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ABSTRACT: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) in children is one of the highest-risk ALL groups. Improved outcome in combination with imatinib has been reported. However, intensive chemotherapy or myeloablative conditioning followed by hematopoietic stem cell transplantation (HSCT) can be associated with significant adverse late effects. We report a case series of five children with Ph + ALL underwent reduced-intensity allogeneic HSCT (RIST) after induction and consolidation in chemotherapy combined with imatinib. Four of the five patients remain first complete remission for a median of 3.1 years after RIST. These results are preliminary, but suggest the feasibility and effectiveness of RIST with imatinib. Pediatr Blood Cancer 2013;9999:1-3. © 2013 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 03/2013; · 1.89 Impact Factor
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Kayo Yamada MD,
Masahiro Yasui MD,
PhD Akihisa Sawada MD,
Masami Inoue MD,
Masahiro Nakayama MD,
PhD Keisei Kawa MD,
Kayo Yamada, Masahiro Yasui,
Akihisa Sawada,
Masami Inoue,
Masahiro Nakayama,
Keisei Kawa
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ABSTRACT: 2-Chlorodeoxyadenosine (2-CdA) has been successfully used in children to treat refractory Langerhans cell histiocytosis and juvenile xanthogranuloma (JXG) as salvage therapy. Although 2-CdA is generally well-tolerated, with temporary myelosuppression as the primary dose-limiting toxicity, prolonged myelosuppressive, and immunosuppressive effects have been reported. We describe an adolescent patient with refractory multiple central nervous system JXG, with the lesion size markedly reduced after treatment with 2-CdA. However, severe transfusion-dependent bone marrow failure developed after five courses of 2-CdA. He underwent successful bone marrow transplantation from his HLA compatible sister with reduced intensity conditioning. Pediatr Blood Cancer 2012; 58: 300–302. © 2011 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 01/2012; 58(2):300 - 302. · 1.89 Impact Factor
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ABSTRACT: Herpesviruses cause life-threatening diseases after hematopoietic stem cell transplantation (HSCT). It is necessary that viral diseases are identified early and safely diagnosed. The purpose of this study was to evaluate the efficacy of multiplex polymerase chain reaction (PCR) for qualitative detection of the six herpesviruses simultaneously: herpes simplex virus type 1 and type 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus (EBV) and human herpesvirus 6B.
Multiplex PCR was applied to patients with various clinical manifestations including central nervous system, cutaneous and mucosal complications after allogeneic HSCT, and the data were retrospectively analyzed.
Patients positive for cytomegalovirus in peripheral blood by multiplex PCR might need pre-emptive treatment, but a positive result for EBV had no specific correlation with EBV-associated post-transplant lymphoproliferative disease, and positive result for human herpesvirus 6B failed to show any clinical significance. The multiplex PCR was safe and helpful to diagnose viral diseases of local regions, for example, the central nervous system, skin and mucosa.
It may be worthwhile to survey the six herpesviruses with multiplex PCR after HSCT.
Pediatrics International 08/2011; 53(6):1010-7. · 0.63 Impact Factor
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ABSTRACT: 2-Chlorodeoxyadenosine (2-CdA) has been successfully used in children to treat refractory Langerhans cell histiocytosis and juvenile xanthogranuloma (JXG) as salvage therapy. Although 2-CdA is generally well-tolerated, with temporary myelosuppression as the primary dose-limiting toxicity, prolonged myelosuppressive, and immunosuppressive effects have been reported. We describe an adolescent patient with refractory multiple central nervous system JXG, with the lesion size markedly reduced after treatment with 2-CdA. However, severe transfusion-dependent bone marrow failure developed after five courses of 2-CdA. He underwent successful bone marrow transplantation from his HLA compatible sister with reduced intensity conditioning.
