could prevent the hypoxia-induced decrease of the anti-apoptotic Bcl-2 and Bcl-x<inf>L</inf> on the mitochondria. 2-Deoxy-L-ribose and its analogs may enhance apoptosis and suppress the growth of tumors by competitively inhibiting the activities of 2-deoxy-D-ribose and thus these analogs show promise for anti-tumor therapy. © 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1006/bbrc.2002.6432

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PubMed

記述言語：日本語   出版者・発行元：Leukemia and Lymphoma  

Arsenic trioxide (As<inf>2</inf>O<inf>3</inf>) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G<inf>1</inf> phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of AS<inf>2</inf>O<inf>3</inf>-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72h at clinically tolerable concentrations of As<inf>2</inf>O<inf>3</inf> (1-2 μmol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As<inf>2</inf>O<inf>3</inf> treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked AS<inf>2</inf>O<inf>3</inf>-induced apoptosis but not G<inf>1</inf> phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-α neutralizing Ab did not show such inhibitions in these cells. In conclusion, As<inf>2</inf>O<inf>3</inf> induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-α receptor independent caspase activation.

DOI： 10.1080/10428190290021461

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PubMed

出版者・発行元：一般社団法人 日本血液学会  

症例は75歳，男性。1997年11月胸やけのため当科を受診した。上部消化管内視鏡検査で胃前庭部から体部の広範囲にわたる潰瘍を伴う隆起性病変，前庭部大弯に平盤状隆起性病変を認めた。同部位の生検の結果CD4陽性悪性リンパ腫で，抗HTLV-I抗体が陽性であったため胃原発急性型成人T細胞白血病/リンパ腫(ATLL)と診断した。多剤併用化学療法を施行し完全寛解となった。1998年12月に胃体上部から穹窿部の後壁に再発がみられたが，放射線療法により消失した。1999年5月に胃体部大弯と十二指腸下行脚に2回目の再発をしたが約5カ月で自然消失した。2000年5月に全身性に再発し，多剤併用化学療法を行ったが無効，肺炎を合併し呼吸不全のために死亡した。ATLLではしばしば消化管病変を伴うことが知られているが，初発後2年6カ月間病変が胃・十二指腸に限局し緩慢な経過でATLLとしてはきわめて稀なので報告した。

DOI： 10.11406/rinketsu.43.554

記述言語：英語   掲載種別：学位論文（博士）  

記述言語：日本語   出版者・発行元：Leukemia and Lymphoma  

A novel therapeutic potential for acute promyelocytic leukemia using arsenic trioxide (As<inf>2</inf>O<inf>3</inf>) has been reported. Recent in vitro studies demonstrated that As<inf>2</inf>O<inf>3</inf> effectively inhibits the growth of some cell lines derived from patients with malignant lymphoma, chronic lymphocytic leukemia and multiple myeloma. Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T-cell origin caused by human T-cell leukemia virus type-I (HTLV-I) the prognosis of which still remains very poor. A possible role of As<inf>2</inf>O<inf>3</inf> for the treatment of ATL is demonstrated from evidence that As<inf>2</inf>O<inf>3</inf> significantly inhibits the growth of HTLV-I infected T-cell lines and induces apoptosis in fresh ATL cells at clinically achievable concentration of the agent. The growth inhibition of As<inf>2</inf>O<inf>3</inf> treated HTLV-I infected T-cell lines was induced by both apoptosis and G<inf>1</inf> phase accumulation. Cleaved bcl-2 protein and an enhanced expression of bak protein in the cells were coincidentally observed during As<inf>2</inf>O<inf>3</inf> treatment. A broad spectrum caspase inhibitor, z-Val-Ala-DL-Asp-fluoromethylketone inhibited the apoptosis induced by As<inf>2</inf>O<inf>3</inf>. Increased expression of p53, Cip1/p21 and Kip1/p27, and dephosphorylation of retinoblastoma protein (pRb) were detected in the As<inf>2</inf>O<inf>3</inf> treated cells. In conclusion, As<inf>2</inf>O<inf>3</inf> might become a new therapeutic tool in the treatment of ATL as As<inf>2</inf>O<inf>3</inf> induces apoptosis by destruction of the bcl-2 protein and enhancement of the bak protein production proceeding to activate caspases, and also induces G1 phase accumulation by enhancement of p53, Cip1/p21, Kip1/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.

DOI： 10.3109/10428190009058521

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PubMed

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1403103080

出版者・発行元：(株)医学書院  

ATLの消化管浸潤は広範囲かつ高度で,多発性又はび漫性の浸潤病変が多い傾向にあった.画像所見の検討により浸潤・発育進展様式とその肉眼像を基本的に以下の3つに分類した. 1)腫瘍細胞が腫瘤をつくらず消化管壁を連続性にび漫性に浸潤するタイプで,肉眼像は粘膜面の凹凸が目立たない平坦病変を呈す-びまん浸潤型(表層型). 2)腫瘍細胞がリンパ装置に浸潤し腫瘤を形成するタイプで,肉眼像はMLP様の多発性の隆起性病変を呈す-多発結節型. 3)腫瘍細胞が多数のリンパ装置に浸潤し小さな腫瘤を形成するタイプで,肉眼像はたこいぼびらん様の小隆起がび漫性に多発した病変を呈す-多発びまん浸潤型

