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Annals of Hematology | 2005

Treatment with valproic acid for myelofibrosis with myeloid metaplasia

Yasuyuki Inoue; Takao Suzuki; Madoka Takimoto; Michiko Irei; Shinji Yoshioka; Yasushi Shibuya; Masayuki Kato; Mitsuru Koike; Masatomo Takahashi

Dear Editor Myelofibrosis with myeloid metaplasia (MMM) is a clonal hematopoietic stem cell disorder characterized by bone marrow fibrosis, leukoerythroblastosis, splenomegaly, and extramedullary hematopoiesis. The average age at diagnosis of MMM is approximately 60 years, with a median survival of 3 to 5 years [1]. There is no effective therapy for elderly patients with advanced MMM. We report herein a case of MMM resistant to danazol and prednisone that responded to treatment with valproic acid (VPA). The histone deacetylase (HDAC) inhibitor, VPA, may be useful in a subset of MMM cases, as well as in cases of acute leukemia and myelodysplastic syndrome (MDS). A 74-year-old female patient presented at our hospital with seizures and tendency to bleed. She had been diagnosed with MMM 2 years earlier, but she did not receive any therapy. As her bicytopenia deteriorated, she received danazol (20 mg/day), prednisone (10 mg/day), and blood transfusion. Her hemoglobin level at that time was approximately 6 g/dl, and platelet count was approximately 5.0×10/l. On admission, she had purpura and severe bicytopenia (hemoglobin level 4.2 g/dl, platelets 3.0×10/l, WBC 12.4× 10/l, myeloblasts 0.1%, myelocytes 0.5%, band 1.4%, segmented cells 78.5% lymphocytes 13.5%, monocytes 5.5%, basophils 0.5%). Her reticulocyte count was zero. The spleen size was about 24 cm. As electroencephalography exhibited a diffuse slow wave, she received VPA (800 mg/day) for epilepsy prophylaxis. Approximately 2 weeks later, her reticulocyte count increased markedly; and 3 weeks later, her red blood cell and platelet counts were greater than 10 g/dl and 18×10/l, respectively. Her white blood cell count and neutrophil levels involving premature cells, such as myeloblasts, also appeared to increase (Fig. 1). Her dizziness and bleeding symptoms improved, too. The blood concentration of VPA was 50 μg/ml, a therapeutic level for seizure prevention, with no adverse effects. Her spleen size decreased by approximately 3 cm. Bone marrow aspiration revealed hypocellularity with normal karyotype (46XX) on the 35th day after starting VPA treatment, although the aspirate was a dry tap at diagnosis. The differential count of the bone marrow was myeloblasts 0.4%, myelocytes 1.2%, metamyelocytes 0.2%, band 0.2%, segmented cells 61.0%, basophils 3.0%, monocytes 2.6%, lymphocytes 19.6%, plasma cells 0.2%, erythroblasts 11.6%, and megakaryocytes 2/μl. The favorable effect of VPA treatment continued for 110 days.


Journal of The American Academy of Dermatology | 2008

Transforming growth factor–β overexpression in cutaneous extramedullary hematopoiesis of a patient with myelodysplastic syndrome associated with myelofibrosis

Tamihiro Kawakami; Satoko Kimura; Masayuki Kato; Masako Mizoguchi; Yoshinao Soma

Extramedullary hematopoiesis (EMH) is a relatively rare, but well-documented, manifestation of chronic myeloproliferative disorders. Microscopically, foci of EMH consist of erythroid and myeloid precursors intermixed with megakaryocytes. It typically occurs in the spleen and liver, but very occasionally manifests as cutaneous EMH. We report a 76-year-old Japanese man with cutaneous EMH arising from myelodysplastic syndrome associated with myelofibrosis. His cutaneous manifestations showed multiple skin-colored firm nodules over the head, trunk, and extremities. We detected high plasma levels of transforming growth factor (TGF)-beta1 in our patient. Immunohistochemical analysis of the skin biopsy sample revealed TGF-beta1 overexpression in immature hematopoietic cells and dermal fibroblasts within the cutaneous EMH mass of the dermis. These findings suggest that TGF-beta could play some role in the onset of cutaneous EMH. Five months after his first visit to our dermatologic clinic, the patient developed bone-marrow failure and died. Based on our observations, accelerated malignancy in the bone marrow should be considered in any patient with cutaneous EMH. It is presumed that TGF-beta released from hematopoietic cells within the cutaneous EMH play a critical role in the activation of hematologic malignancy.


Leukemia & Lymphoma | 2013

Role of serum high mobility group box 1 in hematological malignancies complicated with systemic inflammatory response syndrome and effect of recombinant thrombomodulin

Yasuyuki Inoue; Tasuku Saito; Kohei Ogawa; Yuji Nishio; Shigeki Kosugi; Yoshinori Suzuki; Hirotaka Sakai; Masayuki Kato; Masatomo Takahashi; Ikuo Miura

Abstract High mobility group box 1 (HMGB1) mediates inflammation. We investigated the role of serum HMGB1 in 54 patients with hematological malignancies with and without systemic inflammatory response syndrome (SIRS). There was no difference between groups 1 (complete remission of hematological disease: n = 13) and 2 (no remission: n = 16) in serum HMGB1 levels. However, those of group 3 (complicated by SIRS: n = 25) were significantly higher (vs. group 1: p < 0.001 and vs. group 2: p = 0.008, respectively). Seventeen patients in group 3 also developed disseminated intravascular coagulation and received recombinant human thrombomodulin (rhTM). Thirteen of those with SIRS improved, and serum HMGB1 levels significantly decreased (p = 0.047). Seven patients in group 3 who died within 28 days of SIRS onset had significantly higher serum HMGB1 levels than the survivors (p = 0.016). The anti-HMGB1 properties of rhTM might be useful therapy if serum HMGB1 is associated with the development of SIRS in the presence of hematological malignancies.


Journal of Clinical Pharmacy and Therapeutics | 2011

Pharmacokinetics of cyclosporine A at a high‐peak concentration of twice‐daily infusion and oral administration in allogeneic haematopoietic stem cell transplantation

Yasuyuki Inoue; Tasuku Saito; Kohei Ogawa; Yuji Nishio; Shigeki Kosugi; Yoshinori Suzuki; Yasushi Shibuya; Masayuki Kato; Masatomo Takahashi; Ikuo Miura

What is known and Objective:  The most appropriate immunosuppressive strategy with calcineurin inhibitors for the prevention of acute graft‐versus‐host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) has not yet been established. To estimate the safety and efficacy of a new strategy, we investigated the pharmacokinetics of cyclosporine A (CyA) delivered by twice‐daily infusion and oral administration maintained with a peak level above 1000 ng/mL to keep 24 h area under the concentration–time curve (AUC0–24) higher than 10 000 ng·h/mL in 12 patients.


British Journal of Haematology | 2013

Acute myeloid leukaemia with cup-like nuclei associated with t(9;22)(q34;q11.2).

Hirotaka Sakai; Kazuyuki Sato; Yuka Tsuruoka; Masayuki Kato; Masatomo Takahashi; Ikuo Miura

An 86-year-old man presented with a 1-month history of dyspnea. Blood examination showed a white blood cell count of 137 9 9 10/l, a haemoglobin concentration of 89 g/l and a platelet count of 86 9 10/l. A peripheral blood film revealed immature granulocytes with 68% blasts, which showed a prominent nuclear indentation (top). Electron microscopy showed an accumulation of mitochondria in the nuclear indentation (bottom left). Neither cytochemistry nor flow cytometry showed myeloperoxidase in the blast cells. Flow cytometry showed a lack of early haematopoietic antigens (CD34 and HLA-DR), but there was expression of myeloid antigens (CD13 and CD33). Chromosome analysis demonstrated 46,XY,t(9;22)(q34;q11.2)[1]/47,idem,+mar[7]/ 47,idem,-18,+r1[4]/46,idem,del(7)(p?)[3]. Fluorescence in situ hybridization showed fusion signals for BCR-ABL1 in 98% of nuclei, both in round-shaped nuclei (immature and blast cells) and segmented nuclei (neutrophils) (bottom right). A diagnosis of BCR-ABL1-positive acute myeloid leukaemia with cup-like nuclei (AML-CN) was made. Given that there was no hepatosplenomegaly at presentation and the complete blood counts had been normal approximately 7 months before the visit, a diagnosis of blast crisis of chronic myeloid leukaemia was considered unlikely. Dasatinib was administered for 11 d, but was then replaced by nilotinib when generalized erythema appeared. The blood counts returned to normal following the first 2 weeks of treatment, the blasts disappeared by 3 weeks, and a molecular response was achieved by 6 months (<50 copies of BCR-ABL1 mRNA by quantitative reverse transcription polymerase chain reaction). AML-CN is a rare subset of leukaemia with nuclear indentation, a CD34and HLA-DR-negative immunophenotype, and mostly a normal karyotype with NPM1 mutation. This case demonstrates that cup-shaped nuclei can also be associated with Philadelphia-positive AML.


International Journal of Hematology | 2015

PAX5-positive plasma cell myeloma with t(9;14;11)(p13;q32;q13), a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32)

Kazuyuki Sato; Hirotaka Sakai; Masayuki Kato; Yuji Nishio; Yuka Tsuruoka; Yu Uemura; Satoshi Yokoi; Tasuku Saito; Manabu Matsunawa; Yoshinori Suzuki; Yasushi Isobe; Yasuyuki Inoue; Masatomo Takahashi; Ikuo Miura

We describe herein the case of a 64-year-old man with a diagnosis of plasma cell myeloma (PCM). A chromosome analysis based on G-banding and spectral karyotyping revealed the following complex karyotype: 46,XY,del(3)(p?), t(4;15)(q31;q24),t(9;14;11)(p13;q32;q13),add(15)(q24),add(18)(q21). Fluorescence in situ hybridization (FISH) detected one signal each for the immunoglobulin heavy chain (IGH) and cyclin D1 (CCND1) genes, and three fusion signals of IGH and CCND1. FISH analysis of metaphase spreads revealed fusion signals on the derivative chromosomes 9, 11, and 14. Immunohistochemical analysis identified abnormal expression of CCND1 and PAX5. PAX5-positive PCM is rare because the down-regulation of PAX5 is essential for the terminal differentiation of B cells into plasma cells. To the best of our knowledge, this is the first reported case of a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32).


