Shohei Yokota

Successful treatment with Erwinia L-asparaginase for recurrent natural killer/T cell lymphoma.

We describe a patient with natural killer (NK)/T cell lymphoma who relapsed after autologous peripheral blood stem cell transplantation (auto-PBSCT) and was successfully treated with Escherichia coli (E. coli ) and Erwinia l -asparaginase. A 38-year-old male patient with ulcerated tumor at the left thigh was diagnosed as having nasal type NK/T cell lymphoma on the basis of histopathological and flowcytometric findings of tumor, revealing diffuse infiltration of atypical lymphoid cells into blood vessels and expression of CD7 and CD56 antigens, but not CD3. He had tumor infiltration in the bone marrow and at the right lower lung field. After five cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) therapy, the patient achieved complete remission and received high-dose chemotherapy with auto-PBSCT, although the tumor recurred in the right leg 10 months later. Despite salvage chemotherapy, followed by local irradiation and surgical amputation, a tumor recurred at the left upper gingiva 10 days after. Using E. coli l -asparaginase (6000 U/m 2 /day), the tumor regressed, fever was alleviated and the serum lactate dehydrogenase decreased to normal range after several days. The asparagine synthetase expression in tumor cells was immunohistochemically negative on paraffin-embedded tissues. Because of the anaphylactoid reaction developing after E. coli l -asparaginase, alternative Erwinia l -asparaginase (6000 U/m 2 /day) was administered, resulting in regression of tumor and fever lysis. l -asparaginase is a promising agent for the treatment of NK/T cell lymphoma.

The unbalanced 1;7 translocation in de novo myelodysplastic syndrome and its clinical implication

In our chromosome study of 97 patients with myelodysplastic syndrome (MDS), six showed an unbalanced translocation between chromosomes 1 and 7 [−7, +der(1)t(1;7)(p11;p11)]. All of them had morphologic myelodysplasia in trilineage of bone marrow cells, and cytopenia was the major finding in the peripheral blood. All six patients had symptoms of infection at the time of diagnosis, and five showed immunologic abnormalities (polyclonal hypergammaglobulinemia in four and increased marrow plasma cells in three). None of the patients survived more than 11 months after the diagnosis; the median survival time was 4 months. Both of the two patients whose karyotypes were reexamined in the course of their disease showed karyotypic evolution accompanying the coincidental leukemic transformation. Six patients with MDS who had the same chromosome abnormality [t(1;7)] are described and their characteristic clinical features are presented.

Interphase detection of immunoglobulin heavy chain gene translocations with specific oncogene loci in 173 patients with B-cell lymphoma

To detect immunoglobulin heavy chain (IGH) gene translocations with specific oncogene loci, we established an interphase cytogenetic approach using double-color fluorescence in situ hybridization (DC-FISH), which we used to analyze 173 patients with B-cell lymphoma. DC-FISH using the IGH gene (14q32.3) in combination with c-MYC (8q24.1), BCL1 (11q13.3), BCL2 (18q21.3), BCL6 (3q27), and PAX-5 (9p13) gene probes detected IGH translocations in 70 (40.5%) of 173 patients. The partner genes involved in IGH translocations were identified in 56 (80%) of 70 patients, and fusion of the IGH gene with specific oncogenes was detected in 53 of 56 patients, particularly in interphase nuclei of 28 patients for whom cytogenetic analysis was not informative. The most common partner gene was BCL2 (19 patients; 27% of IGH translocation-positive patients), followed by BCL6 (16; 23%), BCL1 (11; 16%), c-MYC (7; 10%), and PAX-5 (2; 3%). These oncogenes were closely associated with subtypes of B-cell lymphoma. The other partners were 19q13 (BCL3), 6p25 (MUM1/IRF4), 1q36, and chromosome 8 identified in one patient each. Six of the nine patients with add(14)(q32) showed a BCL6/IGH translocation. Double translocations of the IGH gene were found in three patients; c-MYC+BCL1, c-MYC+BCL2, and c-MYC+BCL6 in each one. Interphase FISH using specific IGH-translocation probes is valuable for defining clinically meaningful subgroups of B-cell lymphoma.

An additional segment at 1p36 derived from der(18)t(14;18) in patients with diffuse large B-cell lymphomas transformed from follicular lymphoma

The particular translocation in follicular lymphomas (FLs) is a t(14;18)(q32;q21), recombining the immunoglobulin heavy chain (IgH) gene on chromosome 14 with the B-cell leukemia/lymphoma 2 (BCL2) gene on chromosome 18. Some low-grade FLs are aggressively transformed into diffuse large B-cell lymphomas, presumably by acquisition of secondary chromosomal changes, including chromosomal band 1p36. A common example is add(1)(p36). Because it is difficult to identify the origin of add(1)(p36) even on high-resolution G-banding analysis, we used spectral karyotyping (SKY) and double-color fluorescence in situ hybridization (DC-FISH) to define the t(14;18) and the extra band at 1p36 in two cases of diffuse large B-cell lymphoma (DLBCL). SKY revealed that the extra chromosomal segment on 1p36 was derived from chromosome 18. DC-FISH defined BCL2/IgH fusion signals at 1p36 in addition to t(14;18), suggesting that BCL2/IgH fusion at 1p36 was an evolutionary alteration following the primary BCL2/IgH translocation on der(18) in both cases. Our results indicate that IgH alleles, implicated in chromosomal rearrangement, may themselves frequently be targets for secondary translocations, suggesting that multiple IgH translocations and insertions are associated with the progression of FL.

Close pathogenetic relationship between ocular immunoglobulin G4-related disease (IgG4-RD) and ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma

Immmunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic sclerosing inflammatory disease characterized by mass-forming lesions such as swelling, nodules or hypertrophy in one or more organs...

