Atsushi Notoya

Pulmonary veno-occlusive disease following allogeneic peripheral blood stem cell transplantation for chronic myeloid leukaemia

A 49-year-old Japanese woman was admitted to our hospital on 23 July 1998 because of leucocytosis noted at a medical check. Her leucocyte and platelet counts were 14Æ1 · 10 ⁄ l and 637 · 10 ⁄ l respectively. She was diagnosed as having chronic myelogenous leukaemia (CML) based on the presence of a Philadelphia chromosome (Ph), and a BCR–ABL fusion gene was demonstrated. She was initially treated with interferon-a but became depressed. After 6 months of interferon-a, allogeneic peripheral blood stem cell transplantation (PBSCT) was carried out. Her human leucocyte antigen (HLA)-matched sister was treated with 300 lg of granulocyte colony-stimulating factor (G-CSF) for 6 d, and 119Æ25 · 10 of CD34-positive cells (2Æ93 · 10 ⁄ kg of recipient body weight) were obtained. After high-dose cyclophosphamide (60 mg ⁄ kg ⁄ d for 2 d) and total body irradiation (2 Gy twice daily for 3 d), PBSCT was performed on 18 March 1999. She received a short course of methotrexate and daily cyclosporin A to suppress acute graft-versus-host disease. Four days after PBSCT, 300 lg of G-CSF was administered, and her leucocyte and platelet counts improved. Her blood type changed to that of her sister and the BCR–ABL gene was no longer demonstrated by reverse transcriptase polymerase chain reaction. On 2 September, she complained of dyspnoea after walking. Her blood gas analysis showed severe hypoxia (PaO2 56Æ1 torr, SaO2 90%, PaCO2 32Æ0 torr). A computerized tomography scan of her thorax suggested decreased blood flow in both lower lobes of her lungs. Pulmonary blood perfusion scintigraphy confirmed this (left). Pulmonary digital subtraction angiography showed no thrombus-associated obstruction, but a reduction of blood flow in this area (right). A diagnosis of pulmonary veno-occlusive disease (PVOD) was made, and she was treated with pulse steroid therapy. Although her hypoxia improved transiently, she developed pneumonia and died of acute renal failure 1 month later. An autopsy showed severe pneumonia but the pulmonary vessels were normal. Although PVOD is very rare, it should be recognized as an important reversible complication of stem cell transplantation.

Liver dysfunction due to apoptosis in a patient with systemic lupus erythematosus

We report on a 23-year-old Japanese female with a 13-year history of systemic lupus erythematosus (SLE), and two episodes of deterioration followed by treatment with high dose prednisolone. Although she had been recently treated with prednisolone (12.5 mg daily), her liver function became worse in July 1998. Results of a liver biopsy revealed multi-focal hepatic cell death in a severe fatty liver, without any inflammatory cell invasion. The biopsy also showed a positive TUNEL (Tdt-catalysed DNA nick end labelling) reaction indicating apoptosis. Her liver function recovered rapidly following steroid pulse therapy. Serum soluble Fas ligand (sFasL) was found to be elevated to a concentration of 0.395 ng/ml at the time of liver damage, but was less than 0.03 ng/ml before liver damage and after prednisolone treatment. The liver damage in this case appeared to be involved with apoptosis induced by sFasL. Although hepatitis associated with SLE is rare, apoptosis directly related to elevated sFasL levels might cause this complication.

Rheumatoid arthritis complicated with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis: a case report.

This article describes a patient with rheumatoid arthritis (RA) with crescentic glomerulonephritis (CrGN) associated with myeloperoxidase–antineutrophil cytoplasmic antibodies (MPO-ANCA), who responded well to methotrexate (MTX). A 48-year-old woman with a 4-year history of RA was admitted with fever and elevated C-reactive protein. On laboratory evaluation, her level of MPO-ANCA was 422 EU, and urinalysis revealed proteinuria and hematuria. Because she was also suffering from episcleritis, vasculitis was considered. A renal biopsy was performed, which revealed necrotizing CrGN. We diagnosed RA complicated with MPO-ANCA-associated vasculitis. We considered treatment with high-dose oral prednisolone for vasculitis, but the patient refused this treatment. We started MTX at a dose of 8 mg/week for RA from the time of admission, and the patient responded immediately. Biochemical parameters, including C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and MPO-ANCA, improved. Seven months later, MPO-ANCA had decreased to 46 EU. In clinical studies, few patients have been reported with RA complicated with ANCA-associated CrGN. This case differs from previous cases in the treatment given. No high-dose steroid with intensive immunosuppression or plasma exchange was required.

