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Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome is a rare multisystem disorder. Overproduction of vascular endothelial growth factor (VEGF) by plasmocytoma could be responsible for the symptoms. The authors treated four patients with high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Within 6 months, symptoms associated with rapid normalization of serum VEGF levels improved.

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogeneous EBV-related disorder, ranging from mild/moderate forms to rapidly lethal disorders. The lethal form of CAEBV is characterized by multiple organ failure, hemophagocytic syndrome, and development of lymphomas. Allogeneic stem cell transplantation is considered as the only potentially curative treatment for the lethal form of CAEBV, but it is not always desirable because of the high incidence of regimen-related toxicities. A 17-year-old female with CAEBV, who was refractory to conventional therapies and considered to be unable to receive a myeloablative regimen because of multiple organ dysfunction, underwent allogeneic nonmyeloablative stem cell transplantation (allo-NST) before developing a hematological malignancy. She has been well without any signs of CAEBV for 27 months after allo-NST, and we confirmed that specific cytotoxic T lymphocyte activity against EBV was reconstituted. This outcome suggests that allo-NST can control CAEBV by reconstituting the host immunity against EBV., (Copyright 2004 Wiley-Liss, Inc.)

Late-onset noninfectious pulmonary complications (LONIPCs) occurring beyond 3 months after allogeneic stem cell transplantation (allo-SCT) have become recognized as life-threatening complications, and they reduce the recipient's quality of life. However, the pathogenesis and optimal treatment for LONIPCs are still unclear. In this study, we retrospectively analyzed the incidence and outcome of LONIPCs among allo-SCT recipients. Between October 1993 and September 2001, 96 patients underwent allo-SCT and 76 patients who survived and were free of disease for more than 3 months after SCT were enrolled. Among the 76 patients, 18 patients (23.7%) developed LONIPCs at a median interval of 227 days after allo-SCT (range, 91-1105 days). The patients with LONIPCs were subclassified into those with bronchiolitis obliterans (BO) (6 patients), with interstitial pneumonia (IP) (11 patients), or with both BO and IP (1 patient). The presence of extensive chronic graft-versus-host disease (GVHD) was significantly associated with the development of LONIPCs (P =.0008). Liver or skin involvement in chronic GVHD was not associated, but sicca syndrome was significantly associated with the development of LONIPCs (P <.0001). Most of the IP patients (58.3%) responded well to immunosuppressive treatment, while BO patients did not respond to the therapy. Eight of the 18 patients with LONIPCs died. The major cause of death was respiratory failure (62.5%). The relapse rate of primary malignant disease in the LONIPC patients was significantly lower than that of non-LONIPC patients (1 of 17 [5.9%] versus 16 of 52 [30.8%]; P =.0387). These results indicate that the development of LONIPCs was strongly associated with chronic GVHD and especially with sicca syndrome and the graft-versus-leukemia (GVL) effect.

Intimal hyperplasia is a key lesion for various vascular disorders such as atherosclerosis, postangioplasty restenosis and transplant arteriopathy. It has widely been accepted that intimal smooth muscle cells (SMC) originate from the medial layer in the same artery. However, recent studies suggest that bone marrow can also provide circulating progenitors for vascular SMC. Bone marrow-derived SMC participate in neointimal formation in animal models of allotransplantation, severe mechanical injury and hyperlipidemia-induced atherosclerosis. In human, transplantation arteriopathy also seems to involve circulating SMC, but their role in atherosclerosis and restenosis remains to be elucidated. Mobilization, differentiation and proliferation steps of SMC progenitors will provide promising targets for novel therapeutic approaches against proliferative vascular diseases.

