NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia.

A recent study identified a variant of the NUDT15 gene (rs116855232 C>T) associated with intolerance to thiopurine in Korean patients with Crohn's disease. This study prompted us to substantiate the finding in a Taiwanese population. Four hundred and four children with acute lymphoblastic leukemia (ALL), and 100 adults with chronic immune thrombocytopenic purpura or localized lymphoma having normal bone marrow were examined. Two candidate gene approaches, pyrosequencing for NUDT15 and TaqMan assay for thiopurine methyltransferase (TPMT) genotyping (rs1142345 A>G), were performed. We showed a risk allele frequency of NUDT15 of 11.6% in children with ALL and 15.5% in adults. By contrast, the risk allele frequency of TPMT was only 1.6% in children with ALL and 0.5% in adults. The high frequency of risk variant for NUDT15, but not the very low frequency of risk variant for TPMT, was closely associated with the intolerance to mercaptopurine in children with ALL in Taiwan, contrast to that of European descent. In regard to NUDT15 polymorphism, the maximal tolerable daily doses of mercaptopurine in homozygotes, heterozygotes and wild-type groups were 9.4 mg m-2, 30.7 mg m-2 and 44.1 mg m-2, respectively. The outcomes did not differ significantly among the different genotypes.

Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients.

Our study was designed to prospectively determine whether or not unrelated cord blood transplantation (CBT) can produce outcomes comparable to related donor transplantation for children with ß-thalassaemia. In 35 patients, 40 transplants were performed between October 2003 and September 2009. HLA matching at enrolment was 6/6 (n=8), 5/6 (n=16), 4/6 (n=27), or 3/6 (n=1) by low-resolution HLA-A, -B, and high-resolution DRB1. These patients received non-manipulated grafts without ex vivo expansion or T-cell depletion. The median number of nucleated and CD34+ cells infused was 7.8 × 10(7)/kg (range, 2.8-14.7 × 10(7)/kg) and 4.0 × 10(5)/kg (range, 1.7-19.9 × 10(5)/kg), respectively. The 5-year OS and thalassaemia-free survival after the first transplant were 88.3 and 73.9%, respectively. The cumulative incidence of TRM at 2 years was 11.7%. Fourteen patients developed chronic skin GVHD. Thirty patients were alive and transfusion-independent with a Lansky performance score ≥80% achieved between 6 and 76 months post transplant (median, 36 months). These data compare acceptably with the survival rates of related-donor BMT for thalassaemia and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for CBT.

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia.

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3+/-1.9% in 1997-2001 to 77.4+/-1.7% in 2002-2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997-2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

Evaluation of readmission in children receiving allogeneic hematopoietic stem cell transplantation: an institutional experience.

BACKGROUND: Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased potential of graft-versus-host disease. We sought to ascertain whether the use of UCB transplantation for pediatric patients changed the rates of unscheduled readmission. METHODS: We analyzed the rate, causes, and evolution of hospitalization among patients receiving UCB versus matched sibling bone marrow. A retrospective analysis of the data from 54 patients who received a matched sibling hematopoietic stem cell transplantation (HSCT; n = 25; 46.3%) versus an unrelated cord blood transplantation (CBT; n = 29; 53.7%) was performed on subjects treated between 1998 and 2006. Patients who died before discharge (n = 4) were excluded from the readmission analysis. RESULTS: A total of 50 patients were recruited for the analyses. Their median age was 6.7 years (range = 0.2-17 years). The median duration of hospitalization was 18 days shorter in the sibling HSCT group than in the unrelated CBT group. There were 89 readmissions in 25 patients (50%): 49 readmissions (55%) in the related HSCT and 40 (45%) in the unrelated CBT cohorts. Forty-two percent of readmissions were due to infections. Mortality following transplantation in 10 patients (19%) included sepsis (n = 3), intracranial hemorrhage (n = 1), pulmonary hemorrhage (n =1), and relapse (n = 5). Seven patients received HSCT from HLA-identical sibling donors and three from a cord blood donor. CONCLUSION: For both groups, infection was the most common reason for readmission followed by graft failure and extramedullary relapse. Although the median hospital stay was shorter in the sibling donor group, some uncertainty exists as to whether the increased risk for readmission was related to proportionally more malignancies or to the severity of the illness. After HSCT, there was a frequent use of hospital resources: 46% of patients were hospitalized for a median of 11 days. The resulting health expenses seem to be useful, since 81% of subjects survived at 36-month follow-up.

Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples.

c-KIT mutations have been described in core-binding factor (CBF) acute myeloid leukemia (AML) at diagnosis. The role of c-KIT mutations in the relapse of CBF-AML is not clear. The role of CSF1R mutation in the pathogenesis of AML remains to be determined. We analyzed receptor tyrosine kinases (RTKs) and Ras mutations on 154 children with AML. