Mitsuyuki Nagano

Emmprin, a cell surface inducer of matrix metalloproteinases (MMPs), is expressed in T-cell lymphomas.

Degradation of the extracellular matrix by matrix metalloproteinases (MMPs) is a crucial step in tumour invasion and metastasis. In human carcinomas, tumour cell–fibroblast interactions (TFIs) have been demonstrated to play a role in the up‐regulation of MMP levels in tumours, and emmprin is a surface molecule on tumour cells that stimulates nearby fibroblasts to produce MMP‐1, 2, and 3. T‐cell lymphomas frequently show extranodal organ involvement and skin invasion, but a role for TFIs in their invasion has not been examined in detail. This study investigated TFIs in T‐cell lymphomas with special reference to emmprin expression and MMP production. Immunohistochemically, only germinal centre cells and some histiocytes expressed emmprin in non‐neoplastic lymph nodes (ten cases), while all T‐cell lymphomas [14 cases of adult T‐cell leukaemia/lymphoma (ATLL), six cases of lymphoblastic lymphoma, seven cases of anaplastic large cell lymphoma, and nine cases of angio‐immunoblastic T‐cell lymphoma] expressed emmprin strongly and diffusely. FACS analysis of peripheral blood from normal individuals revealed that small fractions of B‐cells, T‐cells, and monocytes expressed emmprin, whereas emmprin‐expressing T‐cells were much increased in number, and expressed this protein to a higher level, in ATLL patients. In vitro co‐cultures of emmprin‐positive HTLV‐1‐transformed lymphocytes (MT‐2) and emmprin‐negative human fibroblasts enhanced the production of pro‐MMP‐2 (gelatinase A) and active MMP‐2, compared with cultures of either cell type alone. This stimulation was inhibited by an activity‐blocking peptide against emmprin. Moreover, in histopathological sections from patients with ATL skin involvement, MMP‐2 was demonstrated in fibroblasts around infiltrating ATL cells, but not in fibroblasts in non‐diseased areas. In conclusion, emmprin is overexpressed by T‐lymphoma cells, when compared with normal counterparts, and facilitates MMP‐2 production via interactions with fibroblasts, which could play a role in stromal invasion by lymphoma cells. Copyright

Successful treatment of a patient with cardiac lymphoma who presented with a complete atrioventricular block

A patient with primary cardiac lymphoma, which is very rare, generally is regarded to have a poor prognosis. We herein report a patient with cardiac lymphoma who was treated successfully by systemic chemotherapy and radiotherapy using a pacemaker to control the complete atrioventricular (A‐V) block. A 70‐year‐old man had a syncope caused by a complete A‐V block. An echocardiogram, a computed tomographic scan, and magnetic resonance imaging of his chest showed a cardiac tumor. At this time, a biopsy of the cardiac tumor disclosed malignant lymphoma (diffuse large cell type, B cell type). The patient was thus treated with systemic chemotherapy and radiotherapy and, as a result, achieved a complete remission with a disappearance of the A‐V block. Recently, several successful outcomes involving primary cardiac lymphoma have been reported because of the progress in diagnostic techniques including echocardiography, computed tomographic scanning, and magnetic resonance imaging, as well as improvement in the therapy of malignant lymphoma. Our clinical experience indicated that an early and accurate diagnosis combined with the appropriate therapy can thus help in obtaining a long survival in patients with primary cardiac lymphoma. Am. J. Hematol. 59:171–174, 1998.

Jumping translocation of homogeneously staining region and tetraploidy with double minutes in acute myelomonocytic leukemia.

We report a 71-year-old patient with acute myelomonocytic leukemia (AMMoL) who had complicated chromosomal abnormalities showing diploidy with a jumping translocation of a homogeneously staining region (hsr) and tetraploidy with double minutes (dmin). The analysis of gene amplification showed that hsr and dmin were the results of C-ETS 1 gene amplification. After induction chemotherapy, tetraploidy with dmin completely disappeared, while diploidy with hsr and del(11)(q23) remained until the patient died. It is speculated that hsr is more stable than dmin during chemotherapy and that the presence of tetraploidy is not necessarily a factor of poor response to chemotherapy for acute leukemia.

High occurrence of primary malignant neoplasms in patients with adult T‐cell leukemia/lymphoma, their siblings, and their mothers

Attempts were made to clarify the correlation between human T‐cell leukemia/lymphoma virus (HTLV)‐1 infection and malignant oncogenicity other than adult T‐cell leukemia/lymphoma (ATL) in a case–control study.

