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Although sickle cell disease (SCD) is common in endemic areas of malaria, it is one of the rare diseases in Japan. Hence, SCD and its complications are not well established in Japan. An 11-year-old girl was referred to the specialized pediatric center of our hospital. She was born in Brazil and diagnosed with SCD after birth. However, she did not have a routine checkup in Japan. Owing to influenza viral infection, she developed vaso-occlusive pain crisis (VPC) and needed hospitalization for pain management. After admission, she developed dyspnea, needing intratracheal intubation and mechanical ventilation. A chest X-ray revealed bilateral pulmonary infiltration, suggesting acute chest syndrome (ACS) complicated with SCD. Intensive care, including transfusion of red blood cells, successfully improved her condition. Reportedly, half cases of VPC develop ACS, and the mortality of ACS is very high. Hence, when managing VPC cases, the prevention of ACS, through transfusion of red blood cells or infectious control, is imperative. Thus, Japanese hematologists and pediatricians should recognize SCD and its complications owing to an anticipated increase of foreign travelers or migrants in the future.

This study aimed to investigate the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with total body irradiation-based myeloablative conditioning (TBI-MAC) in pediatric patients with acute lymphoblastic leukemia (ALL). We retrospectively examined patients with ALL who underwent HSCT with TBI-MAC from January 2000 to August 2016 at our institute. We enrolled 67 patients with a median follow-up period of 8 years. The 5-year event-free survival (EFS) and overall survival (OS) were 51.2% and 59.6%, respectively. At the first complete remission, HSCT exhibited significantly superior EFS and OS in our patients than that in patients with other diseases. We encountered 57.9% of patients with at least one late complication. Major late complications were short stature (26.3%) and hypogonadism (18.4%). While late complications were observed in several recipients of HSCT, late complication-related deaths occurred in three patients. The TBI-MAC regimen led to favorable clinical outcomes in pediatric patients with ALL who underwent HSCT. Thus, proper evaluation and management of late complications are mandatory.

Herein, we report a successful treatment experience with romiplostim in a child with immune thrombocytopenia (ITP) refractory to eltrombopag. A 9-year-old female developed chronic ITP, which was refractory to standard treatments, including intravenous immunoglobulin, cepharanthine and splenectomy, and she thus became dependent on prednisolone (PSL). At age 12 years, eltrombopag was started, but failed to increase her platelet count. Another thrombopoietin receptor agonist (TPO-RA), romiplostim, possibly having a different mechanism of action, was then administered. Platelet counts increased and PSL could thus be terminated. Our case suggests TPO-RA alteration to potentially be effective for chronic refractory ITP.

Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required.

Asparaginase (ASNase) is one of the most important key drugs in the treatment of acute lymphoblastic leukemia (ALL). However, clinical hypersensitivity reactions often occur and lead to the discontinuation of ASNase treatment. Here, we report a retrospective study of 68 Erwinia ASNase (Erw-ASNase) administrations in 11 patients with childhood ALL who developed allergic reactions to E.coli-ASNase in our hospital between 2006 and 2012. The median age of the patients was 6 (range, 0 to 14). Erw-ASNase purchased overseas by the patients' guardians had already been administered when we obtained informed consent from the guardians. In all patients, fibrinogen and/or anti-thrombin III levels were decreased, but thrombosis did not develop. There was only one mild adverse event (grade 2 urticaria) in one patient, in whom Erw-ASNase could be continued after increasing the doses of premedication with antihistamine and prednisolone. Erw-ASNase could be safely administered to all patients.

