Yoshihisa Nagatoshi

Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients

Summary:Adenovirus (AdV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. We treated 16 patients with AdV hemorrhagic cystitis (HC) following HSCT with cidofovir (CDV; 1 mg/kg/day, three times weekly for 3 weeks). Patients included 10 males and six females with a median age of 50 years (range 10–62). Two of the 16 patients were unevaluable because of early death from nonadenoviral causes. CDV therapy cleared AdV from urine in 12 of 14 patients (86%). Of 14 patients, 10 (71%) showed clinical improvements in HC. Among 14 patients, seven (50%) had avoided renal damage, the most important CDV toxicity. One patient previously treated with foscarnet for cytomegalovirus (CMV) required hemodialysis, and CDV treatment was discontinued. In another patient, CDV treatment was discontinued because of grade 2 nephrotoxicity. Four patients became positive for CMV antigenemia while being treated with CDV, and two developed herpes simplex virus (HSV) stomatitis while being treated with CDV. CDV proved effective in treating AdV HC in transplant patients. However, CDV at 1 mg/kg/day given three times weekly failed to prevent breakthrough infection with CMV and HSV in some patients.

Polymorphisms of transforming growth factor-β1 and transforming growth factor-β1 type II receptor genes are associated with acute graft-versus-host disease in children with HLA-matched sibling bone marrow transplantation

The aim of this study was to determine whether the gene polymorphisms of Th1/Th2 and immunoregulatory cytokines were associated with aGVHD in Japanese children receiving allogeneic bone marrow transplantation (allo BMT). We investigated polymorphisms of genes encoding interleukin (IL)-4, IL-4 receptor (IL-4 R), IL-10, transforming growth factor (TGF)-β1, TGF-β1 type II receptor (TGF-β1 RII), interferon (IFN)-γ, IFN-γ type 2 receptor (IFN-γ R2), and IFN regulatory factor (IRF)-1. Sixty-seven patients were treated with alloBMT from HLA-identical siblings, and aGVHD was observed in 38. TGF-β1 codon 10 leucine (Leu) /proline (Pro) polymorphism in donors was associated with the development of aGVHD. Patients having donors with the Pro allele had aGVHD more frequently than those without Pro allele (30/45 vs 8/20, odds ratio = 3.00; P = 0.04). TGF-β1 RII 1167 C/T polymorphism in recipients was also associated with the development of aGVHD. The incidence was significantly higher in recipients with T allele than in those without T allele (21/27 vs 16/35, odds ratio = 4.16; P = 0.01). In conclusion, genetic backgrounds of TGF-β1 and TGF-β1 RII may be involved in the development of aGVHD in HLA-matched sibling BMT in Japanese children.

Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan.

Langerhans cell histiocytosis (LCH) that is refractory to conventional chemotherapy has a poor outcome. Hematopoietic stem cell transplanta tion (SCT) is a promising approach for refractory LCH because of its immunomodulatory effect. In this study, the outcomes of children with refractory LCH undergoing SCT in Japan were analyzed. Between November 1995 and March 2007, 15 children younger than 15 years (9 males, 6 females) with refractory LCH underwent SCT. The patients’ median age at diagnosis was 8 months (range, 28 days to 28 months), and all had failed conventional chemotherapy. The median age at SCT was 23 months (range, 13–178 months). Nine had risk organ involvement at diagnosis, including liver (n=6), spleen (n=5), lung (n=5), and/or hematopoietic system (n=4). For SCT, a myeloablative regimen was used for 10 patients, and a reduced-intensity conditioning regimen (RIC) was used for five. The donor source varied among the patients, but allogeneic cord blood was primarily used (n=10). Subsequently, 11 of 15 patients have survived with no evidence of disease, with a 10-year overall survival (OS) rate (median±standard error) of 73.3±11.4%. The 10-year OS rate of nine patients with risk organ involvement at diagnosis was 55.6±16.6%, whereas six without risk organ involvement have all survived with no evidence of disease (P=0.07). These results indicate that SCT is promising as a salvage approach for children with refractory LCH.