記述言語：日本語   出版者・発行元：Biochemical and Biophysical Research Communications  

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is expressed at higher levels in a wide variety of solid tumors compared to adjacent normal tissues. Patients with PD-ECGF/TP-positive colon and esophageal tumors have a poorer prognosis than those with negative tumors. The expression of PD-ECGF/TP is a prognostic factor independent of microvessel density suggesting that TP has effects on tumor progression independent of its angiogenic activity. Evidence that hypoxia and apoptosis affect tumor growth prompted us to determine whether increased expression of PD-ECGF/TP prevents apoptosis induced by hypoxia. KB/TP cells transfected with a PD-ECGF/TP cDNA were resistant to hypoxia-induced apoptosis. Among the degradation products of thymidine produced by PD-ECGF/TP, 2-deoxy-D-ribose and thymine partially prevented hypoxia-induced apoptosis. The ability of 1 μM 2-deoxy-D-ribose in combination with the same concentration of thymine to prevent hypoxia-induced apoptosis was similar to that of the overexpressed TP in KB cells. A concentration of 1 μM 2-deoxy-D-ribose abrogated the effects of these degradation products of thymidine. These findings suggested that TP can confer resistance to apoptosis induced by hypoxia and the degradation products of thymidine are involved in this resistance. Expression of PD-ECGF/TP may play an important role in the progression of solid tumors, and inhibitors of TP and analogs of the degradation products of thymidine may suppress the growth of tumors by promoting apoptosis.

DOI： 10.1006/bbrc.1998.9852

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PubMed

記述言語：日本語   出版者・発行元：British Journal of Haematology  

Adult T-cell leukaemia (ATL) is difficult to cure using conventional therapies. Recently the therapeutic possibility of retinoic acids (RA) has been reported. In this study, suppression of in vitro growth of human T-cell leukaemia virus type I (HTLV-I) infected T-cell lines and fresh ATL cells by arsenic trioxide (As<inf>2</inf>O<inf>3</inf>) were evaluated by comparison with a series of RA derivatives. Proliferation of four HTLV-I-infected T-cell lines was significantly reduced within 72 h by 1.0 μmol/l As<inf>2</inf>O<inf>3</inf>. Growth of two out of four HTLV-I-infected T-cell lines was also inhibited by 1.0 μmol/l RA, but to a lesser extent than by As<inf>2</inf>O<inf>3</inf>. The mechanism of this growth inhibition was due to the induction of apoptosis. Apoptosis was also induced in fresh ATL cells from patients by As<inf>2</inf>O<inf>3</inf>, but far less by RA. As described in patients with acute promyelocytic leukaemia, 1.0 μmol/l of As<inf>2</inf>O<inf>3</inf> can be safely achieved in the serum of patients; however, it is difficult to maintain this concentration of RA. In conclusion, As<inf>2</inf>O<inf>3</inf> has therapeutic potential for the treatment of ATL and may be far more clinically beneficial than RA.

DOI： 10.1046/j.1365-2141.1998.01068.x

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PubMed

記述言語：日本語   出版者・発行元：皮膚リンフォーマ研究学会  

34歳男.1990年,右頸部腫瘤が出現.生検され,Hodgkin's病結節硬化型と診断.1994年10月より腹部膨満出現,1994年12月,腹部CTで大動脈周囲に巨大な腫瘤を認め,肝,脾にも腫瘤を認めた.化学療法施行し,腹腔内腫瘤縮小傾向が認められたが,1995年4月頃より,全身性に落屑を伴う皮膚硬化性病変が出現.皮膚生検では,真皮上層から中層の血管周囲,表皮に小型〜中型の異型リンパ球の浸潤が認められた.免疫染色で,異型リンパ球は,主にCD4細胞で,CD8細胞を混じていた.TCRβ, TCRγ, Immunoglobulin heavy chain遺伝子の再構成の有無を,Hodgkin's病病変と,皮膚病変からのDNAで検討したが,再構成が認められなかった

出版者・発行元：Japan Atherosclerosis Society  

We examined the serum lipids, apoproteins and lipoproteins, and several neutral sterols including cholestanol, desmosterol, lathosterol, campesterol and β-sitosterol in 45 male patients with coronary artery disease (CAD) and 40 normal control male subjects. The results were as follows:<br>(1) Statistically significant differences between both groups were noted in triglycerides, high density lipoprotein cholesterol (HDL-Ch), low density lipoprotein cholesterol (LDL-Ch), β-lipoprotein (β-Lipo), apolipoprotein (Apo) A-I, Apo A-II, Apo B, β-Lipo/HDL-Ch, Apo B/Apo A-I, HDL-Ch/total cholesterol, and Atherogenic index, as reported previously.<br>(2) Serum Lp (a) levels were significantly higher (p<0.001) in the CAD group (162.0±120.7mg/l) than in the control group (76.0±64.1mg/l).<br>(3) No significant differences between both groups were noted in plant sterols (campesterol and β-sitosterol) and desmosterol. While, serum cholestanol, which was an intermediate metabolite in the cholesterol metabolic pathway, and lathosterol, which has been reported to be a good indicator of whole-body cholesterol synthesis, were significantly high in the CAD group.<br>These results showed that patients with CAD had multiple risk factors in the metabolism of lipids, particularly of cholesterol, and lipoproteins.