Angioimmunoblastic T-cell lymphoma with renal involvement: a case report of direct bilateral kidney invasion by lymphoma cells.

A few cases have been reported of renal failure associated with angioimmunoblastic T-cell lymphoma (AILT) [1, 2], but no case has been described showing direct invasion of the kidneys. To our knowledge, this is the first case report showing direct invasion of the kidneys by lymphoma cells in AILT. A 73-year-old Japanese man was hospitalized because of urticaria and malaise in June 2002. His physical examination showed bilateral inguinal lymphadenopathy. Laboratory evaluations were as follows: WBC 5.8×10/l, erythrocytes 3.55×10/l, hemoglobin 11.5 g/dl, platelet count 28.7×10/l, total serum protein 10.9 g/dl with polyclonal hypergammaglobulinemia, albumin 2.6 g/dl, IgG 5101 mg/dl, IgA 175 mg/dl, IgM 242 mg/dl, LDH 305 IU/l, serum creatinine 1.5 mg/dl, creatinine clearance 32.4 ml/min, C-reactive protein (CRP) 0.33 mg/dl, erythrocyte sedimentation rate 117 mm/h, soluble interleukin-2 receptor 2440 U/ml, and interleukin-6 (IL-6) 4.3 pg/ml. Bone marrow aspiration results were as follows: NCC 5.9×l0/μl, MgK 43.75/μl, M/E 2.7, blasts 1.5%, lymphoma cells 0%, and a normal karyotype: 46, XY. The computed tomography (CT) image of the abdomen showed no significant abnormalities including the kidneys. Gallium scintigraphy (Ga) showed bilateral uptake in the kidneys and a bilateral presence in the inguinal lymph nodes (Fig. 1a). These findings suggested interstitial nephritis due to an autoimmune episode. The biopsy of the inguinal lymph node showed a loss of normal architecture with the presence of a few depleted follicles in the cortical area. The interfollicular area of the node showed polymorphic infiltrates of lymphocytes, transformed lymphoid blasts, plasma cells, and macrophages with an increased number of high endothelial venules. Immunohistochemistry showed expansion of the interfollicular areas by a diffuse infiltration of CD3+ T cells. A renal biopsy revealed diffuse parenchymal invasion of atypical CD3+ cells. Electron microscopy revealed no glomerulonephritis, and no electron dense deposits were demonstrated. He was diagnosed as having AITL with renal invasion, and chemotherapy was started. Three months later, Ga showed no uptake in the kidneys and inguinal lymph nodes (Fig. 1b). Complete remission (CR) was achieved, and he had no recurrence at 20 months follow-up. The incidence of renal involvement in patients with non-Hodgkin’s lymphoma (NHL) is reported to range from 2.4 to 14% [3, 4]. In a clinical study by Morel et al., renal involvement diagnosed by CT scan or histological examination was reported [5]. Among the 48 patients with renal involvement, histology showed diffuse large cell lymphoma in 60% of the patients and AITL in none. Multiple intraparenchymal nodules, direct spread into the kidney from a perirenal mass, and single intraparenchymal nodules were demonstrated, with diffuse infiltration observed in 19% of the patients. After treatment with chemotherapy, CR was achieved in 57% of the patients. The estimated 4-year disease-free survival was 39%. AILT is a lymphoma characterized by systemic disease, and laboratory findings frequently manifest as a polyclonal hypergammaglobulinemia with circulating immune complexes. In clinical studies, some patients show renal failure associated with AILT [1, 2]. They show immunoglobulins and/or complement deposits in glomeruli by immunofluorescence study and foot process effacement and/or electron dense deposits in the mesangium by electron microscopy. AILT is considered to be an atypical lymphoproliferative disorder with clinical features that can resemble autoimmune diseases with poor prognosis. In A. Goto . S. Yamamoto . A. Notoya . M. Mukai (*) Division of Clinical Immunology and Haematology, Department of Medicine, Sapporo City General Hospital, Kita 11-jo, Nishi 13-chome, Chuo-ku, Sapporo, 060-8604, Japan e-mail: masaya.mukai@doc.city.sapporo.jp Tel.: +81-11-7262211 Fax: +81-11-7269541