Pediatric Blood & Cancer 03/2011; 58(2):300-2. · 1.89 Impact Factor
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ABSTRACT: Polymorphisms in Epstein-Barr virus (EBV) latent genes can identify virus strains from different human populations and individual strains within a population. An Asian EBV signature has been defined almost exclusively from Chinese viruses, with little information from other Asian countries. Here we sequenced polymorphic regions of the EBNA1, 2, 3A, 3B, 3C and LMP1 genes of 31 Japanese strains from control donors and EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) patients. Though identical to Chinese strains in their dominant EBNA1 and LMP1 alleles, Japanese viruses were subtly different at other loci. Thus, while Chinese viruses mainly fall into two families with strongly linked 'Wu' or 'Li' alleles at EBNA2 and EBNA3A/B/C, Japanese viruses all have the consensus Wu EBNA2 allele but fall into two families at EBNA3A/B/C. One family has variant Li-like sequences at EBNA3A and 3B and the consensus Li sequence at EBNA3C; the other family has variant Wu-like sequences at EBNA3A, variants of a low frequency Chinese allele 'Sp' at EBNA3B and a consensus Sp sequence at EBNA3C. Thus, EBNA3A/B/C allelotypes clearly distinguish Japanese from Chinese strains. Interestingly, most Japanese viruses also lack those immune-escape mutations in the HLA-A11 epitope-encoding region of EBNA3B that are so characteristic of viruses from the highly A11-positive Chinese population. Control donor-derived and T/NK-LPD-derived strains were similarly distributed across allelotypes and, by using allelic polymorphisms to track virus strains in patients pre- and post-haematopoietic stem-cell transplant, we show that a single strain can induce both T/NK-LPD and B-cell-lymphoproliferative disease in the same patient.
Journal of General Virology 01/2011; 92(Pt 5):1032-43. · 3.36 Impact Factor
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Akihisa Sawada,
Naoki Sakata,
Banryoku Higuchi,
Yasufumi Takeshita,
Takashi Ishihara,
Akifumi Sakata,
Masahiko Kouroki,
Osamu Kondo,
Maho Koyama,
Shinya Hirano, Masahiro Yasui,
Masami Inoue,
Akira Yoshioka,
Keisei Kawa
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ABSTRACT: Invasive fungal infection (IFI) is a serious complication of chemotherapy for hematological malignancies and autologous/allogeneic hematopoietic stem cell transplantation in children and shows a high mortality rate. We performed a randomized trial comparing micafungin (MCFG), a new anti-fungal agent, with fosfluconazole, a prodrug of fluconazole (FF) conventionally used as a prophylactic agent, for prophylaxis against IFI. Cefpirome was administered as prophylaxis against bacterial infection, and meropenem+minocycline as an empiric window therapy for febrile neutropenia. MCFG 2 mg/kg/day (max 100 mg/day) and FF 10 mg/kg/day (max 400 mg/day) were both safe and effective (event free ratio of IFI, MCFG 94.4% vs FF 94.3%) without significant difference. Thus, MCFG is safe and can be used for prophylaxis against IFI in children.
[Rinshō ketsueki] The Japanese journal of clinical hematology 12/2009; 50(12):1692-9.
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Akihisa Sawada,
Naoki Sakata,
Tomoko Kishimoto,
Banryoku Higuchi,
Maho Koyama,
Osamu Kondo,
Emiko Sato,
Takayuki Okamura, Masahiro Yasui,
Masami Inoue,
Akira Yoshioka,
Keisei Kawa
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ABSTRACT: Newly diagnosed children with ALL (n=32) were treated on a protocol incorporating minimal residual disease (MRD)-based treatment decisions. MRD was monitored at 4 time points by semi-quantitative PCR detection of antigen receptor gene rearrangement, flow cytometry, quantitative RT-PCR detection of chimeric gene transcripts and overexpressed WT1 mRNA. Four patients positive for MRD at week 5 were treated with an intensified regimen. Median follow-up was 5.0 years (range 3.8-6.6 years) with a 4-year event-free survival rate of 93.8+/-4.3%. This MRD-based treatment strategy seems to be highly successful and may improve the outcomes of children with ALL. A large study is warranted.
