[Show abstract][Hide abstract] ABSTRACT: A 16-month-old girl was diagnosed with Epstein-Barr virus hemophagocytic lymphohistiocytosis and transferred to our hospital on the 58th day of the hemophagocytic lymphohistiocytosis after treatment failure according to the Hemophagocytic Lymphohistiocytosis-2004 protocol. On admission to our hospital, she had a flaccid paralysis of her lower limbs. Nerve conduction studies showed a acute motor axonal neuropathy, and a diagnosis of Guillain-Barre syndrome was established. Intravenous immunoglobulin G was started on the 57th day of the Guillain-Barre syndrome. To date, her neurological recovery is incomplete. For hemophagocytic lymphohistiocytosis, after treatment failure of THP-COP regimen (pirarubicin, cyclophosphamide, vincristine, and prednisone) and 2 courses of ESCAP regimen (etoposide, prednisone, cytarabine, L-asparaginase), we are now in the process of coordinating unrelated umbilical cord blood transplantation. To the best of our knowledge, we report the youngest case of Guillain-Barre syndrome accompanied by Epstein-Barr virus hemophagocytic lymphohistiocytosis. Rapid progression of Guillain-Barre syndrome, the electrophysiological subtype of Guillain-Barre syndrome, and treatment delay possibly led to poor neurological outcome.
[Show abstract][Hide abstract] ABSTRACT: Background:
Advances in cancer immunotherapy in the pediatric field are needed in order to improve the prognosis of children with malignancies. We conducted a prospective phase I/II study of WT1 peptide vaccination for children with relapsed or refractory malignancies.
The main eligibility criteria were affected tissues or leukemic cells expressing the WT1 gene, and patients (and donors for allogeneic hematopoietic stem cell transplantation) having HLA-A*24:02. Vaccination using the WT1 peptide (CYTWNQMNL), which was modified for higher affinity to this HLA-type molecule with the adjuvant Montanide ISA51, was performed weekly 12 times.
Twenty-six patients were enrolled and 13 (50.0%) completed the vaccination 12 times. Evidence for the induction of WT1-specific cytotoxic T-lymphocyte (CTL) responses without severe systemic side effects was obtained. Two out of 12 patients with bulky disease exhibited a transient clinical effect (one mixed response and one stable disease), three out of six patients with minimal residual disease achieved transient molecular remission, and five out of eight patients without a detectable level of the molecular marker, but with a high risk of relapse, had the best outcome of long-term continuous complete remission.
WT1 vaccination is a safe immunotherapy and induced WT1-specific CTL responses in children; however, as a single agent, vaccination only provided patients in remission, but with a high risk of relapse, with "long-term benefits" in the context of its use for relapse prevention. WT1 peptide-based treatments in combination with other modalities, such as anti-tumor drugs or immunomodulating agents, need to be planned.
No preview · Article · Oct 2015 · Pediatric Blood & Cancer
[Show abstract][Hide abstract] ABSTRACT: Background:
Patients with advanced malignancies in non-complete remission (CR) have a dismal prognosis after HLA-matched hematopoietic stem cell transplantation (HSCT). T-cell-replete HLA-haploidentical HSCT has remarkable anti-leukemia/tumor effects on these patients, but also a high risk of severe/extensive graft-versus-host disease (GHVD). Post-transplantation cyclophosphamide (PTCY) is regarded as a GVHD-specific immunosuppressant in adults, but its feasibility is unknown in children.
We performed a prospective feasibility study of PTCY at 50 mg/kg on day 3 for children with advanced leukemias or malignant solid tumors: refractory to chemotherapy or relapsed after conventional allogeneic HSCT. Conditioning consisted of fludarabine (180 mg/m2) and melphalan (140-210 mg/m2).