As a source of hematopoietic stem cells for transplantation, the use of peripheral blood stem cells (PBSCs) has become routine and comparable to that of the use of bone marrow. Recently, elderly patients with hematological malignancies also have been allowed to receive minitransplantations with nonmyeloablative conditioning regimens under sufficient PBSC infusion. As a result of these minitransplantations, elderly donors have been chosen increasingly from the siblings of elderly patients. We analyzed factors influencing the condition of CD34+ cells in the first days of collection in 49 healthy donors from July 1995 to January 2001. The median dose of recombinant human granulocyte colony-stimulating factor was 8 microg/kg/day (range 8 - 10) over 3 days. The target number of CD34+ cells used in this study was > or = 3 x 10(6) cells/kg of recipient body weight. The median apheresis volume was 12 L. Except for one 60 year old man, we obtained an adequate number of stem cells. In the regression analysis, a negative correlation was seen between donor age and the number of CD34+ cells/kg of recipient body weight per 12 L volume (Y = aX + b; a = -0.07507; b = 6.629996; r = -0.50985; p = 0.000252). Significantly higher apheresis results were obtained in donors younger than 45 years compared with donors 45 years old and older (p < 0.0227). There were no correlations among the number of CD34+ cells, donor body weight, and the number of leukocytes in peripheral blood on the first day of apheresis.

A 26-year-old male with acute lymphoblastic leukemia (ALL) in its second complete remission received an unrelated bone marrow transplantation (UBMT) following cyclophosphamide plus total body irradiation conditioning. The patient relapsed 7 months after the BMT. He received a second UBMT from a different donor 15 months after the initial UBMT. Conditioning for the second UBMT consisted of busulphan, melphalan, and anti-thymocyte globulin. The regimen was well tolerated, and engraftment was achieved. Both acute and chronic graft-versus-host diseases occurred but were successfully controlled with immunosuppressive drugs. He is alive and disease-free 29 months after the second UBMT. This is the first report of a successful second UBMT for ALL that had relapsed after the first UBMT and for which a different donor was used., (Copyright 2002 Wiley-Liss, Inc.)

A 42-year-old man with chronic myelogenous leukemia underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor in January 1998. About 100 days later, he developed skin eruption and a diagnosis of chronic graft-versus-host disease (cGVHD) was made by skin biopsy. The eruption improved with steroid therapy, and the dose of steroid was gradually tapered. On day 151, the patient developed nephrotic syndrome with proteinuria up to 20 g/day. A renal biopsy carried out on day 160 showed minimal change in the glomeruli. The proteinuria disappeared 19 days after the onset of nephrotic syndrome without any additional therapy, and no recurrence was observed upon re-tapering of the steroid. In this case, cGVHD might have been related to development of the nephrotic syndrome. Nephrotic syndrome after allo-HSCT is a rare complication, and only ten cases have been reported. The histological findings were mainly membranous nephropathy, and immunosuppressive therapy was effective. As seen in this case, transient nephrotic syndrome with cGVHD may occur after allo-HSCT, and care is necessary to ensure that treatment of cGVHD is sufficient.

CTLA-4 is expressed on the surface of activated T cells and negatively regulates T cell activation. Because a low-level expression of CTLA-4 on the cell surface is sufficient to induce negative signals in T cells, the surface expression of CTLA-4 is strictly regulated. We previously demonstrated that the association of CTLA-4 with the clathrin-associated adaptor complex AP-2 induces internalization of CTLA-4 and keeps the surface expression low. However, the mechanism to induce high expression on the cell surface upon stimulation has not yet been clarified. To address this, we investigated the intracellular dynamics of CTLA-4 by analyzing its localization and trafficking in wild-type and mutant CTLA-4-transfected Th1 clones. CTLA-4 is accumulated in intracellular granules, which we identified as lysosomes. CTLA-4 is degraded in lysosomes in a short period, and the degradation process may serve as one of the mechanisms to regulate CTLA-4 expression. Upon TCR stimulation, CTLA-4-containing lysosomes are secreted as proven by the secretion of cathepsin D and beta-hexosaminidase in parallel with the increase of surface expression of CTLA-4 and lysosomal glycoprotein 85, a lysosomal marker. These results suggest that the cell surface expression of CTLA-4 is up-regulated upon stimulation by utilizing a mechanism of secretory lysosomes in CD4(+)T cells.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif ((165)YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain-containing tyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinase upon phosphorylation, the mechanism of negative signaling remains unclear. Here, we report a new mechanism of negative signaling based on the analysis of murine T cell clones transfected with various mutants of CTLA-4. Upon T cell activation by cross-linking with anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibited both proliferation and interleukin 2 production in tyrosine mutants as well as in wild-type CTLA-4 transfectants. Furthermore, the mutant CTLA-4 lacking most of the cytoplasmic region strongly suppressed interleukin 2 production as well. These data suggest that negative signals by CTLA-4 could be mediated through the membrane-proximal region of CTLA-4 but not through the YVKM motif and that the association of CTLA-4 with SHP-2 is not required for CTLA-4-mediated suppression of T cell activation.

