Susumu Konda

Sweet's syndrome during therapy with granulocyte colony-stimulating factor in a patient with aplastic anaemia

Summary. A patient with aplastic anaemia developed Sweets syndrome (a febrile neutrophilic dermatosis) during granulocyte colony‐stimulating factor (G‐CSF) therapy. Three repeated episodes of appearance and disappearance of erythematous nodules after administration and withdrawal of G‐CSF confirmed that G‐CSF induced Sweets syndrome in the patient. Sweets syndrome has been reported in patients with myelodysplastic syndrome and acute leukaemia, but not in patients with aplastic anaemia. This is the first report of a patient with aplastic anaemia who developed G‐CSF‐induced Sweets syndrome.

Non-IgM monoclonal gammopathy in patients with Sjögren's syndrome

Two Japanese patients with Sjögrens syndrome with non-immunoglobulin M(IgM) class monoclonal gammopathy are described. The monoclonal IgA lambda detected in the serum and saliva was confirmed to possess rheumatoid factor activity in the first patient with a hypergammaglobulinemic purpura and hyperviscosity syndrome. Idiotype specificity was present on the surface membrane of peripheral blood lymphocytes as well as in the cytoplasm of infiltrating cells in the salivary glands. Common idiotypic specificity was found in four of 60 other patients who had rheumatoid factors. In the serum and saliva of the other patient, a monoclonal immunoglobulin G, kappa type (IgG kappa), was detected. Kappa type IgG was found in most of the infiltrating cells in the salivary glands and also in the saline extract from a resected submandibular gland. Our findings indicate that non-IgM class monoclonal gammopathy is also one of the complications of Sjögrens syndrome.

A high incidence of rheumatoid factor idiotypes in monoclonal proteins in the serum and in lymphoma cells in patients with Sjögren's syndrome

Patients with Sjögrens syndrome (SS) develop lymphoproliferative disorders such as monoclonal gammopathies and non-Hodgkins lymphomas. Cross-reactive idiotypes (CRI) were studied in 22 serum monoclonal immunoglobulins (Igs) and in cytoplasmic Ig in four B-cell lymphoma cells in patients with SS. This was done by utilizing monoclonal anti-idiotypic antibodies which were produced against monoclonal rheumatoid factors (RF) derived from three patients with SS and one patient with Waldenströms macroglobulinemia. By the Western blotting or dot immunobinding technique, CRI was detected not only in monoclonal RFs but in monoclonal Igs which had different heavy- or light-chains from the original monoclonal RF used for immunization. A higher incidence of CRI was found in 22 monoclonal Igs associated with SS than in 27 monoclonal Igs in patients with Waldenströms macroglobulinemia, multiple myeloma or malignant lymphoma. In four patients with malignant lymphoma associated with SS, three showed one or three CRI in the lymphoma cells, whereas only two out of 20 patients with other malignant lymphoma showed CRI, demonstrating a significant difference between two groups. These data indicate that monoclonal proliferation of B-cell lineage in patients with SS, benign or malignant, takes place more often among RF-producing clones than other B-cell disorders.

Monoclonal gammopathies in Japanese patients with Sjögren's syndrome

We report 10 Japanese patients with Sjögrens syndrome (SS) who developed monoclonal gammopathies (MG). One was of the IgG class, five of IgA, three of IgM, and one of IgG/IgM. The monoclonality of 7 of 10 M proteins was studied using antiidiotypic (Id) antibodies against M proteins. Four (three IgA and one IgM) of 10 M proteins had rheumatoid factor (RF) activity. Hemagglutination inhibition tests and enzyme-linked immunosorbent assays (ELISA) showed that the RF activity was inhibited by anti-Id antibodies in all four monoclonal RFs. In two patients examined, many cells infiltrating into the salivary glands were stained with anti-Id antibodies. Our review of 19 Japanese SS patients with MG revealed that the non-IgM class predominated (13/19). This contrasts with 19 reported non-Japanese SS patients, among whom 14 were IgM. In both Japanese and non-Japanese patients there was a higher incidence of MG in primary than in secondary SS. The difference in the dominant heavy-chain class may reflect a difference in the genetic factors affecting B cell differentiation in immunologically disordered states.

Interleukin-7 (IL-7)-induced proliferation of CD8+ T-chronic lymphocytic leukemia cells

Interleukin-7 (IL-7) is a growth factor for pro-B cells, pre-B cells, and thymocytes and is known to induce the proliferation of normal human peripheral T cells. Moreover, human B and T acute leukemia cells with immature surface markers proliferate in response to IL-7. Here we describe a case of T-chronic lymphocytic leukemia, in which the leukemic cells showed a proliferative response to human recombinant IL-7in vitro. The patient was a 74-year-old woman with anemia and thrombocytopenia, whose bone marrow was fibrosed and infiltrated with pathologic cells. Surface markers of the leukemic cells were CD2(+), CD3(+), CD5(+), CD7(+), CD8(+), and CD4(−). Both T-cell receptor β-chain and γ-chain genes were found to be rearranged by immunogenotypic analysis. The leukemic cells proliferated in response to IL-7 dose dependently. The DNA synthesis of CLL cells was stimulated by not only IL-7 but also IL-2 and IL-4. The IL-7-induced proliferation was not inhibited by antibodies to IL-2 receptors or the anti-IL-4 antibody. These findings indicate that IL-7 may induce the proliferation of peripheral CD8+ T cells, even on its pathological counterpart.

