Eijiro Oku

Periostin and bone marrow fibrosis

Periostin is a secreted protein that shares structural homology with the insect axon guidance protein fasciclin 1. Periostin is expressed predominantly in collagen-rich fibrous connective tissues that are subjected to constant mechanical stresses. We have shown previously that periostin is a novel component of subepithelial fibrosis in bronchial asthma. Here, we investigated the relationship between periostin and bone marrow (BM) fibrosis. Periostin was expressed in the stroma and stromal cells of BM fibrosis specimens and to a great extent its expression levels correlated closely to the grade of fibrosis, as estimated by silver staining. However, in the present study, we found no relationship between plasma periostin levels and the extent of BM fibrosis. We also demonstrated that periostin is secreted by human BM hTERT stromal cells and that its secretion is enhanced by TGF-β, a cytokine produced by clonal proliferation of megakaryocytes and/or monocytes. These results indicate that periostin is a component of BM fibrosis and that it may play a role in the disease progression.

A Case of 8p11 Myeloproliferative Syndrome with BCR-FGFR1 Gene Fusion Presenting with Trilineage Acute Leukemia/Lymphoma, Successfully Treated by Cord Blood Transplantation

The 8p11 myeloproliferative syndrome is a rare neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene located at chromosome 8p11–12. FGFR1 encodes a transmembrane receptor tyrosine kinase. The resultant fusion proteins are constitutively active tyrosine kinases that drive the proliferation of hematopoietic cells, whose uncontrolled growth can present as a myeloproliferative neoplasm. We report here the case of a 50-year-old man harboring the t(8;22)(p12;q11) chromosomal translocation in cells from both bone marrow and lymph nodes. He presented with acute leukemia and lymphoma with trilineage features. A novel mRNA in-frame fusion between exon 4 of the breakpoint cluster region (BCR) gene at chromosome 22q11 and exon 9 of FGFR1 gene on chromosome 8p11–12 was identified by reverse transcription polymerase chain reaction analysis and was confirmed by DNA sequencing. Because the patient was refractory to chemotherapy, cord blood transplantation was performed in progressive disease. It resulted in a successful outcome in which cytogenetic complete remission has been maintained for 2 years till date.

Characterization of the light chain-restricted clonal B cells in peripheral blood of HCV-positive patients.

To investigate the association between hepatitis C virus (HCV) and B cell proliferation, we searched for the clonal B cells by flow cytometric analysis of the surface immunoglobulin kappa (κ):lambda (λ) light chain ratios of the circulating B (CD19+) cells in 240 HCV-positive patients and 150 negative controls with liver diseases. Clonal B cells with light chain restriction (κ:λ ratio >3:1 or <1:2) were analyzed for CD5 expression and the presence of monoclonal immunoglobulin heavy-chain (IGH) gene rearrangements and the t(14;18) chromosomal translocation. Clonal B cells were detected in 7 cases with HCV (2.9%), but was never detected in the controls (p < 0.05). Of the 7 cases, all had monoclonal IGH gene rearrangements and one had the t(14;18) chromosomal translocation. These HCV-related clonal B cells are not uniform in the intensity of CD5 expression and showed no increase in the frequencies of CD5+ population compared with non-clonal B cells. No “chronic lymphocytic leukemia-phenotype” cells were found. The loss of clonality was observed in 2 cases treated with interferon and in one case treated with splenectomy. The longitudinal study is required to determine whether these circulating clonal B cells progress to lymphoproliferative disorders in future or not.

Simultaneous Hepatic Relapse of Non-Hodgkin’s Lymphoma and Hepatocellular Carcinoma in a Patient with Hepatitis C Virus-Related Cirrhosis

We report a 66-year-old man with hepatitis C virus (HCV)-related cirrhosis and simultaneous hepatic relapse of non-Hodgkin’s lymphoma (NHL) and of hepatocellular carcinoma (HCC). Although the liver is frequently involved by NHL, hepatic colocalization of NHL and HCC is rarely detected by imaging techniques. HCV has been suggested to be lymphotrophic as well as hepatotrophic, and therefore has attracted speculation about a causative role in some cases of lymphoma. The patient had a past history of cutaneous diffuse large B cell lymphoma (DLBCL) in concurrence with HCC 32 months previously. Complete remission (CR) had been maintained for both diseases until February 2004, when ultrasonography and computed tomography (CT) showed multiple liver tumors. Two of these, appearing hyperattenuating in the arterial phase of contrast-enhanced CT, were diagnosed histopathologically as HCC, and treated with radiofrequency ablation. The other tumors, hypoattenuating in the portal phase CT, were diagnosed histopathologically as DLBCL, and treated with cyclophosphamide, tetrahydropyranyl-Adriamycin, vincristine and prednisolone (THP-COP) in combination with rituximab. CR was achieved for both DLBCL and HCC. Given the previously demonstrated immune system tropism and perturbation by HCV, the virus might have contributed to the occurrence of the NHL as well as the HCC.

Promyelocytic crisis of chronic myelogenous leukaemia during imatinib mesylate treatment.