Subclinical Alterations in Coagulation and Fibrinolysis in Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation

We monitored 30 laboratory hemostatic parameters in an attempt to better comprehend alterations in coagulation and fibrinolysis in 10 patients with hematological malignancies subjected to autologous peripheral blood stem cell transplantation (APBSCT). These parameters were assessed before and just after high-dose conditioning chemotherapy, on days 1, 7, 14 and 28. Although, clinical manifestations associated with fibrino-coagulation disorders never occurred, including veno-occlusive disease, a statistically significant increase was seen in 7 of 30 parameters, compared to values seen before conditioning chemotherapy. These were subdivided into early and late phase parameters. The early phase parameters, which increased during the first day after the conditioning chemotherapy was given, then returned to baseline values, included protein C, plasma tissue factor and tissue-plasminogen activator. The late phase parameters, which increased over baseline values during days 7 to 28, included free-protein S, fibrinogen, plasmin-alpha2-plasmin inhibitor complex and soluble-thrombomodulin. The increase of early phase parameters, as produced by the liver and by endothelial cells, may reflect tissue damage by conditioning chemotherapy. Late phase parameters increased in parallel with C-reactive protein, which suggests a correlation with the degree of inflammation, such as the presence of infective disease during neutropenia. These subclinical alterations in coagulation and fibrinolysis which take on a biphasic pattern during the course of APBSCT should be kept in mind by the attending physicians during therapy.

Mobilization of Peripheral Blood Progenitor Cells Following CHOP Treatment Combined with Delayed Granulocyte Colony-Stimulating Factor Administration in Patients with Non-Hodgkin's Lymphoma

The kinetic change in peripheral blood progenitor cells (PBPC) during 3 to 6 cycles of standard CHOP regimen supported with human recombinant granulocyte colony-stimulating factor (rG-CSF) was investigated in three patients with newly diagnosed intermediate grade, diffuse large cell type, non-Hodgkins lymphoma (NHL) without bone marrow invasion. Patients were given rG-CSF subcutaneously (2 mu g/kg/day) initiated when total leukocytes was < 3.0 x 10(9)/1. When the leukocyte count remained at >3.0 x 10(9)/1, rG-CSF was started 10 days following the prior CHOP. Treatment with rG-CSF was discontinued after the leukocyte count reached >10.0 x 10(9)/1, and CHOP was started the next day (CHOP-G regimen). The number of PBPC was monitored by clonal assay in patients 1-3. No severe leukopenia with <0.5 x 10(9)/1 of neutrophils was seen in any patient. Colony-forming unit granulocyte-macrophage (CFU-GM) significantly increased after 2-3 days of consecutive administration of rG-CSF. The magnitudes of maximum amplification of CFU-GM in patients 1, 2, and 3, were 56-fold (during 3 cycles of CHOP-G), 216-fold (during 2 cycles), and 67-fold (during 4 cycles), respectively, and the absolute numbers of the maximum CFU-GM/ml blood were 983, 7,568, 9,865, respectively. In one patient who was given 6 cycles of CHOP-G, the peak values of mobilized CFU-GM in each cycle did not substantially decrease until 6 cycles of CHOP-G had been completed. Thus, the CHOP-G regimen described here seems to be very efficient increasing the circulating CFU-GM prior to harvesting PBPC.

Proliferation and differentiation of myelodysplastic CD34+ cells in serum-free medium: II. Response to combined colony-stimulating factors.

