Hidetsugu Kawai

Clinical outcome of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era.

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)‐positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV‐positive DLBCL is controversial. To compare the clinical outcome of EBV‐positive and EBV‐negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV‐encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV‐positive DLBCL patients. The median overall survival and progression‐free survival times in patients with EBV‐positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression‐free survival could not be determined in EBV‐negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV‐positive DLBCL remains poor, even in the rituximab era.

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

Functional analysis of the SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia

We analyzed the function of a SEPT9-ABL1 fusion identified in a case of T-prolymphocytic leukemia with tyrosine kinase inhibitor (TKI) resistance. Five isoforms with different N-termini, including SEPT9a-ABL1, SEPT9b-ABL1, SEPT9d-ABL1, SEPT9e-ABL1 and SEPT9f-ABL1, were detected in the leukemic cells. All isoforms except SEPT9d-ABL1 are localized in the cytoplasm, undergo autophosphorylation and phosphorylate the downstream targets, STAT-5 and Crkl, and provided IL-3-independence and in vivo invasiveness to 32D cells. Additionally, these SEPT9-ABL1 isoforms were resistant to TKIs in vitro and in vivo, in comparison to BCR-ABL1. These findings demonstrated that SEPT9-ABL1 had oncogenic activity and conferred resistance to TKIs.

Association of Promyelocytic Leukemia Protein with Expression of IL-6 and Resistance to Treatment in Multiple Myeloma

Background/Aims: Promyelocytic leukemia protein (PML) was originally identified as a tumor suppressor but has been recently shown to have the ability to control stem cell function in multiple tissues including malignancies. This study aimed to evaluate the biological and clinical significance of PML in multiple myeloma (MM). Methods: We knocked down PML in myeloma cells with a lentiviral vector expressing microRNA to target PML, which were used for in vitro analyses. We also evaluated the association between PML expression in the bone marrow and patients’ clinical parameters. Results: The expression of IL-6 was decreased in myeloma cells with knocked-down PML expression. Immunohistochemical study showed that the PML expression level varied widely in the bone marrow of 48 MM patients, and that IL-6 expression correlated with PML expression in these patients. In addition, MM with high PML expression at diagnosis showed a poor prognosis regarding the 2-year survival, and PML and IL-6 positivity increased with the progression of disease in 13 sequentially analyzed cases. Conclusions: These results suggest that PML expression was positively associated with IL-6 expression in patients and was also related to tumor development and resistance to treatment in MM.

Identification of a novel SEPT9-ABL1 fusion gene in a patient with T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL), a rare type of peripheral T-cell leukemia, is characterized by marked splenomegaly with rapidly progressive lymphocytosis and a poor prognosis. Nine kinds of ABL1 chimeric genes have been identified in various kinds of hematological malignancies, such as chronic myeloid leukemia and B- or T-lymphoblastic leukemia. However, there have been no reports describing T-PLL cases with ABL1 rearrangements. We herein report a case of T-PLL with a novel SEPT9-ABL1 fusion gene which induced strong resistance to tyrosine kinase inhibitors such as imatinib and dasatinib.

Erratum to: Successful bypass surgery for esophageal carcinoma under adequate factor XIII/13 replacement therapy in a case of intractable autoimmune hemorrhaphilia due to anti-Factor XIII/13 antibodies

Autoimmune hemorrhaphilia due to anti-factor XIII (FXIII) antibodies (AH13) is a life-threatening disease associated with high risk of surgical bleeding. Since AH13 occurs mainly in the elderly, patients of AH13 tend to be complicated with other life-threatening diseases that may require surgical procedures. During our nation-wide survey on AH13, supported by the Japanese Ministry of Health, Labor, and Welfare, patients with unexplained bleeding were examined for FXIII-related parameters and anti-FXIII autoantibodies. A 64-year-old man had previously been tentatively diagnosed with AH13 and received immunosuppressive therapies, as FXIII inhibitor was detected by functional cross-mixing studies. About 2 years later, he was definitively diagnosed with AH13, because our immuno-chromatographic test and enzyme-linked immuno-sorbent assay detected FXIII-bound anti-FXIII-A subunit autoantibodies. Since routine endoscopic examination revealed suspected esophageal carcinoma, a preparatory FXIII pharmacokinetic (PK) analysis was performed by infusing FXIII concentrates prior to biopsy. Consequently, biopsy of this lesion was done without bleeding complications. One month later, a second PK study was carried out before surgery, and esophageal bypass surgery was completed successfully under FXIII replacement therapy. Our experience with this case suggests that operations can be performed safely and with confidence even in patients with such life-threatening hemorrhagic diseases.