Leukemia research 08/2009; 33(12):1710-3. · 2.36 Impact Factor
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Taizo Wada, Masahiro Yasui,
Tomoko Toma,
Yuko Nakayama,
Mika Nishida,
Masaki Shimizu,
Michiko Okajima,
Yoshihito Kasahara,
Shoichi Koizumi,
Masami Inoue,
Keisei Kawa,
Akihiro Yachie
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ABSTRACT: X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (gammac) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual gammac expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression.
Blood 07/2008; 112(5):1872-5. · 9.90 Impact Factor
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International Journal of Hematology 01/2008; 86(5):466-7. · 1.27 Impact Factor
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ABSTRACT: The results of allogeneic stem cell transplantation for patients with chemotherapy-resistant non-remission acute leukemia have been very poor. We have used a melphalan-preceding intensified preparative regimen in which a six-day interval is set between melphalan 70 mg/m2 and the main part of the preparative regimen to avoid toxicity in 15 consecutive pediatric patients with refractory acute leukemia. Only one patient died of transplant-related toxicity within 100 days of transplant. One patient had refractory anemia originating from donor cells at three months after transplant. Eight patients relapsed at a median of six months after transplant; therefore, five of 15 patients have been in complete remission (CR) for a median of 61 months. Four of six patients who did not have blasts in their peripheral blood before melphalan are in CR This method seems to be safe and effective for refractory acute leukemia.
[Rinshō ketsueki] The Japanese journal of clinical hematology 12/2007; 48(11):1470-7.
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Journal of Oral and Maxillofacial Surgery 04/2007; 65(3):549-52. · 1.64 Impact Factor
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ABSTRACT: We report the results of 39 children who underwent cord blood stem cell transplantation (CBSCT) at our institute during the period from February 1996 to July 2005. The patients consisted of 9 with non-malignant disease, 26 with malignant disease and 4 with Epstein-Barr virus (EBV) associated disease. The median age of the patients was 4 years and 8 months (range, 6 months to 16 years 2 months). The median infused cell dose was 4.9 (range, 1.7-11.4) x 10(7)/kg. Thirty-four transplants were from HLA-mismatched donors, and 33 patients underwent a tacrolimus-containing regimen for GVHD prophylaxis. As for CBSCT as the first transplant, 3 out of 4 children with non-malignant disease achieved engraftment after CBSCT with the use of a reduced-intensity conditioning regimen. For acute leukemia, 3 patients out of 5 in their first remission and 2 out of 9 in advanced stage at CBSCT continue in remission at the time of writing. Fourteen patients received CBSCT as a second or a third transplant. None of 4 patients who underwent CBSCT as rescue therapy after rejection/graft failure achieved engraftment. It should be emphasized that EBV-associated disease seems to be a suitable disease for CBSCT, because all of the 4 patients who underwent CBSCT are still in CR.
[Rinshō ketsueki] The Japanese journal of clinical hematology 12/2006; 47(11):1446-52.
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Akihisa Sawada,
Emiko Sato,
Maho Koyama,
Banryoku Higuchi,
Shigenori Kusuki,
Ji Yoo Kim,
Yasufumi Takeshita,
Akifumi Sakata,
Naoki Sakata,
Takayuki Okamura, Masahiro Yasui,
Masami Inoue,
Keisei Kawa
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ABSTRACT: Epstein-Barr virus (EBV) occasionally infects T and NK cells and causes EBV-infected T/NK-cell lymphoproliferative disease (LPD), which comprises chronic active EBV infection, EBV-associated hemophagocytic syndrome, mosquito allergy, hydroa vacciniforme, aggressive NK-cell leukemia, and NK/T-cell lymphoma. The diagnosis is proven by the monoclonal proliferation of EBV-infected T or NK cells, which is a time-consuming and complicated method. T-cell monoclonality is helpful for the screening of EBV-infected T-cell LPD in patients with EBV-genome burden and is easily shown with T-cell-receptor rearrangement or the T-cell repertoire, whereas NK-cell monoclonality is difficult to prove due to its lacking such rearranged receptors. We investigated a set of killer immunoglobulin-like receptors (KIRs) and also CD94-NKG2 heterodimers on NK cells, namely the NK-cell repertoire. Skewed repertoires were seen in all patients with EBV-infected NK-cell LPD, but not in any patients with EBV-infected T-cell LPD and were restored only after successful treatment. The normal KIR repertoire is variable for each individual and it seems difficult to detect minimal residual EBV-infected lymphocytes. However, the NK-cell repertoire is feasible for identifying EBV-infected NK-cell LPD and evaluating the treatment effect.