記述言語：日本語  

記述言語：日本語   出版者・発行元：[Rinshō ketsueki] The Japanese journal of clinical hematology  

We report a patient with adult T-cell leukemia (ATL) complicated with intestinal tuberculosis. A 57-year old man was admitted to our hospital because of fever and dyspnea. He was diagnosed as ATL by leukocytosis [leukocyte count 18,200/microliters with 56% of abnormal lymphocytes which express CD4(+) and CD25(+)] and seropositive result of anti-HTLV-1 antibody. Combination chemotherapy for ATL improved his serum LDH level and peripheral lymph nodes, but fever was still persistent. He had an emergency operation because of perforation of the cecum during the chemotherapy. Histological examination of the resected cecum revealed caseous necrosis and numerous mycobacterium, which induced a diagnosis of intestinal tuberculosis. Although there have been several reports on pulmonary tuberculosis in patients with ATL, this is the first report of intestinal tuberculosis in ATL as far as we know. We conclude that if the patients with ATL have persistent fever of unknown origin, we should take account of intestinal tuberculosis as one of differential diagnosis.

Scopus

出版者・発行元：(一社)日本血液学会-東京事務局  

57歳男.発熱と呼吸困難を主訴に来院した.白血球数18,200/μl(異常リンパ球56%, CD4, CD25陽性,CD8陰性)抗HTLV-1抗体陽性より成人T細胞白血病(ATL)と診断し多剤併用化学療法を施行した.LDHは正常化し,表在リンパ節は縮小したが原因不明の発熱が続いた.化学療法続行中,回盲部の穿孔を起こし緊急手術を施行した.摘除標本には乾酪壊死と多数の結核菌を認め,腸結核と診断した

記述言語：中国語  

PubMed

出版者・発行元：一般社団法人 日本血液学会  

症例は57歳，男性。発熱と呼吸困難を主訴に来院した。白血球数18,200/&mu;<i>l</i>（異常リンパ球56%, CD4, CD25陽性，CD8陰性）抗HTLV-1抗体陽性より成人T細胞白血病(ATL)と診断し多剤併用化学療法を施行した。LDHは正常化し，表在リンパ節は縮小したが原因不明の発熱が続いた。化学療法続行中，回盲部の穿孔を起こし緊急手術を施行した。摘除標本には乾酪壊死と多数の結核菌を認め，腸結核と診断した。肺結核症の併発はATL患者では比較的多くにみられるとされているが，これまで腸結核の併発症例の報告はない。ATL患者に原因不明の発熱が続くときは腸結核も考慮すべきと考えられる。

DOI： 10.11406/rinketsu.37.139

出版者・発行元：一般社団法人 日本消化器内視鏡学会  

症例は65歳,女性.胃の集団検診にて精査を勧められ内視鏡を施行した.胃角部に境界不明瞭な発赤した粘膜の顆粒状変化を認めた.肉眼所見では,表層型の胃悪性リンパ腫または反応性リンパ細網増生症に類似の形態と思われた.末梢血および骨髄像には異常なく,生検の結果形質細胞腫と診断され,手術を施行した.病理組織診断は胃形質細胞腫で,免疫組織学的にはIgA/λ型であった.深達度は一部粘膜下層に達していたが所属リンパ節には異常所見を認めなかった.

DOI： 10.11280/gee1973b.38.325

記述言語：日本語   出版者・発行元：American Journal of Hematology  

We investigated the expression of a monoclonal antibody (HML‐1) defined antigen that appears on human intestinal T‐lymphocytes in HTLV‐I‐related disease. We studied 25 ATL, and 24 healthy HTLV‐I carriers. Patients with acute ATL showed a variety of the expression of the HML‐1 antigen (range 0.4–74.8%). HML‐1 expression on mononuclear cells (MNCs) in blood from patients with chronic ATL ranged from 1.7–43.6% (mean 13.5%). This level of expression was less than that of patients with acute ATL, but not significantly. In patients with smoldering ATL, the degree of patients with acute ATL, but not significantly. In patients with smoldering ATL, the degree of expression ranged from 1.6–13.3% (mean 8.0%). In contrast to patients wtih acute ATL, MNCs from patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and B‐cell type chronic lymphocytic leukemia (B‐CLL) did not express the HML‐1 antigen, except for the 2 patients with ALL. Healthy HTLV‐I carriers and healthy controls also were negative for HML‐1 reactivity. In acute ATL, patients with gastrointestinal tract infiltration tended to have high expression of the HML‐1 epitope. After stimulation with phytohemagglutinin (PHA), healthy HTLV‐I carriers showed significantly increased expression of the HML‐1 epitope (P < 0.05). Recently, the β7 integrin family has been found to play a specific role in mucosal localization or adhesion, and HML‐1 protein was found to match the deduced β7 N‐terminal sequence. We propose that the cellular gene responsible for HML‐1 epitope expression may, like IL‐2, IL‐2R, etc., be transactivated by infection with HTLV‐I, and that HML‐1 antigen gene expression by HTLV‐I infection may lead to infiltration of ATL cells with highly expressed HML‐1 epitope into the gut mucosa. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ajh.2830500102

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記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

We have studied the incidence and characteristics of associated neoplasms in 210 ATL patients. Twelve patients had other primary neoplasms and the incidence of double cancer was 5.7%. The additional malignancies in ATL patients consisted of 4 cases of stomach, 3 cases of colon and one of each lung, ovary, uterus, liver and bladder cancer. In metachronous double cancer patients, the neoplasm was found before the time of diagnosis of ATL in 5 out of 6 patients.<br>Immunodeficiency due to HTLV-I infection as well as chemotherapy for the preceding neoplasm are suggested to be related to the leukemogenesis of ATL.