Recently, bone marrow transplantation from an unrelated donor has been recommended as an option for the treatment of very severe aplastic anemia (vSAA) refractory to immunosuppressive therapy (IST) in the absence of a human leukocyte antigen-matched related donor (MRD). For SAA patients with complications such as bacterial infections, prompt transplantation using either a mismatched related donor or cord blood (CB) becomes necessary. However, the former option is associated with graft-versus-host disease, whereas the latter option is associated with a more significant risk of graft failure. We report a patient with vSAA refractory to IST that was repeatedly complicated by bacterial infection. An MRD was unavailable for this patient, so we decided on emergent transplantation and successfully performed CB transplantation (CBT) using a low-dose TBI conditioning regimen. Although it may be necessary to examine more clinical cases in the future, a conditioning regimen such as that involving low-dose TBI may decrease the risk of graft failure, and CBT may become a treatment option for vSAA in the absence of a suitable donor.

We report a case of a 15-year-old girl with severe aplastic anemia who underwent orthotopic liver transplantation 5 years ago for fulminant hepatic failure during the course of immunodeficiency of unknown etiology. She previously exhibited similar immunodeficiency and experienced recurrent viral infections. She developed jaundice at 9 years of age and was diagnosed with fulminant hepatitis. One month later, she underwent living donor liver transplantation, with the donor being her father. Five years after the liver transplant, pancytopenia was noted; she did not respond to treatment with increasing doses of tacrolimus/prednisone and administration of granulocyte-colony stimulating factor. Bone marrow biopsy was performed, and severe aplastic anemia was diagnosed. Six years after the liver transplant, she underwent bone marrow transplantation (BMT), with the donor being her HLA-matched sibling. However, she developed liver dysfunction with recovery of white blood cells. She developed sepsis, which eventually led to her death on day 30 after BMT.

Receptor-activator of NF-κB ligand (RANKL) and its specific receptor RANK are key regulators of bone remodeling, lymph node formation, establishment of the thymic microenviroment, mammary gland development during pregnancy, bone metastasis in cancer and sex-hormone, progestin, -driven breast cancer. RANKL and RANK are also expressed in the central nervous systems (CNS) especially existed in the main region of thermoregulation. Central RANKL injection to the rodents induces fever via PGE(2)/EP3R pathway. This pathway is related with inflammation related fever. On the other hand, female mice with RANK gene deletion in neuron and astrocytes show increased their basal body temperature at the dark phase, which suggests RANKL/RANK system also regulates physiological thremoregulation in female. Not only in rodents but also in human, two children with a homozygous RANK mutation exhibit an abrogated fever response in pneumonia compare with the age-matched children with pneumonia. Thus, the central RANKL/RANK pathway has an important role for thermoregulation.

We conducted a multicenter postmarketing study to investigate the efficacy and safety of reinduction therapy with a high-dose cytarabine-containing regimen for pediatric patients with relapsed or refractory acute leukemia. Seven of 13 patients (53.8%) with ALL achieved complete or partial remission, and only 1 of 6 patients (16.7%) with AML achieved partial remission. The frequent non-hematologic adverse events were gastrointestinal toxicities, such as vomiting, diarrhea and abdominal pain, as well as pyrexia and headache. Infection appeared in 9 of 20 (45%) patients. There were two death during reinduction therapy. One died of invasive bronchopulmonary aspergillosis, and the other died of intracranial hemorrhage and renal failure. These results indicated that a high-dose cytarabine regimen is effective as reinduction therapy in pediatric patients with relapsed ALL, and supportive care is essential to prevent or control treatment-related adverse events, such as infection.

We report on a case of pediatric acute lymphoblastic leukemia presenting with massive bone marrow necrosis. A 4-year-old boy complained of fever and leg pain. Laboratory data revealed pancytopenia, but bone marrow examination showed only necrotic materials. About one month later, repeated bone marrow examination showed leukemic cells and the necrotic marrow had disappeared. The patient was treated with standard chemotherapy and was successfully induced to complete remission. Patients with massive bone marrow necrosis should undergo bone marrow examination repeatedly to make the correct diagnosis.

A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: (A) melphalan and busulfan for 40 patients, (B) melphalan, busulfan and TBI for 44 patients, (C) other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 micrograms/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR 1, 41% for 41 patients at CR 2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR 1 and CR 2, the 5-year DFS by conditioning regimen was 63% for regimen (A), 54% for regimen (B) and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation.