American Journal of Hematology 09/2006; 81(8):576-81. · 4.67 Impact Factor
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ABSTRACT: We report a case of botryoid Wilms' tumor that occupied the renal pelvis and extended into the bladder. A 3-year-old boy was referred to us with a chief complaint of gross hematuria and micturition pain. Computed tomography showed tumor occupying the right renal pelvis and ureter and extending into the bladder. Right radical nephroureterectomy was performed. The resected specimen showed a botryoid sarcoma-like appearance, occupied the right renal pelvis and ureter, and protruded into the bladder. Histologic findings showed typical triphasic Wilms' tumor. Botryoid Wilms' tumor has been reported in only 16 cases in the literature and in only 3 cases extended into the bladder.
Urology 05/2006; 67(4):845.e15-7. · 2.43 Impact Factor
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ABSTRACT: The authors describe a 1-year-old boy who was diagnosed with neuroblastoma by mass screening at age 6 months. The tumor originated from the left retroperitoneum and extended over the midline, involving major vessels and invading the spine with compression of the spinal cord. Although seven courses of chemotherapy consisting of vincristine sulfate, cyclophosphamide, pirarubicin hydrochloride, and cisplatin were administered, there was no reduction in tumor size or decrease in tumor markers. The patient received irinotecan 180 mg/m per day for 3 days. Approximately 3 weeks later the tumor had regressed remarkably, and tumor markers normalized after the second course of irinotecan. This therapy was given a total of four courses every 4 weeks, with the tumor shrinking successively in each session. Four years after treatment there is no sign of recurrence and the patient is doing well. This case may be the first report showing the dramatic efficacy of irinotecan in the treatment of chemoresistant neuroblastoma without the use of other antitumor agents. Irinotecan might be a promising drug in the management of patients with high-risk neuroblastoma.
Journal of Pediatric Hematology/Oncology 12/2005; 27(11):604-6. · 1.16 Impact Factor
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ABSTRACT: A 31-year-old woman had been suffering from fever and a sore throat since January 1999, and had a left neck lymphadenopathy in December 1999. Pathological findings of the biopsied lymphnode suggested malignant lymphoma. She was finally diagnosed as having a chronic active Epstein-Barr virus(EBV) infection because of abnormal antibody titers against EBV antigens and an increased EBV load in her peripheral blood. After receiving chemotherapy consisting of CHOP and high dose cytarabine, the amount of the EBV genome decreased below the detection limit before BMT. Therefore, instead of a conventional myeloablative transplant, we performed BMT using reduced-intensity conditioning regimens consisting of fludarabine and melphalan from an HLA-identical sibling donor. After 14 months, the patient remained in complete remission. Menstruation occurred on day 83 following BMT, and the serum level of LH and FSH on day 316 were within normal range. Under these circumstances, RIST seems to be one of the curative treatments for the patients with CAEBV with minimal late side effects.
[Rinshō ketsueki] The Japanese journal of clinical hematology 06/2004; 45(5):393-6.
