Michiaki Koike

Relationship between CD4+/CD8+ T cell ratio and T cell activation in multiple myeloma: reference to IL-16

We found that the ratio of CD4(+) to CD8(+) T cells (CD4/CD8 ratio) was decreased in patients with multiple myeloma (MM) and that this decrease was significantly related to an increase of human leukocyte antigen (HLA)-DR expression by CD8(+) (but not CD4(+)) T cells (P<0.005). In addition, the serum level of interleukin (IL)-16 was significantly higher in stage III MM patients than in healthy controls (P<0.001). The decrease of CD4(+) T cells in MM may be mediated by activation of CD8(+) T cells derived cytokine IL-16. In addition, these T cell phenotypic changes and the IL-16 level appear to be useful indicators of disease activity.

JAK2 , CALR , and MPL mutation spectrum in Japanese patients with myeloproliferative neoplasms

Recurrent somatic mutations in the JAK2 , MPL , and CALR genes have been described in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These mutations are generally

JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan

JAK2V617F, a gain-of-function mutation in the tyrosine kinase JAK2, is frequently detected in classical myeloproliferative neoplasms (MPNs). In the present study, we determined the JAK2V617F allele burden in Japanese MPN patients using alternately binding probe competitive-polymerase chain reaction, a highly quantitative method recently developed by our group. Although we observed strong similarities in terms of epidemiological parameters associated with the JAK2V617F allele burden between our cohort and others, we found a higher JAK2V617F allele burden in Japanese polycythemia vera (PV) patients and lower frequencies of thrombosis in Japanese MPN patients compared with previous reports. In addition, despite the presence of high red blood cell counts, some patients bearing the JAK2V617F mutation were not diagnosed as PV, as their hemoglobin values were lower than the WHO PV criterion. In these patients, the JAK2V617F allele burden was strikingly similar to that in PV patients fulfilling the 2008 WHO criteria, suggesting that these patients can be classified as PV. Although isotopic measurement of red cell mass (RCM) is required for definitive diagnosis of PV, our data suggest that precise measurement of the JAK2V617F allele burden may improve the diagnosis of PV when RCM has not been determined.

Clinical analysis of 52 patients with granular lymphocyte proliferative disorder (GLPD) showed frequent anemia in indolent T-cell GLPD in Japan

We present here clinical and hematological findings of 52 cases of granular lymphocyte‐proliferative disorder (GLPD), which contained 35 indolent T‐cell lineage granular lymphocyte‐proliferative disorder (T‐GLPD), two atypical T‐GLPD, 12 chronic NK‐cell lymphocytosis (CNKL), and three aggressive NK‐cell leukemia (ANKL). The median period of follow up was 24 months. Hemoglobin level <8.0 g/dL was recognized in 21 cases of indolent T‐GLPD (60%), among which 15 patients met the criteria of pure red cell aplasia. Neutrophil counts <500/μL occurred only in two cases of T‐GLPD (6%). Although the median age and male‐to‐female distribution were similar, very frequent anemia and rare neutrocytopenia in indolent T‐GLPD in the present study keenly contrasted with previous reports. CD56 was positive in three of 29 indolent T‐GLPD cases with CD4−CD8+ phenotype, in three of four CD4+CD8−, and in none of two CD4−CD8− cases. Therefore, although two atypical T‐GLPD cases were CD56‐positive, CD56 should not be a specific marker for aggressive T‐GLPD. All CNKL patients had a chronic course with a stable granular lymphocyte count. All three ANKL patients presented high fever and hepatosplenomegaly, barely responded to chemotherapies and died within 6 months. The present analysis of 52 cases of GLPD in Japan showed that Japanese and Western cases of indolent T‐GLPD clearly differ in their hematological complications.

Two cases of reactive hemophagocytic syndrome: a patient with adult-onset Still's disease and a patient with herpes zoster and autoimmune abnormalities.

Abstract We report two cases of bone marrow hemophagocytosis. One patient had adult-onset Stills disease, and the other had herpes zoster associated with potential autoimmune abnormalities. Our findings suggested a pos-sible role of cytokines and/or antibodies in the induction of hemophagocytosis in patients with connective tissue diseases and/or immune abnormalities.

Effects of bestatin (Ubenimex) on human T-cell colony formation.

The antitumor action of bestatin is considered to be an indirect action mediated by T-cells. Therefore, we investigated the effects of bestatin on the differentiation and proliferation of human precursor T-cells using a colony formation technique. Bestatin did not increase the overall number of T-cell colonies, but it significantly increased in CD4+ cell and significantly decreased in CD8+ cell subpopulations. It also induced CD4+ 8+ cells.These findings indicated that bestatin acts on precursor T-cells to induce the differentiation of these cells into CD4+ cells.

Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group

Objective: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. Methods: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. Results: Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (≤10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. Conclusion: These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy.

Autoimmune hemolytic anemia in a patient with TAFRO syndrome

TAFRO syndrome is a systemic inflammatory disorder characterized by low platelet counts, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. Patients with TAFRO syndrome occasionally have courses complicated by immunological diseases. Herein, we describe a case of TAFRO syndrome associated with autoimmune hemolytic anemia (AIHA). The patient was admitted because of menorrhagia. She had thrombocytopenia, pleural effusion and ascites, hepatomegaly, and multiple lymphadenopathies. Her symptoms worsened, especially fever, pleural effusion and ascites, and she developed AIHA. Steroid pulse therapy followed by 45 mg of prednisolone (PSL) improved not only the symptoms of TAFRO syndrome but also those of AIHA. There have been no reports, to our knowledge, of AIHA associated with TAFRO syndrome, and detailed studies on this syndrome are needed.

Lymphomatoid Granulomatosis with Central Nervous System Involvement Successfully Treated with Cyclophosphamide, High-dose Cytarabine, Dexamethasone, Etoposide, and Rituximab (CHASER therapy) Followed by Brain Irradiation: A Case Study

Lymphomatoid granulomatosis (LYG) is a rare subtype of diffuse large B-cell lymphoma. It is an extranodal angiocentric and angiodestructive lymphoproliferative disease involving the lungs, skin, and central nervous system (CNS), including abundant reactive T cells with varying numbers of atypical clonal Epstein–Barr virus (EBV)-infected B cells [1]. Clinical diagnosis of LYG is difficult because of a lack of characteristic manifestations, suitable laboratory tests, and imaging findings. No optimal treatment for LYG has yet been established, especially in cases involving the CNS. Several previous reports of rituximab monotherapy, rituximab-containing chemotherapy, interferon alpha-2b, or hematopoietic stem cell transplantation have been published [2], as well as a report of cyclophosphamide (CPM), high-dose cytarabine, dexamethasone, etoposide, and rituximab (CHASER therapy) for lung lesions of LYG [3]. Spontaneous remission has also been reported in patients with LYG involving the CNS and lungs [4]. Here, we describe a case of LYG with lung onset responsive to corticosteroid treatment, but with subsequent CNS involvement resistant to corticosteroid and rituximab monotherapy, which was successfully treated with CHASER therapy followed by brain irradiation. We also propose the value of repetitive evaluation of specimens and gradient-echo T2*-weighted magnetic resonance imaging (T2*-MRI) for diagnosis of CNS involvement in LYG (CNS–LYG). A healthy 40-year-old woman presented with persistent fever, cough, and dyspnea 2 years before admission to our hospital. Thoracic computed tomography (CT) performed at a local hospital revealed diffuse ground-glass opacity with nodular lesions in both lungs (Figure 1A). Blood examination showed highly elevated soluble interleukin-2 receptor (11,726 U/ml), and slightly elevated aspartate aminotransferase (86 IU/L) and alanine transaminase (131 IU/L). EBV antiviral capsid antigen (VCA) IgG and Epstein–Barr nuclear antigen (EBNA) were positive, and EBV anti-VCA IgM was negative, indicating past EBV infection. Pathological diagnosis was performed using videoassisted thoracic surgery (VATS), revealing atypical large lymphoid cells infiltrating the regions around the blood vessels (Figure 2A). These infiltrating lymphocytes comprised a large number of CD3-positive T cells and a few large CD20-positive B cells (Figure 2B). However, the lymphocytes were negative for EBV-encoded small RNA (EBER) according to in situ hybridization. Although LYG was suspected from the results, a definitive diagnosis was not made at the time. Prednisolone (50 mg/day; 1 mg/kg/day) was administered orally. The patient’s fever and respiratory symptoms disappeared and thoracic CT revealed disappearance of the bilateral nodular lesions (Figure 1B). However, 1 month after initiation of steroid therapy, prednisolone was tapered to 30 mg/day and she developed neurological deficits, including left facial dysesthesia, dysarthria, and gait disturbance due to left dominant spastic paraplegia, limb ataxia, and sensory disturbance. CPM (100 mg/day) was added and prednisolone was repeatedly increased or decreased from 50 to 2.5 mg/day, with no improvement. The patient was therefore

Ursodeoxycholic acid treatment of idiopathic thrombocytopenic purpura with liver dysfunction

Abstract: Ursodeoxycholic acid (UDCA) is known to reduce immunoglobulin from B cells and cytokine production from T cells. We found that UDCA increased the platelet count in two idiopathic thrombocytopenic purpura (ITP) patients who have liver dysfunction. UDCA was tolerated and did not cause diarrhea in the amounts used. Further investigation is needed to evaluate the effectiveness of UDCA in ITP patients.