DOI： 10.11406/rinketsu.36.792

PubMed

記述言語：日本語   出版者・発行元：Leukemia and Lymphoma  

43 patients with the acute or lymphoma type ATL were treated with the new combination chemotherapy (RCM protocol: response-oriented cyclic multidrug protocol) between January 1989 and December 1991. Complete response (CR) and partial response (PR) were achieved in 20.9% and 65.1% of all treated patients respectively. The median duration of survival was 6.0 months. The survival duration of patients with a high serum lactate dehydrogenase (LDH) value (≥ 1,000 unit) and/or a poor performance status (PS) (PS 3 or 4) were also improved but not in patients with a severe leukocytosis (≥ 35,000/μl). Toxicity was mild (grade 1 or 2) except hematologic toxicity in 4 patients (9.3% and alopecia in one patient (2.3% In spite of many patients with a poor PS (PS 3 or 4), our chemotherapeutic results are equal or superior to other previous reports. It seems that response-oriented chemotherapy is suitable for the ATL patients with poor prognostic factors. These results indicate that the RCM protocol is very useful as the first choice chemotherapy for the acute or lymphoma type ATL. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

DOI： 10.3109/10428199509059624

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記述言語：日本語   出版者・発行元：Leukemia and Lymphoma  

Although it has been recognized previously that several markers are present in the cerebrospinal fluid (CSF), their clinical usefulness of these markers in the diagnosis of malignant lymphoma infiltrating to the CNS has not yet beein established. In order to determine their diagnostic usefulness as markers of meningeal infiltration by lymphoma cells in patients with adult T-cell leukemia (ATL), we measured some soluble factors in the CSF of patients with ATL and non- ATL patients. Soluble CD4 (sCD4) was highly elevated in all patients with ATL and meningeal infiltration. The CSF level of the soluble interleukin-2 recepror (sIL-2R; sCD25) was markedly elevated in 13 (72.2% of 18 patients with ATL and meningeal infiltration. Levels of sCD4 and sCD25 in the CSF of patients with ATL and meningeal infiltration were significantly higher than in non-ATL patients (p <01 and p <001, respectively). These findings indicate that levels of sCD4 and sCD25 in the CSF are probably associated with meningeal infiltration by leukemia cells expressing CD4 and CD25 on surface membranes. CSF levels of sCD4 in 14 (60.9% of 23 ATL patients and sCD25 in 13 (72.2% of 18 ATL patients without meningeal infiltration were moderately elevated. These findings suggest that a small number of leukemic cells which were not detected by conventional CSF examination may have infiltrated the meninges in these patients. Sequential measurements of sCD4 and sCD25 in CSF obtained from patients with meningeal infiltration by leukemic cells showed that sCD4 and sCD25 levels reflected the activity of leukemic meningitis and correlated with the number of cells in CSF. However, the levels of sCD4 in CSF did not fall below the limit of detection even when the number of cells in CSF became normal. It is thought that the level of sCD4 in CSF is a more sensitive marker for detecting the infiltration of leukemic cells in CSF than the number of cells present in the CSF considering the clinical course of two patients with acute type ATL. Therefore, ATL patients with meningeal infiltration should receive treatments until sCD4 levels become normal and not just until the number of cells become normal. Our results also suggest that measurement of CSF levels of sCD4 and sCD25 is useful for the differential diagnosis of aseptic meningitis and meningeal infiltration by leukemic cells in patients with smoldering ATL. We conclude that measurement of soluble factors in CSF plays an important role in diagnosis, prophylaxis and treatment of meningitis in patients with ATL. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

DOI： 10.3109/10428199509112202

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記述言語：日本語   出版者・発行元：Japanese Journal of Cancer and Chemotherapy  

We studied the effectiveness of low-dose, oral administration of etoposide for maintenance chemotherapy of patients with adult T cell leukemia (ATL). Sixteen patients (9 males and 7 females) in remission (9 in complete remission and 7 partial remission) were orally administered 25 or 50 mg/day of etoposide. Median response duration of all the patients to the therapy was 18.6 months, ranging from 5.0 to 34.0 months. Thirteen out of the 16 patients relapsed, and 9 of them died of tumor progression. Appetite loss occurred in one case, without any other severe side effects. It has been suggested, therefore, that oral administration of the etoposide is useful for maintenance chemotherapy in ATL patients.

