Jun Amaki

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.

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.

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.

Early disease progression in patients with localized natural killer/T‐cell lymphoma treated with concurrent chemoradiotherapy

Prognosis of patients with localized nasal extranodal natural killer/T‐cell lymphoma, nasal type (ENKL) has been improved by non‐anthracycline‐containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT‐DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT‐DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk‐defining events of the POD24 group was inferior to that of the reference group in both cohorts (P < .00001). In the RT‐DeVIC cohort, pretreatment elevated levels of serum soluble interleukin‐2 receptor (sIL‐2R), lactate dehydrogenase, C‐reactive protein, and detectable Epstein‐Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs.

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.

A case of diffuse large B-cell lymphoma with MYC gene cluster amplification related to chromothripsis

Minoru Kojima , Joaquim Carreras , Yara Yukie Kikuti, Masashi Miyaoka, Tomoki Kikuchi, Jun Amaki, Ai Sato, Daisuke Ogiya, Kiyoshi Ando and Naoya Nakamura Division of Hematology/Oncology Department of Internal Medicine, Tokai University, School of Medicine, Setagaya-ku, Japan; Department of Internal Medicine, Sangenjaya-daiichi Hospital, Isehara, Japan; Department of Pathology, Tokai University, School of Medicine, Isehara, Japan

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.

Human herpesvirus 8-unrelated primary effusion lymphoma-like lymphoma following tyrosine kinase inhibitor treatment for chronic myelogenous leukemia

A 69-year-old man was diagnosed with chronic myelogenous leukemia (CML) and treated with dasatinib. After two years on dasatinib, the patient achieved complete molecular response, but dasatinib treatment was discontinued due to exacerbation of pleural effusion. Nilotinib and imatinib were started but stopped due to an increase in pleural effusion. Thoracentesis was performed and he was diagnosed with human herpesvirus 8-unrelated primary effusion lymphoma (PEL)-like lymphoma. Complex chromosomal abnormality, including BCL6 rearrangement, was found on chromosome analysis. To the best of our knowledge, this is the first report of PEL-like lymphoma following tyrosine kinase inhibitor treatment for CML.

The formation of an aberrant PAX5 transcript in a patient with mixed phenotype acute leukemia harboring der(9)t(7;9)(q11.2;p13)

We experienced the case of a 56-year-old male with B-lymphoid/myeloid lineage mixed phenotype acute leukemia (MPAL). A cytogenetic analysis of the patients bone marrow revealed a complex karyotype, including der(9)t(7;9)(q11.2;p13). We identified an aberrant PAX5 transcript, including the exons 1A to 5 and the contiguous intron 5/6 sequence using the 3′ rapid amplification of cDNA ends-polymerase chain reaction method, and confirmed their expression in the leukemic cells. Our case suggests that der(9)t(7;9)(q11.2;p13) can cause the truncation of the PAX5 transcript, which is supposed to contribute to the generation of MPAL, in addition to three previously reported types of PAX5 fusion.