Human cord blood- and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells

In the present study, we aimed to clarify the capacity of human cord blood‐ and bone marrow‐ derived progenitor cells to generate gastrointestinal epithelial cells in clinical and experimental transplantation settings. First, in a clinical transplantation setting, gastrointestinal tissues derived from female pediatric or juvenile recipients of allogeneic sex‐mismatched bone marrow and cord blood transplantation were examined for the presence of donor‐derived epithelial cells. Gastrointestinal specimens of allogeneic recipients included Y chromosome+ cytokeratin+ epithelial cells at a frequency of 0.4–1.9%. To further determine the capacity of purified human progenitor cells, human cord blood‐ or bone marrow‐derived CD34+ cells were transplanted into newborn NOD/SCID/β2‐microglobulinnull mice as an experimental transplantation assay. When gastrointestinal tissues derived from recipient mice were subjected to FISH and immunofluorescence analyses, human epithelial cells were identified at a frequency of 0.24– 0.58% at 3 months posttransplantation. Finally, double FISH analyses using species‐specific probes revealed that human chromosome+ epithelial cells did not possess any murine chromosomes, indicating that donor‐derived epithelial cells were not generated only by cell fusion. On the basis of these findings, it is concluded that purified human cord blood and bone marrow CD34+ progenitor cells can generate gastrointestinal epithelial cells across allogeneic and xenogeneic histocompatibility barriers.

Acute lymphocytic leukemia in adolescence with multiple osteolytic lesions and hypercalcemia mediated by lymphoblast-producing parathyroid hormone-related peptide: A case report and review of the literature

Osteopathy is one of the common initial symptoms of acute lymphocytic leukemia (ALL) in children and adolescents, but multiple osteolysis accompanied by hypercalcemia is rarely observed.

A study of rasburicase for the management of hyperuricemia in pediatric patients with newly diagnosed hematologic malignancies at high risk for tumor lysis syndrome

Tumor lysis syndrome (TLS), including hyperuricemia, is a frequent serious complication in patients with hematologic malignancies. This study in Japanese patients evaluated the efficacy, safety, and pharmacokinetic profile of rasburicase in pediatric patients with hematologic malignancies. Patients aged <18 years at high risk for TLS, with newly diagnosed hematologic malignancies, were randomized to intravenous rasburicase 0.15 mg/kg/day (n = 15) or 0.20 mg/kg/day (n = 15) for 5 days. Chemotherapy was started 4–24 h after the first rasburicase dose. Response was defined as a reduction in plasma uric acid to ≤6.5 mg/dL (patients <13 years) or ≤7.5 mg/dL (patients ≥13 years) by 48 h after the first administration, lasting until 24 h after the final administration. Response rates were 93.3 and 100% with rasburicase 0.15 and 0.20 mg/kg/day, respectively. Uric acid levels declined rapidly within 4 h of starting rasburicase administration in both groups. Most adverse events were related to the underlying chemotherapy regimens. Two hypersensitivity reactions, including grade 1/2 pruritus, were considered to be related to rasburicase. Rasburicase is effective and well tolerated for the management of hyperuricemia in Japanese pediatric patients at high risk of developing TLS.

Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314 x 10(6) /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Thymus-independent expansion of T lymphocytes in children after allogeneic bone marrow transplantation

The contribution of the thymus-dependent pathway and thymus-independent pathways for T cell regeneration after BMT in children is still unclear. We analyzed the kinetics of T cell regenerative pathways after allogeneic BMT. The number of CD4+CD45RA+ T cells, a thymus-dependent population, was very low until 3 months after BMT. The numbers of CD28− T cells and CD8+ T cells expressing CD8α/α homodimer (CD8α/α+ T cells), a thymus-independent population, increased shortly after BMT, beyond the levels of healthy children in some patients. The numbers of Vγ9+Vδ2+ and Vα24+ T cells, which represent populations of extrathymic development, were less than 200/μl during the 6 months after BMT. There was a significant inverse correlation between the percentages of CD4+CD45RA+ and CD28-T cells at 1 month, and a positive correlation between the percentages of CD28− and CD8α/α+ T cells at 2 and 3 months after BMT. The mean age at BMT was higher in patients with a high level of CD8α/α+ T cells than in those without an increase in these cells, suggesting the influence of thymic function on the regenerative pathways. These results suggest that the thymus-independent pathway is the dominant source of T cells even in children shortly after allogeneic BMT. Bone Marrow Transplantation (2000) 25, 647–652.

Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan

Several studies have suggested that Langerhans cell histiocytosis (LCH) is responsive to treatment with bisphosphonates (BPs). However the efficacy and safety of BPs therapy for childhood LCH is unknown.

Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases

Oshima K, Hanada R, Kobayashi R, Kato K, Nagatoshi Y, Tabuchi K, Kato S; for the Hematopoietic Stem Cell Transplantation Committee of the Japanese Society of Pediatric Hematology. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases.
Pediatr Transplantation 2010: 14:657–663.