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記述言語：日本語   出版者・発行元：American Journal of Hematology  

Levels of the soluble form of the leukocyte surface antigen CD4 (sCD4) were measured by enzyme linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of patients with adult T‐cell leukemia (ATL) and other malignant and non‐malignant diseases. All patients with ATL and meningeal infiltration had markedly elevated levels of sCD4 in the CSF (53.7 ± 34.9 U/ml). ATL patients without CSF pleocytosis often had elevated levels of sCD4 (15.1 ± 9.2 U/ml). Non‐ATL patients with CSF pleocytosis had elevated levels of sCD4 (23.3 ± 12.2 U/ml) and those without CSF pleocytosis also showed elevation of sCD4 levels (16.8 ± 9.3 U/ml). However, the mean levels of sCD4 in CSF from these patients were significantly lower than ATL patients with meningeal infiltration. Soluble CD4 in the CSF from healthy volunteers were below the detectable limit. We conclude that meningeal infiltration of CD4(+) ATL cells is strongly associated with elevated sCD4 levels in CSF, and some part of sCD4 in CSF may be originated from the native cells in the CNS as a response of inflammatory stimulations. Therefore, measurement of sCD4 may be useful in the diagnosis of meningeal infiltration and/or meningeal irritation in patients with ATL. © 1994 Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ajh.2830460208

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記述言語：英語  

PubMed

記述言語：日本語   出版者・発行元：Blood  

Serum tumor necrosis factor-β (TNF-β) from patients with adult T-cell leukemia (ATL) was studied by a sandwich enzyme-linked immunosorbent assay (ELISA) developed in our laboratory using biotinylated monoclonal anti-TNF-β and recombinant TNF-β. Seven of eight patients with hypercalcemia showed elevation of serum TNF-β. On the other hand, TNF-β could not be detected by the ELISA in 28 patients without hypercalcemia. The lower detection limit in this assay was 100 pg/mL, corresponding to 500 pg/mL by the conventional method. In two patients serum TNF-β level decreased after treatment in association with the level of serum calcium. Furthermore, immuno-staining using antiTNF-β and avidin-biotin complex showed the presence of cytoplasmic TNF-β in not only human T-cell leukemia virus type I infected cell lines, but also freshly isolated cells from ATL patients with hypercalcemia. The actual biologic activity of TNF-β in serum was confirmed by a conventional bioassay in a patient with hypercalcemia, and its cytotoxic activity was inhibited by the addition of anti-TNF-β antibody in the assay. These results suggested that serum TNF-β might be one of the factors contributing to the hypercalcemia, at least in patients with ATL. © 1991 by The American Society of Hematology.

DOI： 10.1182/blood.v77.11.2451.bloodjournal77112451

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出版者・発行元：(株)自然科学社  

成人T細胞白血病(ATL)およびヒトT細胞白血病ウイルス(HTLV-1)キャリアーの血清中可溶性インターロキキン-2受容体(sIL-2R)を測定し,ATLの病状との変化を検討した.HTLV-1キャリアーでは,すべてsIL-2Rはカットオフ値以下であり,ATL発症例では1例を除きsIL-2Rは高値を示した.臨床経過を掌握できたATL患者の血清sIL-2Rは,病状に比例して推移していた.血清保存時の間接蛍光抗体法による末梢血リンパ球表面IL-2レセプター陽性細胞比率とsIL-2Rとの相関を回帰分析により検討すると,5%危険率で相関関係が確認された.血清LDH,血清Caとの相関を重回帰分析で検討し,sIL-2Rはいずれとも危険率1%で相関関係を認めた

記述言語：日本語   出版者・発行元：(株)文光堂  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(株)日本臨床社  

記述言語：日本語   出版者・発行元：Haematologica  

DOI： 10.3324/haematol.2023.283992

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記述言語：英語   出版者・発行元：Oxford University Press  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：Leukemia  

Correction to: Leukemia, published online 22 June 2022 At the time of original publication, there was an incomplete listing of contributing authors and their institutions. This revision corrects those omissions.

DOI： 10.1038/s41375-023-01962-5

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

Enhancer of zeste homolog(EZH)はpolycomb repressive complex 2(PRC2)のサブユニットの一つでヒストンメチル基転移酵素活性を持ち,H3K27メチル化を介して遺伝子発現を制御する。EZHは一部の悪性リンパ腫の病態に大きく関与している。濾胞性リンパ腫(FL)ではEZH2の機能獲得型変異と遺伝子増幅がそれぞれおよそ30,15%に見られる。成人T細胞白血病・リンパ腫(ATL)細胞ではEZH1/2の発現亢進によるH3K27のトリメチル化が特徴的であり,ATL細胞において発現が抑制されている遺伝子の半数以上がH3K27のトリメチル化状態にある。現在EZH2,EZH1/2阻害薬がそれぞれ再発・難治FLとATLに使用可能となっている。悪性リンパ腫におけるEZH標的化治療はまだまだ開始されたばかりであり,今後の展開が期待される。(著者抄録)

記述言語：日本語   出版者・発行元：Bone Marrow Transplantation  

DOI： 10.1038/s41409-023-01969-7

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記述言語：日本語   出版者・発行元：Bone Marrow Transplantation  

DOI： 10.1038/s41409-023-01919-3

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PubMed

記述言語：日本語   出版者・発行元：Haematologica  

DOI： 10.3324/haematol.2022.281435

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PubMed

記述言語：日本語   出版者・発行元：(株)日本医事新報社  

記述言語：英語   出版者・発行元：(一社)日本リンパ腫学会  

記述言語：日本語   出版者・発行元：(有)科学評論社  

近年、エピジェネティックな作用機序を有するヒストン脱アセチル化酵素(HDAC)阻害薬が造血器腫瘍の治療薬として登場した。ツシジノスタットは成人T細胞白血病・リンパ腫(ATL)に対する初めてのHDAC阻害薬で、経口剤であるため発症年齢が高齢化してきたATL患者に対して使用しやすい。本剤の開発の経緯と作用機序、臨床試験成績、副作用のマネジメント、使用時のポイントについて概説し、好中球減少と血小板減少の症例を提示した。

