Noriaki Iwao

Combination chemotherapy of carboplatin and cytosine arabinoside for high-risk leukemia: a pilot study.

Fourteen patients with high-risk leukemia (six with relapsed AML, three with relapsed ALL, one with AML-M0, four with CML in myeloid blastic crisis) were treated with a combination chemotherapy of carboplatin (200-300 mg/m2/day) and cytosine arabinoside (100 mg/m2/day) by 24 h continuous infusion for 5-7 days. Five patients (35.7%) achieved complete remission including two patients complicated with myelofibrosis (one with AML-M0 and one with CML in myelo-megakaryocytic crisis). Thirteen patients had nausea and vomiting, five patients had severe, prolonged neutropenia for which it was necessary to administer granulocyte colony-stimulating factor and six patients had severe thrombocytopenia. We concluded that this regimen is effective for the treatment of high-risk leukemia.

Inhibition of VEGF-dependent angiogenesis by the anti-CD82 monoclonal antibody 4F9 through regulation of lipid raft microdomains.

CD82 (also known as KAI1) belongs to the tetraspanin superfamily of type III transmembrane proteins, and is involved in regulating cell adhesion, migration and proliferation. In contrast to these well-established roles of CD82 in tumor biology, its function in endothelial cell (EC) activity and tumor angiogenesis is yet to be determined. In this study, we show that suppression of CD82 negatively regulates vascular endothelial growth factor (VEGF)-induced angiogenesis. Moreover, we demonstrate that the anti-CD82 mAb 4F9 effectively inhibits phosphorylation of VEGF receptor 2 (VEGFR2), which is the principal mediator of the VEGF-induced angiogenic signaling process in tumor angiogenesis, by regulating the organization of the lipid raft microdomain signaling platform in human EC. Our present work therefore suggests that CD82 on EC is a potential target for anti-angiogenic therapy in VEGFR2-dependent tumor angiogenesis.

T cell receptor excision circle levels in CD94-expressing CD8 T Cells during graft-versus-host disease

T cell receptor excision circles (TRECs) have been suggested to be useful markers of recent thymic output and graft-versus-host disease (GVHD) was thought to have an adverse effect on thymic output. On the other hand, TREC concentrations are diluted with T cell expansion. The C-type lectin superfamily inhibitory receptor CD94 expression on T cells might be a consequence of CD8 T cell expansion. Therefore, this study was designed to analyse TREC DNA level in CD4 and CD8 T cell subset expressing CD94 during GVHD. We investigated TREC DNA copy numbers (TREC levels) of CD4+, CD94+/CD8+ and CD94−/CD8+ T cells in 24 patients who had undergone allogeneic stem cell transplantation and also of in vitro activated and expanded CD94-expressing cells by immobilised anti-CD3 mAb and IL-15. TREC level of CD94+/CD8+ T cells in patients with chronic GVHD was lower than that in patients with no GVHD and with remission status of GVHD. In vitro activated and expanded CD94-expressing cells had a significantly lower TREC level than that in untreated CD8 cells. Therefore, the low TREC level of CD94+/CD8+ T cells is related to chronic GVHD and may reflect T cell expansion during chronic GVHD.

Acquired Factor VIII Inhibitor in a Patient of Rheumatoid Arthritis on Tumor Necrosis Factor Inhibitor Therapy

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by an autoantibody to factor VIII (FVIII), with an estimated incidence of 1.48/million/year. The mortality rate has been reported to be between 8 and 22% [1]. Major associations with AHA are postpartum hemorrhage, malignancy, autoimmune disorder, rheumatoid arthritis (RA), and the use of drugs (penicillin, sulfamide, and interferon alpha). In our patient, AHA occurred during tumor necrosis factor alpha (TNF-a) inhibitor treatment for rheumatoid arthritis. A 68-year-old female was diagnosed with RA 10 years earlier, and has been treated with etanercept (tumor necrosis factor alpha (TNF-a) inhibitor) for over 6 years, at 25 mg once every week. She became aware of bruising on her left hip 3 months ago, and whole-body computed tomography (CT) revealed a large muscular hemorrhage. The serum hemoglobin level had decreased to 6.6 g/dL. The area of muscular hemorrhage of her left hip subsequently enlarged, and she was transported to our hospital in hemorrhagic shock. The results of coagulation tests showed a prolonged activated partial prothrombin time (APTT) (86.8 s, normal range 25–40) with a normal prothrombin time (PT) (13.3 s, normal range 11.3–13.3). In addition, a coagulation factor assay revealed decreased levels of FVIII activity of less than 1% (normal range 78.0–165.0%) and a high titer of FVIII inhibitor of 213 Bethesda units/mL (BU/ mL). Therefore, she was diagnosed with acquired hemophilia A (AHA). Whole body CT was performed after hospitalization, and no tumors were detected. She was administered activated prothrombin complex concentrate for the treatment of bleeding. However, new hemorrhage sites developed in her left shoulder and right leg. She was then administered recombinant activated factor VII for the treatment of bleeding. Immunosuppressive therapy was started with oral prednisolone (PSL) at 45 mg/day. However, APTT and the FVIII inhibitor level rose to 150 s and 569 BU/mL, respectively. She was administered cyclophosphamide (CPA) at 50 mg/day and then received CPA pulse therapy (500 mg/body every 4 weeks). The bleeding in soft tissue repeated, and she was administered cyclosporine A at 200 mg/day. The results of coagulation studies showed a normal APTT and disappearance of the FVIII inhibitor 15 weeks after the immunosuppressive therapy. PSL was tapered to 10 mg/day and she was discharged from our hospital on day 150. After discharge, the patient was administrated 10 mg of prednisolone every day continuously. However, after 1 year, the inhibitor was re-redacted. The administration of cyclosporine A was started again. In our patient, AHA occurred during TNF-a inhibitor treatment, and this treatment has been reported to be associated with a high-titer of FVIII inhibitor [2]. In our case, a coagulation factor assay revealed a high-titer of FVIII inhibitor, at 569 BU/mL. It has been reported that it is difficult for AHA patients with a high titer of FVIII inhibitor to achieve complete sustained remission and that they require long-term treatment. Autoantibody to FVIII mainly consists of IgG. In addition, high-titer inhibitors and inhibitors of FVIII in patients with AHA and underlying disease consist predominantly of IgG4 [3]. A study & Tomoyo Mori tomoyo.mori.628@gmail.com

Retroperitoneal relapse in an older patient with multiple myeloma during pomalidomide and dexamethasone treatment

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Role of IL-26+CD26+CD4 T Cells in Pulmonary Chronic Graft-Versus-Host Disease and Treatment with Caveolin-1-Ig Fc Conjugate

Obliterative bronchiolitis is the primary noninfectious pulmonary complication after allogeneic hematopoietic cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In our recent study, we identified a novel effect of IL-26, which is absent in rodents, on transplant related-obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood gradually exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Moreover, we showed that IL-26 increased collagen synthesis in fibroblasts in vitro and that collagen contents were increased in a murine GVHD model using IL26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by CD4 T cells following CD26 costimulation, while immunoglobulin Fc domain fused with the N-terminal of caveolin-1, the ligand for CD26, (Cav-Ig) effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. We concluded that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.