Lymphoproliferative Disorders in Japanese Patients with Sjögren’s Syndrome

Fourteen Sjögrens syndrome (SS) patients with monoclonal gammopathy (MG), 4 SS patients with malignant lymphoma (ML) and one with pseudolymphoma (PL) were described. Among the 14 MG patients, the IgG class was found in 3, IgA in 6, IgM in 3, and 2 M proteins (IgM/IgG and IgA/IgG) were found in 2 patients. The monoclonal rheumatoid factor (RF) was found in 4 patients (3 IgA and one IgM). Idiotypes (Id) of M proteins were studied in 11 out of 14 patients. The histology of ML showed the diffuse, large cell, medium-sized cell and follicular, mixed cell type. The monoclonal surface membrane Ig (SmIg) and/or cytoplasmic Ig (CIg) were identified (3 IgM and one IgG). A review of the Japanese literature on lymphoproliferative disorders (LPD) in SS patients disclosed additional 15 MG patients (3 IgG, 5 IgA, 6 IgM and one Bence Jones protein) and 22 LPD patients (14 non-Hodgkins ML, 4 PL, 2 plasmacytomas and 2 thymomas). The literature was also reviewed on LPD in non-Japanese SS patients; 26 patients with MG (4 IgG, 2 IgA, 19 IgM and one Bence Jones protein) and 104 patients with LPD (59 non-Hodgkins ML, 4 Hodgkins lymphomas, 23 PL, 5 thymomas, 4 immunoblastic lymphadenopathies (IBL), 2 Lennerts lymphomas and 7 others) were found. These results indicate that non-IgM class MG was more dominant in Japanese than in non-Japanese SS patients and that there was a higher incidence of MG in primary than in secondary SS patients, and also that B cell lymphomas (9 in Japanese and 11 in non-Japanese) were more common in SS patients.

Lymphomatous Polyarthritis in Patients with Peripheral T-Cell Lymphoma

Direct involvement of the joints is a rare complication of malignant lymphoma and lymphoma cells in synovium or synovial fluid have been characterized in only a very few cases. We report two cases of CD4-positive, HTLV-I-negative peripheral T-cell lymphomas that manifested polyarthritis infiltrated with lymphoma cells which we further characterized. Patient 1, with a prior 7-year history of cutaneous T-cell lymphoma (mycosis fungoides) and polyarthralgia, developed pain and swelling in the right knee joint and right femoral region. Patient 2 was initially diagnosed with immunoblastic lymphadenopathy, later rediagnosed as the prodromal stage of T zone lymphoma. Seven years later she developed skin eruptions, cervical lymph node swelling, polyarthritis, and pleural effusion. Synovial fluid analysis in both cases showed predominant CD3+ or cytoplasmic CD3+, CD4+, and CD8- atypical lymphoid cell infiltration. In both cases the T-cell receptor beta and gamma chains were rearranged in the synovial fluid mononuclear cells. Analysis of these two cases and a review of the literature suggest that lymphoma cell infiltration of synovium occurs preferentially in patients with CD4+ peripheral T-cell lymphoma.

A monoclonal surface immunoglobulin (IgM/D-L) with specificity for surface antigen of ox red blood cells in a patient with leukemic lymphosarcoma

A patient with B-cell leukemic lymphosarcoma, whose lymphocytes had a monoclonal (IgM/D-L) surface immunoglobulin (SmIg) and formed rosettes with ox red blood cells (ORBC), is described. The leukemic cells were documented to have a monoclonal SmIg and cytoplasmic Ig (CIg) and secreted a monoclonal immunoglobulin (MIg) whose antibody activity was directed to the surface antigen of ORBC. (i) Pretreatment of the leukemic cells with anti-μ, anti-δ, or anti-λ inhibited E(ox) rosette formation specifically. (ii) Pretreatment of the leukemic cells with pronase removed the SmIg and abolished E(ox) rosette formation simultaneously, and regeneration of the SmIg was parallel with recovery of the rosette formation. (iii) A small amount of serum MIg could be detected by agarose gel electrophoresis and antiidiotypic antibody against the 19 S component of the serum revealed that the monoclonal SmIg, CIg, and serum MIg shared the same idiotope. This case suggests that lymphocytes of some B-cell malignancies may bind to ORBC through SmIg.

Phase III Study of Ranimustine, Cyclophosphamide, Vincristine, Melphalan, and Prednisolone (MCNU-COP/MP) versus Modified COP/MP in Multiple Myeloma: A Japan Clinical Oncology Group Study, JCOG 9301

To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%–53.8%] and to MCNU-COP/MP was 56.1 % (95% CI, 46.1 %–65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9–25.8] versus 15.8 months [95% CI, 14.1–19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95% CI, 32.8–59.8]) ( P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival.

Ultrastructural observations on the cytomegalic inclusion cell in peripheral blood

A 31-year-old woman with adult T-cell leukemia developed interstitial pneumonitis. Large abnormal cells different from those of adult T-cell leukemia appeared in the peripheral blood. Hematoxylin-eosin staining of the buffy coat of peripheral blood revealed these cells to be cytomegalic inclusion cells. Electron microscopy disclosed cytomegalovirus particles in these inclusion cells. Virus particles were seen in both the nuclei and cytoplasm. Dense bodies characteristic of cytomegalovirus infection were also seen in the cytoplasm. This is the first report of cytomegalovirus particles found in the peripheral blood mononuclear cells.