記述言語：日本語   出版者・発行元：(株)日本臨床社  

記述言語：日本語   出版者・発行元：(株)日本医事新報社  

記述言語：日本語   出版者・発行元：(一社)日本内科学会  

記述言語：日本語   出版者・発行元：大道学館出版部  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(株)日本医事新報社  

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

記述言語：日本語   出版者・発行元：(一社)日本内科学会  

記述言語：日本語   出版者・発行元：Bone Marrow Transplantation  

DOI： 10.1038/s41409-021-01412-9

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記述言語：日本語   出版者・発行元：(株)南江堂  

＜文献概要＞▼成人T細胞白血病・リンパ腫(ATL)はヒトT細胞白血病ウイルスI型(HTLV-1)が原因となって発症する予後不良な末梢性T細胞腫瘍である.▼アグレッシブATLで同種造血幹細胞移植(allo-HSCT)適応例に対しては強力な多剤併用化学療法後にallo-HSCTを,allo-HSCT非適応例には多剤併用化学療法(±mogamulizumab(CCR4陽性の場合)もしくはbrentuximab vedotin(CD30陽性の場合))を実施する.▼インドレントATLに対してはアグレッシブATLに移行するまで無治療経過観察を行う.▼再発・難治アグレッシブATLに対しては,従来実施してきた多剤併用化学療法のほかmogamulizumab,brentuximab vedotin,lenalidomideの単剤療法が導入されている.

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

成人T細胞白血病・リンパ腫(ATL)はヒトT細胞白血病ウイルスI型が原因の末梢性T細胞腫瘍で,aggressive ATLとindolent ATLに二分し治療が行われてきた。70歳以下のaggressive ATLに対してはVCAP-AMP-VECP療法が標準治療とされ,さらに可能な限り同種造血幹細胞移植が実施されている。新規薬剤としてmogamulizumab,lenalidomide,brentuximab vedotinが導入され,再発・難治例に対しHDAC阻害薬が承認申請中,EZH1/EZH2阻害薬は第II相試験の登録が終了している。Indolent ATLに対しては無治療経過観察が行われてきたが,海外で頻用されるinterferon-αとzidovudineの併用療法について,本邦で前向き臨床試験を実施している。今後ATL患者は高齢化が進むことから,未だ全く決定されていない高齢者に対する標準治療の開発が重要になる。(著者抄録)

記述言語：日本語   出版者・発行元：International Journal of Dermatology  

DOI： 10.1111/ijd.14860

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(株)日本臨床社  

記述言語：日本語   出版者・発行元：International Journal of Hematology  

In the original publication of the article, Table 5 was published with incorrect contents. The correct Table 5 is given in this correction. (Table presented.).

DOI： 10.1007/s12185-020-02850-9

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15019

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出版者・発行元：John Wiley & Sons Australia, Ltd  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(有)科学評論社  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(株)メディカルレビュー社  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(株)文光堂  

出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：British Journal of Haematology  

DOI： 10.1111/bjh.15123

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記述言語：日本語   出版者・発行元：New England Journal of Medicine  

DOI： 10.1056/NEJMc1807852

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：British Journal of Haematology  

DOI： 10.1111/bjh.14634

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PubMed

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(有)科学評論社  

出版者・発行元：(株)最新医学社  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：大道学館出版部  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

出版者・発行元：(有)科学評論社  

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

DOI： 10.3960/jslrt.17008.

記述言語：英語   出版者・発行元：(一社)日本リンパ網内系学会  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

出版者・発行元：(一社)日本血液学会-東京事務局  

成人T細胞白血病・リンパ腫(ATL)はヒトTリンパ球向性ウイルスI型(HTLV-1)によって引き起こされる末梢性T細胞腫瘍である。HTLV-1感染リンパ球は,TaxやHTLV-1 bZIP factorなどによって不死化され,やがてクローナルな増殖を始める。ATLの分子病態の特徴は,ATL細胞が多くのゲノム異常を持ち,しかもそれらのほとんどがいくつかの標的経路に収束すること,ヒストンH3リジン27のトリメチル化に特徴づけられるゲノム全域にわたるエピジェネティックな異常によって機能的microRNAや腫瘍抑制因子の発現が抑制され,腫瘍の発生と維持に関わっていることである。これらATLに特徴的な分子病態のなかで,CCR4を標的とする治療は既に抗体薬として日常診療に導入されたほか,Taxを標的とする免疫療法,免疫チェックポイント阻害薬による治療,EZH1/2を標的とする治療の開発が進んでいる。(著者抄録)