T-stem cell leukemia/lymphoma with both myeloid lineage conversion and T-specific δ recombination

We evaluated retrospectively the clinical and biological characteristics of six patients with CD7+ early T-acute lymphoblastic leukemia and lymphoma (T-ALL/LBL) originating from prothymocyte stage I (pro-T I) or II cells. Patients exhibited mediastinal mass (five of six) and lymphoadenopathy (five of six) but without leukocytosis and circulating blast cells (six of six). All patients achieved a complete remission. All but one had a relapse with a transformation to the mixed type (triphenotype--three cases, biphenotype-two cases) including myeloid features in three patients. The altered phenotypes were myeloperoxidase (MPO)+ (three of five), CD13+ (four of five), CD33+ (three of five) and CD19+ (three of five). The difference for MPO-positivity were observed between the bone marrow (BM)- and lymph node (LN)-blast cells (three of three). On cytogenetic analysis, there is no common abnormality in these patients. Immunomolecular analysis revealed T-cell lineage specific delta gene rearrangements [D delta 2-J delta 1 (five of six) and V delta 1-J delta 1 (one of six)] in all cases. Furthermore, D delta 2-J delta 1 occurred even in the cases with the pro-T I phenotype. Rearrangements of TCR beta, gamma or immunoglobulin heavy chain genes occurred in three patients. The same rearranged band(s) appeared at both diagnosis and relapse, indicating the same originality of the pro-T leukemic cell clone (three of three). We suggest that this type of CD7+ early T-ALL/LBL was transformed from a pro-T I or II cell, such as T-stem cell leukemia/lymphoma, which is a subtype of CD7+ stem cell leukemia as defined by Kurtzberg et al. This study reveals that pro-T I and II cells might be capable of myeloid, T- and B-lymphoid differentiation, and T-cell lineage specific TCR delta recombination occurs.

Clonal dissemination of T‐lymphocytes in scid mice from familial hemophagocytic lymphohistiocytosis

BACKGROUND Although familial hemophagocytic lymphohistiocytosis (FHL) has been considered a disorder of T-cell dysfunction, there is no evidence of the clonal origin of T-cells in this disease. PROCEDURE We engrafted mononuclear cells (MNCs) from five FHL patients into scid mice and examined the infiltration of human cells in mouse organs. The characterization of human cells that infiltrated in the mouse organs was then performed. RESULTS A diffuse infiltration of human lymphoid cells was detected in scid mice treated with 1 x 10(6) MNCs from one of the five patients. These cells were positive for HLA-DR and CD3, but negative for CD4, CD8, CD20, and CD68, suggesting the infiltration of double negative (DN) T-cells. The MNCs from the other four patients induced murine lymphoma-like disease; T-cell lymphoma in one and lymphoma of unknown origin in three. The characterization of these human DN T-cells was performed. The analysis of the Vbeta repertoire showed no preferential usage of the Vbeta family in MNCs, while the dominant expression of Vbeta13 was detected in T-cells infiltrating in the spleen and lung. A Jbeta analysis showed the restricted usage of Jbeta1.2 for Vbeta13 in these cells, and the clonality of Vbeta13-Jbeta1.2 fragment was confirmed by a single-strand confirmation polymorphism analysis. The analysis of the Valpha repertoire showed that Valpha24 was exclusively used in these DN T-cells, but no usage of JalphaQ for Valpha24 was observed. CONCLUSIONS A clonal expansion of T-cells was induced in scid mice by the engraftment of MNCs from an FHL patient. The infiltration of DN alphabeta T-cells bearing invariant Valpha24 T-cell receptor in mouse organs may provide a useful clue to the pathogenesis of FHL. In the patients whose MNCs induced murine lymphoma-like disease, some cytokines or unknown factors that stimulate the growth and the tumorigenicity of murine lymphocytes might be produced by the MNCs engrafted in scid mice. Further study is needed to confirm the validity of our experimental approach and the findings observed in scid mice by using more FHL samples.

Epstein-Barr virus (EBV)-induced B-cell proliferative disorder after chemotherapy in a patient with hemophagocytic lymphohistiocytosis with associated EBV-induced T-cell proliferation.