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Takako Miyamura,
Naoki Sakata,
Takayuki Okamura, Masahiro Yasui,
Masami Inoue,
Keiko Yagi,
Masahiro Sako,
Yoshihiro Komada,
Takaharu Matsuyama,
Megumi Oda,
Yong-Dong Park,
Keisei Kawa
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ABSTRACT: Many studies have assessed the clinical significance of the detection of minimal residual disease (MRD) in acute leukemia. Thus far, many studies have suggested that MRD detection to evaluate the response to chemotherapy is useful for predicting the prognosis of childhood acute lymphoblastic leukemia (ALL). However, few studies have reported on the significance of MRD in childhood acute myeloid leukemia (AML), because of small numbers of patients and limited availability of MRD markers. Therefore, we monitored MRD using currently available markers at several points during the treatment for childhood AML and tried to intensify the treatment based on the results of MRD. Thirty-one patients (26 de novo cases and 5 other cases) were examined for MRD between February 1999 and May 2002. After the first consolidation therapy (consolidation 1), the expression of Wilms tumor gene (WT1) and/or leukemia-specific fusion genes such as AML1/MTG8, PML/RAR alpha, and MYH11/CBF beta were analyzed. Patients with positive MRD but in hematological remission at that point were recommended to undergo stem cell transplantation (SCT). Positive WT1 expression (more than 10(3) copies/microgram RNA) was detected in 18 of 31 patients (58.1%) at onset. After consolidation 1 therapy, the WT1 expression became negative in 14 of 18 patients. The AML1/MTG8 fusion gene was expressed in 8 patients, PML/RAR alpha was expressed in 3 patients, and MYH11/CBF beta was expressed in 1 patient. Four of the 8 patients with AML1/MTG8 expression and all 3 with PML/RAR alpha expression also demonstrated positive WT1 expression at onset. Eight (5 de novo cases and 3 other cases) of the 31 patients had no available MRD markers. Four patients who showed pesistently high expression of WT1 after consolidation 1 therapy underwent SCT, and only 1 patient remained in complete remission (CR). Among 14 patients who became negative for WT1 expression, 6 patients received SCT for various reasons. Among 8 patients with the AML1/MTG8 fusion gene, 2 became MRD negative and 6 continued to be positive. Four of these 6 patients underwent SCT, and all but one who underwent syngeneic SCT became MRD negative. On the other hand, 1 of the 2 patients who continued on chemotherapy continued to be MRD positive, suggesting a graft-versus-leukemia effect in allogeneic SCT. All patients with the PML/RAR alpha and MYH11/CBF beta fusion gene continued to be in CR. The 3-year event-free survival in de novo AML was 69.4% +/- 9.8% (n = 26), a result that is encouraging and superior to other reported outcomes. Thus, an MRD-based treatment strategy together with conventional risk factors appears to be required for further improving the outcomes of AML.
International Journal of Hematology 05/2004; 79(3):243-9. · 1.27 Impact Factor
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ABSTRACT: We performed autologous CD34+ stem cell transplantation in 3 patients with juvenile rheumatoid arthritis (JRA) refractory to conventional treatment. All patients had systemic type JRA. In case 1 (a 3-year-old boy), purified CD34+ cells from bone marrow were transplanted after a preconditioning regimen consisting of cyclophosphamide (200 mg/kg) and antithymocyte globulin (ATG) (40 mg/kg). However, the disease flared soon after transplantation. In case 2 (a 13-year-old girl) and case 3 (a 21-year-old woman), a preconditioning regimen consisting of etoposide (VP16) (2 g/m2), thiotepa (300 mg/m2), and ATG (40 mg/kg) was followed by transplantation of purified CD34+ stem cells harvested from peripheral blood mononuclear cells. The patients in cases 2 and 3 attained complete remission without any medication. Thus for patients with refractory JRA, autologous CD34+ cell transplantation appears to be a safe and feasible choice of treatment in terms of good quality of life. However, a greater number of patients and a longer observation period are needed before definitive conclusions can be drawn.
International Journal of Hematology 01/2004; 78(5):453-6. · 1.27 Impact Factor
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ABSTRACT: Epstein-Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a few weeks of primary infection, whereas the minority who survive have an increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP usually die by the age 40. Similarly, the majority of patients with chronic active EBV infection develop hemophagocytic syndrome, organ failure, opportunistic infection, and/or lymphoma and die within 5-10 years from onset. Recently, HSCT has provided successful outcomes in these patients. In this review, progress in the new therapeutic strategy is summarized, focusing on EBV-associated T/NK-cell lymphoproliferative disease (LPD), which is one of the heterogeneous EBV-associated disorder.
Critical Reviews in Oncology/Hematology 01/2003; 44(3):251-7. · 4.41 Impact Factor