An untreated 66-year-old woman with chronic myelogenous leukaemia (CML) in the chronic phase was initially given imatinib mesylate, rapidly achieving a good cytogenetic response with treatment. However, acute promyelocytic leukaemia complicated by a disseminated intravascular coagulation occurred 9 months after beginning imatinib treatment. Promyelocytic crisis of CML was diagnosed by demonstration of both BCR/ABL and PML/RARα chimeric genes in leukaemic cells by karyotypic and fluorescence in situ hybridization analysis. Clonal evolution with addition of the PML/RARα translocation may have arisen in the early chronic phase of CML, with expansion of this clone during imatinib treatment. Promyelocytic crisis of CML is rare; furthermore, we know of no previous report of promyelocytic crisis occurring during treatment with imatinib.

Successful autologous peripheral blood stem cell transplantation in primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (PCAETCL) is a rare cytotoxic lymphoma marked by an aggressive clinical course and poor prognosis. Although stem cell transplantation (SCT) effectively improves the overall survival rate of patients with high-grade lymphomas, only a small number of patients with PCAETCL have undergone SCT, with merely eight cases reported in the literature [ 1–5 ] . A 38-year-old man presented with a one-year history of multiple ulcerated erythematous lesions across his entire body. His condition had rapidly deteriorated over the previous month. His medical history was remarkable for primary hyperaldosteronism. Physical examination revealed circumscribed ulcers of various sizes (≤ 15 cm in diameter) covering his entire body (Figure 1 a). Laboratory tests showed an elevated white blood cell count of 16,300/ μ L (neutrophils 85.0 %, lymphocytes 5.0 %, atypical lymphocytes 1.0 %) and elevated soluble interleukin-2 receptor levels (732 U/ mL, normal range: < 530 U/mL). Histology of one of the lesions was characterized by an ulceration with atypical lymphocytic infi ltrates in the epidermis, dermis, as well as eccrine ducts and glands (Figure 2 a). Moreover, there were numerous single cell necroses with vacuolar degeneration in the epidermis and eccrine ducts and glands (Figure 2 b). Immunohistochemically, the atypical lymphocytes were positive for CD3, CD8 (Figure 2 c), and TIA-1 (Figure 2 d) but negative for CD4, CD20, and CD30. Southern blot analysis revealed monoclonal T-cell receptor C β 1 gene rearrangement. In situ hybridization of Epstein-Barr virus was negative. Involvement of other organs was ruled out by extensive workup. Based on the aggressive clinical course and the histopathological fi ndings, our patient was diagnosed with PCAETCL. Although etoposide and interferon gamma therapy proved ineffective, complete remission (CR) of PCAETCL was achieved by four courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy (Figure 1 b). It was subsequently decided to employ autologous peripheral blood stem cell transplantation (PBSCT). The patient was given one course of CHASE (cyclophosphamide, cytosine arabinoside, etoposide, and dexamethasone) chemotherapy aimed at mobilizing peripheral blood stem cells for subsequent harvesting. This was followed by two additional courses of CHOP and pretransplant conditioning treatment with MCEC (ranimustine, carboplatin, etoposide, and cyclophosphamide). Autologous PBSCT was eventually carried out seven months after

Donor-derived 47, XXY in an unrelated cord blood transplant recipient

A 65-year-old Japanese male with therapy-related myelodysplastic syndrome was admitted for unrelated cord blood transplantation. A cord blood unit from a male donor was obtained from the Japan Cord Blood Bank Network. The patient then received a conditioning regimen consisting of fludarabine, intravenous busulfan, and total body irradiation. Successful engraftment was obtained. The bone marrow examination on day 28 revealed trilineage engraftment, and chimerism analysis by variable number of tandem repeat polymerase chain reaction confirmed complete donor chimerism. At that time, conventional cytogenetics of the bone marrow aspirate showed 20 out of 20 metaphases with the 47, XXY karyotype characteristic of Klinefelter syndrome. Klinefelter syndrome is the most common genetic cause of human male infertility with a reported prevalence of 0.1–0.2% in the general population. In Japan Cord Blood Bank Network, there is no informed consent from parents about the possibility that post-unrelated cord blood transplantation patient evaluation may reveal donor-origin inherited diseases including cytogenetic abnormality. It is desirable to have opportunities in Japan discussing whether parents will be notified of the possibility that post-unrelated cord blood transplantation evaluation may reveal donor-derived illness incidentally.

Hematopoietic stem cell transplantation in advanced cutaneous T-cell lymphoma

We retrospectively reviewed data pertaining to five patients with cutaneous T‐cell lymphoma (CTCL) who had received hematopoietic stem cell transplantation (HSCT) between 2004 and 2015 at Kurume University Hospital, along with their clinical data until March 2016. For patients with advanced CTCL eligible for HSCT, autologous HSCT was performed when they responded well to chemotherapy, and allogeneic HSCT was selected for patients with advanced mycosis fungoides (MF)/Sézary syndrome (SS) and CTCL other than MF/SS with poor chemosensitivity. Two patients (primary cutaneous anaplastic large cell lymphoma and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T‐cell lymphoma) who responded well to chemotherapy received autologous HSCT: one patient was alive in partial remission and the other died due to therapy‐related acute myeloid leukemia without disease relapse. In the remaining three patients with MF or SS, allogeneic HSCT was performed. Although one patient with MF died due to disease progression, the remaining two patients were alive in complete remission. Although there were two deaths in this study, the outcomes were considered satisfactory.