出版者・発行元：(一社)日本内科学会  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

成人T細胞白血病・リンパ腫(ATL)はヒトTリンパ球向性ウイルスI型(HTLV-1)によって引き起こされる予後不良な末梢性T細胞腫瘍である。主として母乳によって成立したHTLV-1感染者の3〜5%がATLを発症する。現在の本邦の標準治療は,aggressive ATL(急性型,リンパ腫型と予後不良因子を有する慢性型)に対しては多剤併用化学療法,さらに可能な症例では同種造血幹細胞移植を実施すること,indolent ATL(くすぶり型と予後不良因子のない慢性型)に対してはaggressive ATLとなるまで無治療経過観察することである。近年はATL細胞の表面抗原を標的とする抗体療法,ATL細胞の分子異常を標的とする治療,免疫環境を修飾する治療の開発が試みられており,そのうち抗CCR4抗体モガムリズマブと,免疫調整薬レナリドミドはすでに日常臨床に導入されている。(著者抄録)

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

出版者・発行元：(有)科学評論社  

出版者・発行元：(一社)日本皮膚悪性腫瘍学会  

出版者・発行元：(有)科学評論社  

出版者・発行元：(一社)日本検査血液学会  

成人T細胞白血病・リンパ腫(ATL)はヒトTリンパ球向性ウイルスI型によって起こる末梢性T細胞腫瘍である。本邦で2000年から2009年にATLと診断された患者の後ろ向き調査(ATL-PI project)では病型別の生存期間中央値(MST)は急性型8.3、リンパ腫型10.6、慢性型31.5、くすぶり型55.0ヵ月であった。下山らが報告した1980年代後半に診断された患者群のMSTと4年全生存割合(4-OS)を比較すると、MSTの改善は造血幹細胞移植を受けた急性型の患者以外では明らかでなかったが、4-OSは移植を受けた急性型のほか、リンパ腫型の移植・非移植群で延長していた。このことは、急性型では移植、リンパ腫型では化学療法の進歩と移植が予後の改善に貢献していること、長期予後は改善されつつあるが診断後早期に増悪する症例は今も救命に至っていないことを示している。移植群・非移植群での比較は選択バイアスが大きいことに注意が必要だが、移植群の5年生存割合約30%に対し非移植群は約10%に留まる。近年のATL治療の進歩は、抗CCR4抗体 モガムリズマブの導入である。CCR4はほとんどのATL症例の腫瘍細胞で発現しており、本剤はCCR4陽性細胞をADCC活性により傷害する。同種造血幹細胞移植前の投与は移植片対宿主病を増悪させるため慎重に行うべきであることがコンセンサスとなりつつあるが、移植前後の使用の適否のみでなく、至適投与時期、至適投与方法の解明が今後の課題である。免疫調整薬レナリドマイドは承認申請中である。これまで無治療経過観察が行われてきたくすぶり型や慢性型に対してはインターフェロンとジドブジンを併用する早期治療介入の検証試験が実施されている。(著者抄録)

記述言語：日本語   出版者・発行元：(株)南江堂  

出版者・発行元：(有)科学評論社  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

出版者・発行元：(有)科学評論社  

出版者・発行元：(有)科学評論社  

出版者・発行元：(株)東京医学社  

リンパ腫の診療に病理診断は不可欠である。その病理診断の過程は概ね3つに分けられる。最初の過程は、反応性リンパ増殖性病巣とリンパ腫の鑑別である。次は、他系統の悪性腫瘍の除外診断である。そして最後は、リンパ腫の疾患単位の確定である。なかでも最初の作業が難しく、小さな生検組織での鑑別作業には限界もある。診断精度をあげるためには、良質で十分量の組織を採取し、補助的な診断手法を用いて、その結果を総合的に判断しながら鑑別作業を進めなければならない。また、検索結果を解釈する際、独善に陥らぬよう留意し、臨床医と病理医は十分に情報交換する必要がある。(著者抄録)

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

出版者・発行元：(一社)日本血液学会-東京事務局  

出版者・発行元：(株)メジカルビュー社  

出版者・発行元：(公社)日本医師会  

記述言語：日本語   出版者・発行元：(株)日本臨床社  

出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：Journal of Clinical Oncology  

DOI： 10.1200/JCO.2012.45.0288

Scopus

出版者・発行元：(株)ヴァンメディカル  

＜View Points＞▼病型分類を行い、aggressive ATLかindolent ATLかを見極め、直ちに治療を開始するべきかどうかを決定する。▼ATLの治療成績はまだまだ改善の必要があり、臨床試験に組み入れることを積極的に検討する。▼臨床試験外では、aggressive ATLに対しては強力な化学療法を開始し、可能な症例では骨髄破壊的あるいは非破壊的造血幹細胞移植を計画する。▼臨床試験外では、indolent ATLに対しては無治療経過観察、必要に応じて皮膚病変等への局所治療を行う。(著者抄録)

出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：International Journal of Hematology  

DOI： 10.1007/s12185-012-1096-8

Scopus

PubMed

出版者・発行元：(一社)日本血液学会  

出版者・発行元：(株)診断と治療社  

記述言語：日本語   出版者・発行元：Journal of Clinical Oncology  

DOI： 10.1200/JCO.2010.32.1380

Scopus

PubMed

出版者・発行元：福岡大学研究推進部  

出版者・発行元：(株)ヴァンメディカル  

＜View Points!＞骨髄抑制に対する支持療法はがん化学療法の成否の鍵を握る。発熱性好中球減少症は緊急事態として対応する。血小板、貧血に対する輸血の適応を吟味し、不必要な輸血は行わない。(著者抄録)