We report a case of Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD) which developed after chemotherapy for hemophagocytic lymphohistiocytosis (HLH), who had no history of immunodeficiency or familial X-linked LPD. In HLH, the presence of EBV in T-cells was confirmed by a combination of in situ hybridization (ISH) and immunostaining. Southern blot analysis using EBV-TR and immunoglobulin JH probes revealed oligoclonal proliferation of B-cells in each organ involved by abnormal B-lymphoid cells at autopsy. Combined ISH and immunostaining disclosed the presence of EBV in proliferating B-cells. Cytokine analysis during the period of T-cell activation in HLH revealed marked elevation of interferon (IFN) m¨, interleukin (IL)-10 and soluble IL-2 receptor (sIL-2R) and mild to moderate increases of tumor necrosis factor (TNF)-α were observed, while IFNm`, IL-10 and sIL-2R were elevated initially during the HLH phase, which then decreased as LPD developed and B-cell proliferation predominated. Immunosuppressive chemotherapy for HLH may then have allowed latent EBV in B lymphocytes to induce transformation and oligoclonal proliferation of B-cells, finally resulting in LPD. Mechanisms of EBV-induced cell proliferation remain unclear, but alteration of various cytokines may be responsible for it.

Effect of chemotherapy and stem cell transplantation on T lymphocyte clones in familial haemophagocytic lymphohistiocytosis

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare disorder in infancy, curative only by an allogeneic stem cell transplantation (SCT). We recently confirmed the clonal evidence of T cells in FHL. To confirm the effect of chemotherapy and SCT in FHL, the change of T‐cell clones was analysed in two patients using inverse reverse transcription‐polymerase chain reaction (RT‐PCR) of the T‐cell receptor variable region (TCR V) gene, followed by PCR for the junctional region (Jβ‐PCR), a single‐strand conformation polymorphism (SSCP) and sequencing analysis at diagnosis, after chemotherapy and after SCT. A high frequency (> 15%) of αβ T‐cell clones and a predominant bias (Jβ1:Jβ2, 85:15) for the Jβ1 subgroup were observed in the two patients at diagnosis. In one patient, however, an inverted predominant bias (Jβ1:Jβ2, 9:91) for the Jβ2 subgroup and oligoclonal expansion were observed at relapse after chemotherapy. In the other patient, correction of both restricted Jβ cluster usage and variation of TCR were observed after chemotherapy and SCT. Using sequence analysis, the clonal T cells detected at diagnosis were found to be substituted at low frequency (< 0.75%) by several new clones after chemotherapy and SCT. These results indicate that any genetic defect could influence the regulation of the T‐cell network, and normalization of both the variation in each Vβ repertoire and the Jβ1/Jβ2 ratio is needed to achieve remission, and might support the rationale that the only acceptable curative therapy of FHL is allogeneic SCT.

Hemorrhage from abdominal non-Hodgkin's lymphoma treated successfully by emergency transcatheter arterial embolization.

A 49‐year‐old Japanese woman with follicular lymphoma who presented with severe abdominal and back pain is reported. She was known to have malignant lymphoma and had been previously treated with combination chemotherapy. An abdominal tumor occurring at the root of the mesentery and involving the superior mesenteric artery (SMA) had been diagnosed by computed tomography (CT), magnetic resonance imaging, and abdominal angiography. Emergent ultrasonography and CT findings showed intraperitoneal bleeding from the abdominal tumor. Selective SMA angiography revealed extravasation from a small branch originating from the dorsal pancreatic artery, which was embolized through a catheter by using platinum coils. It should be noted that a large tumor of malignant lymphoma, involving large vessels, may bleed, and in such a case selective transcatheter arterial embolization may be one of the effective modalities for hemostasis.

Pregnancy complicated with pure red cell aplasia: a case report.

Abstract A 31-year-old Japanese pregnant woman had no remarkable previous medical and family histories except for artificial abortion in 1993. A full-term normal infant was subsequently delivered in 1998. In this pregnancy, she began to experience general fatigability with a hemoglobin concentration of 8.5 g/dl at 19 weeks of gestation. Although she had been treated with intravenous iron, the hemoglobin decreased to 6.0 g/dl. She was referred to our hospital at 34 weeks of gestation. The laboratory data were as follows on this admission; hemoglobin 5.1 g/dl, RBC 128 × 104/l, reticulocytes 1.1%, WBC 7.1 × 109/l, platelet count 229 × 109/l, folic acid 5.6 ng/ml, serum vitamin B12 200 pg/ml, ferritin 184 ng/ml, parvovirus B19 (−). A bone marrow aspiration revealed normal granulopoiesis and megakaryocytes, but almost complete absence of erythropoietic precursors. A diagnosis of pure red cell aplasia was made due to these findings. Treatment with prednisone (50 mg/day) and blood transfusion was started before delivery. She was delivered transvaginally at 37 weeks of gestation. The neonate was a normal female infant without anemia (hemoglobin 17.9 g/dl) and the 1 minute Apgar score was 8. Her hemoglobin level rose to 12.1 g/dl spontaneously two weeks after delivery.