It has been reported that extramedullary plasmacytoma (EMP) tends to be characterized by an indolent clinical course and lower incidence of progression to multiple myeloma. Primary plasmacytoma of lymph nodes is extremely rare and details of its clinical picture remain unclarified. We recently encountered an unusual case of EMP of lymph nodes that progressed to refractory multiple myeloma only 18 months later. A 74-year-old woman was admitted to our hospital because of a painless swelling in the right inguinal region. A tumor was removed surgically, and a histological diagnosis of EMP of the lymph nodes was made. Bence Jones protein (BJP) was detected in the urine, but there was no other evidence of systemic myelomatosis. The patient received local irradiation, which resulted in the elimination of BJP. Eighteen months later, however, a tumor developed in her right stemo-clavicular joint. A bone survey revealed multiple osteolytic lesions, and many atypical plasma cells were observed in the bone marrow, indicating multiple myeloma. The patient deteriorated despite several regimens of combination chemotherapy, and died four and a half years after the initial diagnosis of EMP.

CPT-11 + ADM therapy (CPT-11 40 mg/body x 2 days; Day 1 & 2, combined with ADM 20 to 60 mg/body x 1 day; Day 3) was given to four patients with relapsed and advanced non-Hodgkin's lymphoma, which was refractory to conventional chemotherapies. The symptoms of the patients at the beginning of CPT-11 + ADM therapy were fever (in two cases), dyspnea due to pleural effusion (in two), severe backache (in one), and jaundice with splenomegaly (in one). Their Karnofsky performance scales were 20 or 30%. Soon after the initiation of CPT-11 + ADM therapy, their clinical conditions improved dramatically, and they obtained a partial remission lasting 3.5 to 9 months. During the period of controlling lymphomas by this therapy, all patients had some time at home for 2 to 8 months. The adverse effects were vomiting, diarrhea, neutropenia and thrombocytopenia, but no lethal infection or hemorrhage was seen. We conclude that CPT-11 + ADM therapy is very useful for improvement of QOL and life prolongation of patients with non-Hodgkin's lymphoma, which is refractory to conventional chemotherapies and is even disseminated.

CTLA-4 (CD152) transduces inhibitory signals for T cell activation. Phosphorylation and dephosphorylation of tyrosine residue (Y)-165 in the cytoplasmic region of CTLA-4 play an important role in the signal transduction and in the cell surface. While signaling molecules such as SHP-2 and the p85 subunit of PI3 kinase associate with this tyrosine residue through SH2 domains upon phosphorylation, the adapter complex AP-2 interacts with the same tyrosine when dephosphorylated, leading to clathrin-mediated endocytosis of CTLA-4. We searched for the tyrosine kinase responsible for the phosphorylation of CTLA-4. Src family tyrosine kinases Fyn, Lyn, and Lck associate with CTLA-4 and phosphorylate both Y-165 and Y-182 that are mainly responsible for interaction with Fyn through its SH2 domain. SHP-2 associates with CTLA-4, in a Fyn-dependent manner. Our observations show that src family tyrosine kinases associate with and phosphorylate CTLA-4 and thereby have an important role in the signal transduction and the endocytosis of CTLA-4., (Copyright 1998 Academic Press.)

Acute respiratory failure (ARF) occurred at the time of leukocyte recovery promoted by granulocyte colony-stimulating factor (G-CSF) in three patients with the preceding infection (S. aureus pneumonia, varicella zoster, and P. aeruginosa bacteremia, respectively) which had developed during leukopenia after cancer chemotherapy. G-CSF was used for 4 to 6 days, and the leukocyte counts at onset of ARF were 19,300/microliter, 11,300/microliter, and 4,100/microliter, respectively. All of the three patients received high-dose methylprednisolone and the artificial respiration was used in two. Consequently two patients responded well and survived, but one died of respiratory failure 2 weeks after occurrence of ARF. Autopsy of the dead case revealed mild interstitial pneumonia in the both lungs together with bacterial pneumonia in the right lobe. These cases indicate that G-CSF-induced leukocyte recovery can cause severe ARF in patients with precending infection. Therefore, G-CSF should be administered very carefully to granulocytopenic patients with infection.