Cytogenetic analysis of de novo CD5-positive diffuse large B-cell lymphoma.

Aims:  De novo CD5‐positive diffuse large B cell lymphoma (CD5+DLBL) is a subtype of DLBL with poor clinical outcome. To investigate the cytogenetic pathogenesis of CD5+DLBL, we analyzed the chromosomal findings of 18 patients with CD5+DLBL.

Multiple bone lesions after allogeneic bone marrow transplantation in a patient with relapsed adult acute lymphoblastic leukemia: minimal residual disease analysis may predict extramedullary relapse.

We describe a patient with acute lymphoblastic leukemia (ALL, L2) who relapsed with multiple bone lesions after allogeneic bone marrow transplantation (allo-BMT). Allo-BMT was performed from an HLA-identical sibling during the first hematological complete remission (CR). Minimal residual disease (MRD) assessed by polymerase chain reaction (PCR) with primers for T cell receptor δ (TCRδ) gene became positive in the bone marrow sample on day 46 after allo-BMT. On day 113, the patient complained of a painful tumor at the right clavicle. The examination of biopsy specimen revealed infiltration of leukemic cells. After partial response was achieved by local radiotherapy, disseminated bone lesions were demonstrated by 99mTC scintigraphy scan, followed by bone marrow relapse on day 137. The patient died of cardiac tamponade on day 236 after Allo-BMT. MRD assessed by PCR assay for TCRδ gene in the bone marrow is useful for the prediction of extramedullary as well as medullary relapse after BMT.

Clonotypic analysis of acute lymphoblastic leukemia with a double TEL-AML1 fusion at onset and relapse

Clonotypic analysis of acute lymphoblastic leukemia with a double TEL-AML1 fusion at onset and relapse

Graft-versus-host Disease Confined Solely to Intestine after Allogeneic Peripheral Blood Stem Cells Transplantation in a Patient with Chronic Myelogenous Leukemia

Abstract We describe a patient with chronic myelogenous leukemia who developing severe intestinal bleeding after allogeneic peripheral blood stem cells transplantation (allo-PBSCT). PBSC were obtained from an HLA one-locus mismatch sibling donor. On day 26 after PBSCT, although there was no sign of graft-versus-host disease (GVHD) in either the skin or the liver, diarrhea and severe intestinal bleeding occurred. The histopathological examination of the colon revealed complete denudation of the epithelial cells of the mucosa and no obvious apoptosis. Neither red cell fragments nor hemorrhagic diathesis was seen during this episode and the patient was diagnosed as having GVHD. Methylpredonisolone followed by FK506 may be effective in controlling intestinal bleeding and was used in our patient. Acute GVHD involving only the intestine has rarely been described but when using HLA-mismatched PBSCs, acute GVHD may occur severely and atypically.

Long-term molecular remission after nonmyeloablative stem cell transplantation in a patient with chronic myelogenous leukemia in the chronic phase.

cytogenetic analysis demonstrated the Philadelphia (Ph) chromosome in 100% metaphases. A diagnosis of CML was made and hydroxyurea at 40 mg/kg and interferon· 2b at 4 MU/m 2 s.c. were initiated until the WBC count was normalized. Afterwards, hydroxyurea was given for at least 10 months, whereas interferon treatment was stopped for 2 months because of the appearance of melancholia. Considering his age, we performed a nonmyeloablative peripheral blood SCT from his HLA-identical brother in November 2001. The conditioning regimen consisted of fl udarabine at 30 mg/m 2 i.v. on days –8 to –3 and busulfan p.o. at 4 mg/kg in divided doses. To prevent graft-versus-host disease (GVHD), cyclosporin A was administered starting on day –1 at 3 mg/kg per day as a continuous intravenous infusion and methotrexate at 10 mg/m 2 i.v. on day 1 and at 7 mg/m 2 i.v. on days 3 and 6. The dose of total CD34+ cells infused was 2.7 ! 10 6 /kg recipient weight. Posttransplant hematological recovery was prompt. Neutrophils reached 6 0.5 ! 10 9 /l by day 11 and platelets 6 50 ! 10 9 /l by day 14. The chimerism evaluated by PCR for microsatellite regions showed that peripheral blood mononuclear cells were 100% donor type on day 58. Cytogenetic analysis of bone marrow asSeveral groups have explored a nonmyeloablative conditioning regimen for patients ineligible for myeloablative stem cell transplantation (SCT). The use of nonmyeloablative regimens reduces the risk of treatment-related toxicity and can extend the use of allotransplantation for older patients [1] . This approach allows engraftment and generation of graft-versus-leukemia effects. Nonmyeloablative SCT for chronic myelogenous leukemia (CML) is being evaluated in this context and may successfully replace myeloablative SCT [2] . We successfully performed a nonmyeloablative SCT in an elderly patient with chronic phase CML, who had been forced to stop interferon· because of side effects. A 57-year-old man with a cough and fever was admitted in January 2001. The physical examination did not reveal hepatosplenomegaly. His peripheral blood cell count revealed Hb 10.7 g/dl, platelets 2,056 ! 10 9 /l, WBC 74.21 ! 10 9 /l, myeloblasts 2.5%, promyelocytes 1.0%, myelocytes 5.0%, metamyelocytes 12.0%, bands 24.5%, segments 27.5%, eosinophils 10.0%, basophils 10.0%, monocytes 2.0%, and lymphocytes 5.0%. Bone marrow aspirate showed hypercellularity (nucleated cell count 480 ! 10 9 /l), increased to a 66.0% myeloid lineage with 8.0% eosinophils and 8.8% basophils. Bone marrow Received: November 17, 2003 Accepted after revision: April 5, 2004