Long-term engraftments were achieved in 11 patients (73.3%) after bone marrow transplantation (BMT, n = 13) or peripheral blood (PB) stem cell transplantation (n = 2). The incidence of severe acute GHVD was 25.0% and that of extensive chronic GVHD 0.0% after evaluable BMT. CR was achieved in 6/15 and partial response in 4/15 as the best response. Finally, 11/15 experienced disease progression/relapse, 2/15 suffered treatment-related mortality without evidence of disease, and 2/15 are alive in continuous CR.
PTCY is feasible in children; however, for a better outcome in such patients with advanced malignancies, some modifications are anticipated.
No preview · Article · Oct 2014 · Pediatric Hematology and Oncology
[Show abstract][Hide abstract] ABSTRACT: Chronic Epstein-Barr virus-associated T-/natural killer-cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal, but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9 ± 6.9% and 93.3 ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and one patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor-cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, the patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor.
No preview · Article · Nov 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] 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.
No preview · Article · Aug 2011 · Pediatrics International
[Show abstract][Hide abstract] 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.
Preview · Article · Apr 2011 · Journal of General Virology
[Show abstract][Hide abstract] ABSTRACT: Since we reported the first successful case of allogeneic hematopoietic SCT (allo-HSCT), we have performed allo-HSCT for 29 patients with chronic active EBV infection (CAEBV), using either myeloablative conditioning (MAC) allo-HSCT (MAST) or reduced-intensity conditioning (RIC) allo-HSCT (RIST). In this retrospective analysis we compared the outcomes after MAST and RIST to identify the optimal conditioning for patients with CAEBV. Of 29 patients, 11 underwent allo-HSCT with MAC, consisting of TBI (12 Gy), etoposide (900 mg/m²) and CY (120 mg/kg) or melphalan (210 mg/m²), and the remaining 18 patients received allo-HSCT after RIC, consisting of fludarabine (∼ 180 mg/m²) and melphalan (140 mg/m²) or CY (120 mg/kg), with/without antithymocyte globulin and low-dose irradiation. Donor sources were 8 related BM, 2 related peripheral blood, 5 CD34 selected cells from HLA-haploidentical donors, 8 unrelated BM and 8 unrelated cord blood. The 3-year-EFS rate was 54.5 ± 15.0% for MAST group and 85.0 ± 8.0% for RIST group, and the 3-year OS rate was 54.5 ± 15.0% for MAST group and 95.0 ± 4.9% for RIST group (P = 0.016). Allo-HSCT after RIC seems to be a promising approach for the treatment of CAEBV.
Full-text · Article · May 2010 · Bone marrow transplantation
[Show abstract][Hide abstract] 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.
No preview · Article · Dec 2009 · [Rinshō ketsueki] The Japanese journal of clinical hematology
[Show abstract][Hide abstract] 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.
No preview · Article · Aug 2009 · Leukemia research
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
No preview · Article · Dec 2007 · [Rinshō ketsueki] The Japanese journal of clinical hematology
[Show abstract][Hide abstract] ABSTRACT: Purpose : To report two cases of hereditary retinoblastoma that rapidly multiplied after detection soon after birth. Cases : Retinoblastoma was detected in a female infant 5 days after birth and a male infant one month after birth. Only one eye was affected in both cases. The tumor was present as a single focus in the former and as 5 foci in the latter. Their fathers had been patients of retinoblastoma. The tumors became scarred after photocoagulation. Soon later, retinoblastoma developed bilaterally and grew rapidly in both cases in spite of photocoagulation and cryotherapy. Systemic chemotherapy was effective in preventing further occurrence of retinoblastoma in both cases after one year of age. Conclusion : Early-onset hereditary retinoblastoma need utmost care regarding occurrence and recurrence of tumors.
[Show abstract][Hide abstract] 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.
No preview · Article · Dec 2006 · [Rinshō ketsueki] The Japanese journal of clinical hematology
[Show abstract][Hide abstract] 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.
Full-text · Article · Aug 2006 · American Journal of Hematology
[Show abstract][Hide abstract] 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.