CTLA-4 is a costimulation receptor that binds to the same ligands, CD80 and CD86, as CD28 with high affinity and is transiently expressed on the cell surface of activated T cells. CTLA-4 delivers an inhibitory signal through association of a phosphotyrosine-containing motif in the cytoplasmic domain with Syp tyrosine phosphatase. We now demonstrate that CTLA-4 interacts with the mu2 subunit of the plasma membrane-associated adaptor complex, AP-2, through the same motif involved in the interaction with Syp, except that the interaction with mu2 requires unphosphorylated tyrosine. The interaction with mu2 likely induces rapid internalization of CTLA-4 from the cell surface. Our results suggest that the phosphorylation state of a single tyrosine residue determines whether CTLA-4 delivers a negative signal or is internalized.

Myelodysplastic syndromes (MDS) are clonal haematological disorders and MDS neutrophils have various abnormal functions which cause an increased risk of infective mortality. We examined luminol-dependent chemiluminescence and cytoplasmic Ca2+ increase in order to characterize the mechanisms of a signalling defect in MDS neutrophil respiratory burst. In MDS patients, chemiluminescence stimulated with N-formyl-L-methionyl-L-leucil-L-phenylalanine (FMLP) and calcium ionophore A23187 was defective (17.2 +/- 13.7 v 44.3 +/- 16.6, P = 0.001; 42.2 +/- 21.3 v 82.0 +/- 23.6, P < 0.05, respectively), but phorbol 12-myristate 13-acetate (PMA) chemiluminescence was normal (73.4 +/- 26.9 v 79.5 +/- 23.8, P = 0.52). There were no statistical significances in cytoplasmic Ca2+ increase stimulated with FMLP and recombinant human interleukin-8 (rhIL-8) compared with controls (251.1 +/- 104.3 v 272.7 +/- 41.2, P = 0.295; 238.6 +/- 65.0 v 253.9 +/- 38.3, P = 0.567, respectively). Flow cytometric analysis of MDS neutrophils disclosed that most MDS patients showed normal neutrophil cytoplasmic Ca2+ response to FMLP and rhIL-8. However, two patients with refractory anaemia with excess of blasts displayed a significant decrease of both chemiluminescence and cytoplasmic Ca2+ response to FMLP, and they also displayed low expression of FMLP receptor. These data suggest that most MDS patients have low FMLP chemiluminescence which is not due to a defect in the FMLP receptor. It is proposed that defective FMLP chemiluminescence in MDS results from a putative defect in protein kinase C- and Ca(2+)-independent cell-signalling mechanisms. Only a small group of patients have numerical or structural defects in the FMLP receptor, causing significant decrease of neutrophil respiratory burst.

A 46-year-old man with idiopathic thrombocytopenic purpura (ITP) refractory to corticosteroid, splenectomy and other drugs was admitted to our hospital in August, 1994, because of aseptic necrosis of the right femoral head. Although high-dose intravenous gamma-globulin was ineffective, the platelet count was increased within two weeks by the combination therapy that consisted of 0.02 mg/kg vincristine alternating with 0.1 mg/kg vinblastine by slow infusion at a 1-week interval, and oral 1.5 mg/day colchicine. He subsequently underwent the femoral head replacement. This combination therapy seems to be useful for refractory ITP in preparation for surgery.

A 36 year-old man had suffered from psoriasis vulgaris for about 25 years. He had received corticosteroids ointment and PUVA therapy with partial response. In 1987, he was diagnosed as having aplastic anemia (AA) and treated with various medications, but failed to respond. He received an allogeneic bone marrow transplantation (BMT) from his histocompatible sister in 1993. Conditioning regimen of BMT consisted of total lymphoid irradiation (7.5 Gy) and cyclophosphamide (200 mg/kg). Cyclosporin A and methotrexate were given for prophylaxis of graft-versus-host disease. On day 24, bone marrow examination disclosed normocellular marrow and karyotypic analysis completely confirmed the donor's origin. Before BMT, he had systemic psoriatic plaques with scales, together with nail involvement. After BMT, psoriatic plaques disappeared and nail deformity improved. He has remained in remission of his AA and completely free of psoriasis in the absence of immunosuppressive or other treatments. The cause of psoriasis is thought to be an immune-mediated disorder. Our case supports the observation that changing the host's immune system through allogeneic BMT can achieve remission of psoriasis. It is suggested that allogeneic BMT may be one strategy for the treatment of intractable immune-mediated disorders.