Three patient with hemophilia B who developed anti-factor IX antibodies were reported. All 3 had allergic and/or anaphylactoid symptoms when the antibodies were found. The antibodies were noted between 4 and 17 days after exposure to factor IX. It was suggested that the anaphylactoid symptoms were closely related to the occurrence of anti-factor IX antibodies.

Hearing impairment is not often considered as a potential complication of general anesthesia, despite several reports of post-operative sensorineural hearing loss. These disorders have occurred after otological as well as cardiobypass surgery. We experienced two patients both of whom had undergone orthopedic surgery. In both cases the patients experienced bilateral reversible hearing impairment after general anesthesia with nitrous oxide. It is likely that a change in the middle ear pressure as a result of Eustachian tube dysfunction may have caused transient conductive hearing loss added to sensorineural hearing disorder. After these cases we interviewed a series of 115 patients who had undergone general anesthesia to assess the extent of this problem. Contrary to our expectation, 7 patients complained of ear fullness or autophony after inhalation of nitrous oxide, although these symptons diminished within 24 hours. It is important to be aware of the possibility of hearing impairment when nitrous oxide is used especially if the patient has a history of a previous middle ear disease.

Site-specific recombination of the TAL1 gene was analyzed by Southern blotting and polymerase chain reaction (PCR) in 44 cases of childhood T-cell acute lymphoblastic leukemia (T-ALL), 20 cases of childhood T-cell non-Hodgkin's lymphoma (T-NHL) and 35 cases of adult T-cell malignancies. This recombination was found in 10 (22.7%) of 44 childhood T-ALL patients, but in none of the T-NHL or adult T-cell malignancies. Recombination of the TAL1 gene was therefore suggested to be specific for childhood T-ALL. The immunophenotypic features of the 10 T-ALL patients with this recombination were CD1-, CD2+, CD4-, CD7+, CD10-, and they had a significantly better outcome than other T-ALL cases without the recombination. The PCR technique revealed minimal residual disease (MRD) in 2 patients. One showed persistent MRD, while in the other MRD was recognized only at initial diagnosis. Further investigation is needed whether T-ALL with this recombination constitutes a distinct clinical subgroup among childhood T-ALL patients.

Correlations between alterations of the p53 gene and clinical features were examined in childhood acute lymphoblastic leukemia (ALL). We analyzed 147 patients and 38 cell lines for p53 mutations within exons 5 to 9 (2 to 11 in some of them) by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. p53 gene mutations were found in 3 of 62 (5%) patients at diagnosis, 1 of 14 (7%) patients at relapse, and 13 of 20 (65%) cell lines in T-ALL, 2 of 20 (10%) patients at diagnosis, 4 of 4 (100%) patients at relapse, and 4 of 5 (80%) cell lines in t(1;19)-ALL, 1 of 23 (4%) patients at diagnosis, 2 of 22 (9%) patients at relapse, and 5 of 12 (42%) cell lines in common ALL other than t(1;19) or t(9;22)-ALL and 3 of 3 (100%) patients at diagnosis in B-ALL. In t(1;19)-ALL, p53 gene alterations were associated with a poor prognosis. The patients with p53 mutations had a trend towards poor prognosis in childhood ALL without B-ALL. p53 gene mutation is not always associated with the current prognostic factors. This alteration may become one of the important prognostic factors, if the detection of a small number of the leukemic cells with the p53 gene mutation would be possible.

A 9-year-old with chronic myelogenous leukemia (CML) who received bone marrow transplantation from an unrelated donor (UBMT), is reported. He also suffered from congenital heart disease (CHD) consisting of corrected transposition of the great arteries and dextrocardia. The cardiac output was within normal limits. The conditioning regimen included busulfan, melphalan, ALG and TLI. Cyclophosphamide was not used because of it cardiotoxicity. The HLA-phenotype of the donor was identical with that of the patient. DNA typing showed was haplodentical DRB1. The patient is alive 18 months after the UBMT. This case showed that UBMT was possible in a CML patient with CHD, without congestive heart failure.