International Journal of Hematology | 2018

Cell dynamics during differentiation therapy with all- trans retinoic acid in acute promyelocytic leukemia

Kazuyuki Sato; Hirotaka Sakai; Yusuke Saiki; Akiko Uchida; Yu Uemura; Satoshi Yokoi; Yuka Tsuruoka; Yuji Nishio; Manabu Matsunawa; Yoshinori Suzuki; Yasushi Isobe; Masayuki Kato; Naoto Tomita; Yasuyuki Inoue; Ikuo Miura

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.


Journal of Clinical and Experimental Hematopathology | 2015

Cytogenetic Study and Analysis of Protein Expression in Plasma Cell Myeloma with t(11;14)(q13;q32): Absence of BCL6 and SOX11, and Infrequent Expression of CD20 and PAX5.

Satoshi Yokoi; Hirotaka Sakai; Akiko Uchida; Yu Uemura; Kazuyuki Sato; Yuka Tsuruoka; Yuji Nishio; Manabu Matsunawa; Yoshinori Suzuki; Yasushi Isobe; Masayuki Kato; Yasuyuki Inoue; Masahiro Hoshikawa; Ikuo Miura

The t(11;14)(q13;q32) translocation is the most common chromosomal translocation in plasma cell myeloma (PCM), but the cytogenetic and immunophenotypic features of PCM with t(11;14)(q13;q32) remain to be fully elucidated. To address the issue, we retrospectively analyzed 21 newly diagnosed PCM patients with the t(11;14)(q13;q32) translocation in our institute. CD20 is a B-cell-specific transmembrane protein that is the topic of much focus as a potential target in immunotherapy. We observed a low incidence of CD20 expression (2 of 21 patients, 11%), although the expression of CD20 was previously reported to be associated with t(11;14)(q13;q32). PAX5 is an essential transcriptional factor involved in B-cell development and commitment, and is down-regulated upon plasma cell differentiation. We observed one patient (6%) with expression of PAX5. The expression of CD19, CD56, and CD138 was detected in one (0.7%), nine (60%), and 13 patients (87%), respectively. Cyclin D1, CD38, and BCL2 were detected in all patients; on the other hand, neither BCL6 nor SOX11 was detected in any of the evaluated patients. Abnormalities of chromosome 13 were detected in six patients (38%), but deletion of TP53 was not observed in any of the evaluated patients. Our results suggest the absence of BCL6 and SOX11 expression, and infrequent expression of CD20, PAX5, and CD56 in PCM with t(11;14)(q13;q32), in contrast to the findings of earlier reports.


International Journal of Hematology | 2010

Intensified consolidation therapy with dose-escalated doxorubicin did not improve the prognosis of adults with acute lymphoblastic leukemia: the JALSG-ALL97 study.

Itsuro Jinnai; Tohru Sakura; Motohiro Tsuzuki; Yasuhiro Maeda; Noriko Usui; Masayuki Kato; Hirokazu Okumura; Taiichi Kyo; Yasunori Ueda; Yuji Kishimoto; Fumiharu Yagasaki; Kosuke Tsuboi; Shigeo Horiike; Jin Takeuchi; Masako Iwanaga; Yasushi Miyazaki; Shuichi Miyawaki; Kazunori Ohnishi; Tomoki Naoe; Ryuzo Ohno


International Journal of Hematology | 2008

Close relation between 14q32/IGH translocations and chromosome 13 abnormalities in multiple myeloma: a high incidence of 11q13/CCND1 and 16q23/MAF

Madoka Takimoto; Kohei Ogawa; Yo Kato; Tasuku Saito; Takao Suzuki; Michiko Irei; Yasushi Shibuya; Yoshinori Suzuki; Masayuki Kato; Yasuyuki Inoue; Masatomo Takahashi; Hiroki Sugimori; Ikuo Miura

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Ikuo Miura

St. Marianna University School of Medicine

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Yasuyuki Inoue

St. Marianna University School of Medicine

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Masatomo Takahashi

St. Marianna University School of Medicine

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Yoshinori Suzuki

St. Marianna University School of Medicine

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Yuji Nishio

St. Marianna University School of Medicine

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Hirotaka Sakai

St. Marianna University School of Medicine

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Kazuyuki Sato

St. Marianna University School of Medicine

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Tasuku Saito

St. Marianna University School of Medicine

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Yasushi Isobe

St. Marianna University School of Medicine

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Yuka Tsuruoka

St. Marianna University School of Medicine

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