Between July, 1990 and March, 1994, 31 patients with hematological malignancies or severe aplastic anemia underwent allogeneic bone marrow transplantation (BMT) at the Second Department of Internal medicine, Chiba University Hospital. Among the 29 evaluable patients who survived over 100 days after transplant, 11 patients (37.9%) developed late-onset hemorrhagic cystitis with a median time of onset of 57 days (range 11-205) from BMT. Adenovirus type 11 was isolated from the urine of 4 patients. Five patients recovered with fluid hydration and forced diuresis, while 6 patients had persistent gross hematuria with clot formation, 5 of whom also developed hydronephrosis. Seven-day courses of 500 micrograms prostaglandin E1 (PGE1) bladder instillations was initiated to control hematuria in these 6 patients. Complete resolution of gross hematuria was achieved in 4, and partial response with decreased clot formation and partial clearing of the urine was observed after 4 of 9 courses of the treatment. Although all patients experienced bladder spasm or lower abdominal pain during the PGE1 instillations, these symptoms were manageable with sedative drugs and morphine. No systemic side effect was apparent. PGE1 bladder instillations is a safe and useful treatment for severe, life-threatening late-onset hemorrhagic cystitis after allogeneic BMT.

We performed retrospective analysis of hepatic veno-occlusive disease (VOD) in 57 cases with leukemia after allogeneic bone marrow transplantation (BMT). Prostaglandin E1 (PGE1) was used to prevent VOD in 8 cases at a dose of 0.3 micrograms/kg/hr from day -8 to day 30. No VOD was noted in the PGE1 group, while the incidence of VOD was 8/49 (16.3%) in the non PGE1 group. In twelve patients with pretransplant liver dysfunction, VOD was noted in 0/3 in the PGE1 group and 4/9 (44.4%) in the non PGE1 group, respectively. However, prophylactic effects of PGE1 on VOD is not significant in this study, so further studies are needed to determine the efficacy of PGE1. One of 8 patients with PGE1 prophylaxis had edema and erythema on extremities, however, severe toxicity was not experienced.

A 39-year-old female with AML (M2) underwent allogeneic bone marrow transplantation (BMT) on July 8th, 1991. The post transplantation course had been going well until day 85 post BMT, when severe hemorrhagic cystitis with right hydronephrosis and ureter stenosis developed. Adenovirus type 11 was isolated from the urine. She received instillations of prostaglandin E1 (PGE1) directly into the bladder after the appearance of clots in the urine. Complete resolution of hematuria was obtained by two courses of this treatment. PGE1 bladder instillations seem to be effective for the control of hematuria caused by severe hemorrhagic cystitis after BMT.

Chromosomal abnormalities in Castleman's disease with high levels of serum IL-6 were reported. A 69-year-old male was found to have superficial lymph node swelling and polyclonal hypergammaglobulinemia, when he was admitted to the department of otolaryngology for carcinoma of the tongue in July 1991. In December, he was referred to our department after completing radiation therapy. Laboratory examination revealed 7.7 g/dl hemoglobin, 10.8 g/dl total protein, and 56.0% gamma-globulin. Serum electrophoresis revealed polyclonal hypergammaglobulinemia and no Bence-Jones protein. Bone marrow aspirates showed an increase of plasma cells to 21.8%. Serum IL-6 was 252 pg/ml. Chromosomal analysis of cells in the lymph node showed a karyotype of 46,XY,t(7;14)(p22;q22). The lymph node histology showed marked hyperplasia of plasma cells at interfollicular areas. These plasma cells were stained with both anti-kappa and anti-lambda antibody. He was diagnosed as multicentric form Castleman's disease. Treatment with prednisolone and melphalan resulted in improvement of clinical findings such as anemia, lymph node swelling and hypergammaglobulinemia in concurrence with decrease in serum levels of IL-6. Since the IL-6 gene is located on 7p21-22, the translocation 7; 14 may be related to the high level of serum IL-6.