We performed an open heart surgery for ventricular septal defect and right coronary cusp prolapse in a 5-year-old boy with hemophilia A. He has only 3.5% of factor VIII activity. This paper describes a successful perioperative management of hemophilia A. Previous infusion study of factor VIII concentrate showed an administration of 500 units of factor VIII increased its level from 3.5 to 25% two hours after the infusion. With this result we administered 1,500 units of concentrate 14 and 2 hours before the operation, factor VIII level was 201% after the induction of anesthesia. Sternotomy was uneventfully performed. Subarterial VSD was patch closed and right coronary cusp hung down into the defect was plicated. After intra cardiac repair, we administered 2,000 units of VIII factor concentrate, followed by an injection of protamin and its level was 240% at CCU. During the initial 3 postoperative day, patient was maintained with 1,500 units of factor VIII every 12 hours. Chest drains were removed on 2 postoperative day with no evidence of bleeding. Additional infusion of 1,000 units per a day was continued on postoperative days 4 through 17th. Subsequently factor VIII level was maintained more than 60%, so that we achieved successful perioperative course in a patient with hemophilia A.

E2A gene rearrangements and E2A-PBX1 chimeric mRNA produced by t(1;19) were examined in 50 cases with acute lymphoblastic leukemia (ALL). Nine of 10 ALL cases with t(1;19) showed the rearrangement by Southern blotting using the E2A gene probe when digested with Xba I, Bgl II, and Eco RI, and the remaining one having hyperdiploidy which was considered to be a sign of good prognosis, lacked E2A rearrangement. Six of 7 ALL cases with t(1;19) that were tested showed the predicted 164 bps band of E2A-PBX1 chimeric mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR), while a case having t(1;19) without E2A rearrangement and 10 cases lacking t(1;19) did not. Three ALL cases tested did not have E2A-PBX1 mRNA at the time complete remission 4 months after diagnosis. Forty ALL cases lacking t(1;19), including 4 cases with t(11;19), did not reveal rearrangement of E2A. We conclude that t(1;19)-ALL can be molecularly diagnosed, and minimal residual disease could be detected by the RT-PCR method.

We administered recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 5 micrograms/kg/day by intravenous drip infusion for 21 consecutive days in autologous bone marrow transplanted patients. The period of posttransplant neutropenia was markedly shortened by the rhG-CSF treatment; mean days required for neutrophil recovery (greater than 500/mm3) of 14.3 days in the rhG-CSF group (n = 21) versus 27.8 days in the historical control group (n = 11). More importantly, the numbers of febrile days between day 15 and day 28 were found to be fewer in the rG-CSF group than in control group. These effects were obtained without delay in the recovery of other blood cell series and without any side effect. We conclude that the posttransplant use of the rhG-CSF is beneficial for prevention and treatment of infectious complications after autologous bone marrow transplantation.

A preparative regimen for allogeneic bone marrow transplantation, consisting of total lymphoid irradiation (TLI) with 750 cGy and cyclophosphamide (CY), was used in five girls with aplastic anemia. All patients received bone marrow from HLA matched/mixed lymphocyte culture negative siblings. In our regimen the "inverted Y" field to irradiate the pelvic nodes was modified, which did not include the whole pelvic cavity in an attempt to protect the ovaries from irradiation. Although some of the pelvic nodes was supported not to be irradiated in order to protect the ovaries, engraftment occurred in all five patients including four who had been transfused prior to transplantation. All five are alive from 47 days to 1378 days (median 285 days) after transplantation without transplantation-associated complications. The calculated dose to the ovaries was sixteen percent of the entire dose of the regimen. Both of the two evaluable patients that had received transplantation just before or during the puberty are developing normal sex maturity including menstruation. This study suggests that our preparative regimen is effective not only for engraftment of the donor marrow but also for protecting the ovaries from irradiation.