Abstract: To investigate the role of colony stimulating factors (CSFs) in the proliferation and differentiation of progenitor cells from myelodysplastic syndromes (MDS), marrow progenitor cells from 18 MDS patients were highly purified using CD34 monoclonal antibody and immunomagnetic microspheres (MDS CD34+ cells). These cells were cultured in serum‐free medium with various combinations of five colony stimulating factors (CSFs): recombinant human interleukin‐3 (rIL‐3), granulocyte/macrophage‐CSF (rGM‐CSF), granulocyte‐CSF (rG‐CSF), macrophage‐CSF (rM‐CSF), and erythropoietin (rEP). Among the tested CSFs, such as rM‐CSF, rG‐CSF, rGM‐CSF and rIL‐3, a combination of the first three CSFs was the most effective stimulus for the proliferation of non‐erythroid MDS progenitor cells. An increase of undifferentiated “blast” cell colonies in 5/18 MDS patients occurred and these 5 patients belonged to the high‐risk group. In the presence of these three CSFs, rIL‐3 had no effect on the proliferation and differentiation of MDS CD34+ cells; however, IL‐3 was efficient for the proliferation of MDS CD34+ cells to the erythroid lineage. rGM‐CSF or rIL‐3 alone did not efficiently support proliferation and differentiation of CD34+ cells. M‐CSF is present in normal human serum at a concentration of 550 ±110 U/ml, a concentration exceeding that used in this study (100 U/ml). Therefore, in vivo administration of G‐CSF combined with GM‐CSF to MDS patients may be one of the most effective CSF combinations for proliferation of MDS progenitor cells to the non‐erythroid lineage. However, the effect on the capacity for differentiation was minimal, especially in patients belonging to the high‐risk group.

Transient myopia with severe chemosis as an initial manifestation of systemic lupus erythematosus

Abstract A 24-year-old woman suffered from blurred vision and periorbital edema with remittent fever. She was diagnosed as having systemic lupus erythematosus (SLE), complicated with myopia and retinopathy and severe chemosis. Antiphospholipid syndrome (APS), hemophagocytic syndrome, and liver involvement were also proven. We considered that APS might cause chemosis as a result of thrombosis-induced perfusion failure in the conjunctiva. In such cases, APS should be considered and anticoagulation therapy associated with steroid therapy should be initiated. In systemic lupus erythematosus (SLE), chemosis, severe hepatitis, and hemophagocytic syndrome (HPS) are rare complications. It is well known that many cases of SLE are complicated with antiphospholipid syndrome (APS), which causes arteriovenous thrombosis. We report a case of SLE with transient myopia and severe chemosis complicated with severe hepatitis and HPS. As this patient had antiphospholipid antibodies, these ocular complications were considered to be related to APS.

Vasculitis following implantation of a ventriculoperitoneal shunt tube made of silicone

Abstract A 56-year-old man presented with hyperproteinemia and renal dysfunction associated with antineutrophil cytoplasmic antibodies (ANCA). He had had a ventriculoperitoneal shunt tube made of silicone implanted 4 years earlier. In his renal biopsy, necrotizing crescentic glomerulonephritis was identified: tests for both myeloperoxidase ANCA and proteinase 3 ANCA were initially weakly positive. Antinuclear and other autoantibodies were also present. We diagnosed ANCA-associated vasculitis, probably induced by the silicone tube.

Leukemia Cutis in an Elderly Patient Treated with Low Dose Cytosine Arabinoside and Etoposide

A 78-year-old man presented with a generalized erythematous papular rash. Such skin lesions were not painful, tender or pruritic, and spread over the truncus. He was admitted to our hospital for examination of the skin lesions. Laboratory tests indicated microcytic hypochromatic anemia and thrombocytopenia, although gave a normal leukocyte count with normal differentiation. His bone marrow showed hypercellularity, with 43% peroxidase positive blasts that displayed positive immunophenotypes for CD4, CD13, CD33, CD41a, KP-1 (CD68), and HLA-DR. His skin specimen revealed infiltration in the dermis and subcutaneous fat tissue by leukemic cells that were positive for the leukocyte common antigen (LCA, CD45), CD15, CD33, CD68, and HLA-DR. He was diagnosed as having M4 subtype of acute myelogeneous leukemia (AML) with leukemia cutis. After three courses of low dose cytosine arabinoside (LDAC), combined with low dose etoposide, he achieved complete remission (CR). He remained well, with no evidence of relapse nine months later. LDAC should be considered as initial treatment for such cases of leukemia cutis with poor general condition.