Four hepatosplenic T-cell lymphoma cases of Japanese patients

Hepatosplenic T-cell lymphoma (HSTCL), a rare type of γδ T-cell lymphoma, is characterized by hepatosplenomegaly and cytopenias. It is associated with immunodeficiency and its age of onset is reportedly between the 20s and 30s. We herein report 4 Japanese HSTCL cases. Three of them, including an elderly case that was 74 years of age, were not at adolescence. No cases had a history of immunodeficiency. All other disease phenotypes were similar to the typical HSTCL cases. These findings suggest that there are a certain proportion of HSTCL patients who presented after middle age.

Strong effect of mogamulizumab on splenic residual disease of adult T cell leukemia/lymphoma

Dear Editor, A 54-year-old female complained of multiple subcutaneous masses. A histological study and southern blotting for HTLV1 proviral DNA led to a diagnosis of the acute type of ATLL. FDG accumulation was observed in the abdominal lymph nodes, liver, and spleen (Fig. 1, left panel). She received two cycles of multidrug chemotherapy, including vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin (VCAP–AMP–VECP) [1]. A single residual ATLL lesion in the spleen remained following the administration of VCAP–AMP–VECP (Fig. 1, middle panel). Thereafter, the patient received intravenous infusions of mogamulizumab (1.0 mg/kg) once a week for 3 weeks and the splenic lesion completely disappeared (Fig. 1, right panel). The patient underwent umbilical cord blood transplantation (UCBT) following of cyclophosphamide (120 mg/kg) and total body irradiation (12 Gy). The HLA disparity was two loci mismatched at HLA-B and DR. The total nucleated cell and CD34-positive cell counts were 2.42× 10/kg and 0.75×10/kg, respectively. Prophylaxis for graftversus-host disease (GVHD) included tacrolimus and shortterm methotrexate. Neutrophil engraftment was achieved on day 23. STR-based chimerism testing performed on day 28 revealed BM cells to be 100 % of the donor type [2]. A skin rash emerged on day 30, and the patient was diagnosed with grade II acute GVHD. The acute GVHD immediately disappeared following the dose escalation of tacrolimus. However, after elevation of the total bilirubin level and the development of massive ascites on day 40, she died due to multiple organ failure on day 110. The autopsy results revealed widespread omission of hepatic cells and acute tubular necrosis. No findings of relapse of ATLL, GVHD, microthromboembolism, or veno-occlusive disease were observed.

Three cases of spontaneous splenic rupture in malignant lymphoma

Spontaneous splenic rupture is a rare but often life-threatening condition. However, there is no consensus on appropriate management for this condition, due to its rarity. Here, we report three cases of malignant lymphoma with spontaneous splenic rupture. In each case, progression of splenic bleeding was rapid and complicated by malignant lymphoma. Spontaneous splenic rupture complicated by malignant lymphoma may cause exacerbation of anemia and hypovolemic shock. When splenic rupture is indicated by abdominal pain, tachycardia, or hypotension in a patient with splenomegaly, abdominal examination should be performed immediately, and emergency transcatheter arterial embolization and/or splenectomy should be considered.

Dysplastic features seen in a patient with acute myeloid leukemia harboring the KTM2A-TET1 fusion gene

Pancytopenia was noted in an apparently healthy 38-yearold woman at a regular medical checkup. Laboratory tests showed a hemoglobin level of 10.5 g/dL, 10.4 × 109/L platelets, and 1.1 × 109/L leukocytes, including 3.0% blasts. A bone marrow examination revealed 49.1% peroxidase-positive blasts with delicate nuclear chromatin and basophilic cytoplasm. Some of the blasts had Auer rods (Fig. 1 panels A, E). Flow cytometric analysis revealed positivity for CD13, CD33, CD117, HLA-DR, CD34 and CD38 among the blasts. Her bone marrow showed trilineage dysplasia, including pseudo-Pelger-Huët anomaly (Fig. 1 panels A, arrow, B, C) and hypogranular neutrophils, multi-nucleation (Fig. 1 panel D, arrow) and abnormal chromatin clumping in erythroblasts and many megakaryocytes with separated nuclei (Fig. 1 panels F–L, arrow). Paraffin sections of bone marrow aspirate showed the proliferation of dysplastic CD42b-expressing megakaryocytes (Fig. 1 panels M, N). Because dysplasia was observed in > 50% of the erythroid and megakaryocytic lineage cells, she was tentatively diagnosed with acute myeloid leukemia with myelodysplasiarelated changes (AML-MRC). A chromosomal analysis indicated 46,XX,t(10;11)(q22;q23) [7]/46,XX [1]. Reverse transcription polymerase chain reaction and sequencing analyses revealed the KMT2A (MLL)-TET1 fusion gene with KMT2A exon 9 fused to TET1 exon 9 in frame. Her final diagnosis was AML with t(10;11)(q22;q23) ; KMT2A-TET1. Among more than 120 KMT2A rearrangements, KMT2ATET1 has been reported in only 14 leukemia cases (10 AML, one therapy-related AML, two unspecified acute lymphocytic leukemia (ALL), and one T-ALL). Three patients had bone marrow-apparent dysplasia [1]. The TET1 product is