出版者・発行元：(有)科学評論社  

出版者・発行元：(株)医薬ジャーナル社  

化学療法によって誘発される遅発性嘔吐を強力に抑制する新規薬剤neurokinin-1受容体拮抗薬;アプレピタントが、わが国でも2009年12月に上市された。急性嘔吐は、これまでも5-hydroxytriptamine 3(5HT3)受容体拮抗薬によって一定のコントロールが可能であったが、遅発性嘔吐には課題が残っていた。アプレピタントは薬物相互作用に注意を必要とするが、遅発性嘔吐に有用な薬剤として使用可能になったことは非常に有意義である。そのほか、5HT3受容体への親和性が高い第二世代5HT3受容体拮抗薬;palonosetronが申請中で、従来の5HT3受容体拮抗薬と比較して半減期が約40時間と非常に長く、遅発性嘔吐も抑制するとされ、アプレピタントが相互作用等のために使用できない状況等での有用性が期待される。(著者抄録)

出版者・発行元：(株)永井書店  

出版者・発行元：(株)医薬ジャーナル社  

骨髄腫に対する新規薬剤として、ボルテゾミブ、サリドマイド、レナリドマイドの評価はほぼ定着した。次世代の新規薬剤として、新規プロテアソーム阻害剤、新規immunomodulatory drugs(IMiDs)、heat shock protein 90(HSP90)阻害薬、ヒストン脱アセチル化酵素(HDAC)阻害薬、Akt阻害薬の開発が進められている。これらのなかで、新規プロテアソーム阻害剤と新規IMiDsを除くと単剤での抗骨髄腫効果は不十分で、ボルテゾミブ等との併用療法による臨床試験の結果が待たれる。(著者抄録)

出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：British Journal of Haematology  

DOI： 10.1111/j.1365-2141.2008.07351.x

Scopus

PubMed

出版者・発行元：(有)科学評論社  

出版者・発行元：(有)科学評論社  

出版者・発行元：(株)医学書院  

＜ポイント＞●治療方針決定,治療後の経過観察とも,過不足なく計画的に検査を行う.●それぞれの疾患の予想される経過,各種検査の長所と短所を知り,必要な検査を選択して行う.●がん診療におけるFDG-PETのエビデンスの確立が今後の課題である.(著者抄録)

出版者・発行元：(株)医薬ジャーナル社  

出版者・発行元：(株)医薬ジャーナル社  

多発性骨髄腫に対する分子標的治療薬として、プロテアソーム阻害薬、ボルテゾミブに加え、immunomodulatory drugs(IMiDs)であるサリドマイド・レナリドマイドが近い将来本邦でも使用可能となる。現在、臨床試験中の新規分子標的薬では、次世代プロテアソーム阻害薬以外は単剤での強力な抗骨髄腫効果は得難く、他剤との併用にもっぱら関心が注がれている。今後の治療研究は、ボルテゾミブ・サリドマイド・レナリドマイド、それらに従来から使用されてきた化学療法薬との至適併用の研究が進む。その最終目標を、これまで注目してきた奏効率や無増悪生存期間から長期間観察された全生存期間に移していくことが重要である。(著者抄録)

記述言語：日本語   出版者・発行元：British Journal of Haematology  

DOI： 10.1111/j.1365-2141.2008.07000.x

Scopus

PubMed

出版者・発行元：(株)南江堂  

癌化学療法の治療成績の向上には、十分な支持療法・副作用対策が必須である。白血球(好中球)減少は、感染症発症のリスクを伴う。顆粒球コロニー刺激因子(G-CSF)製剤をはじめとする白血球増殖因子と抗菌薬・抗真菌薬のエビデンスに基づいた適切な使用が必要である。悪心・嘔吐は、使用する抗癌薬の惹起する悪心・嘔吐のリスクによって、5HT3受容体拮抗薬や副腎皮質ホルモン薬を適切に使用する。今後使用可能になるNK1受容体拮抗薬による遅延性嘔吐の抑制は、癌患者のQOL向上と治療計画の完遂に貢献すると考えられる。肺毒性・心毒性・神経毒性・皮膚障害に対しては確立した治療法はないが、用量依存性に毒性が発現する薬剤では一定の総投与量を遵守する。(著者抄録)

出版者・発行元：(株)東京医学社  

WHO分類は単に形態だけでなく、発生母地、細胞起源、発生要因、特徴的な臨床像に基づいて疾患単位を明確にした分類法である。免疫形質、遺伝子、臨床像を加味して診断することによって、単なる疾患分類ではなく治療法・予後を含む重要な情報を包括させた分類となっている。リンパ系腫瘍は、(1)前駆細胞型BおよびT細胞腫瘍、(2)成熟B細胞腫瘍、(3)成熟TおよびNK細胞腫瘍、(4)Hodgkinリンパ腫に大別される。骨髄系腫瘍は、(1)急性骨髄性白血病、(2)慢性骨髄増殖性疾患、(3)骨髄異形成/骨髄増殖性疾患、(4)骨髄異形成症候群に分けられる。WHO分類に従った診断を的確に行うためには、各種の免疫染色やフローサイトメーターによる表現型の検索に加え、染色体分析や遺伝子解析が必要になる場合が多いので、プライマリーケア医においても、診断のため検査を行う際にはサンプルの取り扱いに注意が必要である。(著者抄録)

出版者・発行元：(有)科学評論社