Stage I neuroblastoma in a seven-year-girl have had local recurrence with bone metastasis. Second surgery was performed after the aggressive chemotherapy including cisplatin, VP16, cyclophosphamide, vincristine and doxorubicin. She underwent allogeneic bone marrow transplantation from her HLA identical brother, following the preparative regimen consisting of high-dose melphalan and total body irradiation (12 Gy). Clinical course after the transplantation was uneventful. She is still alive with no evidence of disease for twenty-eight months after the transplantation. It is suggested that bone marrow transplantation is an effective way of therapy even in a patient with relapsed neuroblastoma.

A 3-year-old boy was referred to our hospital in September 1985, because of pancytopenia. His bone marrow was normocellular with 18% blasts, which had Auer rod and were positive for peroxidase staining. A diagnosis of refractory anemia with excess blasts in transformation was made according to FAB criteria. Chromosome analysis of bone marrow cells showed normal male karyotype. He attained complete remission with aclarubicin and BH-AC and continued it until August 1987 when pancytopenia and hypoplastic bone marrow developed. Chromosome analysis of bone marrow cells showed normal male karyotype and gene analysis revealed germ-line configuration of breakpoint cluster region (bcr). Overt leukemia developed in May 1988 when his WBC count increased to 60, 600/microliters with 91% blasts, which were negative for peroxidase staining, positive for anti-Ia and CDw 41 by cell surface analysis, and positive for ultrastructurally demonstrable platelet peroxidase. A diagnosis of megakaryocytic leukemia was made. Chromosome analysis of bone marrow cells showed 46, XY, t(9;22) (q34;q11) and gene analysis revealed rearrangement of bcr. He died in November 1988. Our results and review of literature suggest that late appearing ph1 chromosome and rearrangement of bcr may occur in a variety of hematologic malignancies and influence the course of disease.

A 12-year old boy was admitted to Saitama Children's Medical Center because of fever and epistaxis. He had leukocytosis (WBC 40,800/microliters, blast 75%), anemia, thrombocytopenia and high levels of serum LDH, lysozyme, Vitamin B12, and plasma histamine. Bone marrow aspiration revealed hypercellular marrow with 31.2% blasts, 15.2% eosinophils, and 14.2% basophils. Blasts had Auer rods and were positive for peroxidase and negative for alpha-naphthyl butyrate esterase and PAS stainings. Ia, CD13 (My7), and CD19 (B4) antigens were expressed on his leukemic cells. Chromosomal study showed 46, XY, t(7;8) (q35;q22), del(9) (q13q22). Southern blot analysis using immunoglobulin constant region (C) probes revealed germline patterns of C mu, C kappa, C lambda, and breakpoint cluster region. A diagnosis of acute myelomonocytic leukemia (AMMoL, M4) was made. He attained a complete remission with daunorubicin and cytarabine, and 6 months later he received bone marrow transplantation from HLA-identical sister. This case had the common breakpoint 8q22 with ANLL with t(8;21) (q22;q22), and was unique AMMoL with proliferation of eosinophils and basophils in bone marrow.

Four pediatric patients with malignant brain tumors were treated with very high-dose etoposide plus very high-dose cyclophosphamide (HD-VP 16/CPM) followed by autologous bone marrow rescue. There were two brain stem gliomas, which were refractory to radiation therapy, ACNC, and beta-interferon and two relapsed malignant brain tumors. Both of the two with brain stem gliomas achieved response, one with clinical improvement and decrease of tumor size on CT scanning, the other with clinical improvement. Overall response duration was three months and nine months. Two patients with relapsed brain tumors received HD-VP 16/CPM as adjuvant chemotherapy. Low but significant levels of VP 16 and CPM were detected in CSF. Further investigation of HD-VP 16/CPM is needed as a chemotherapy for malignant brain tumors in children.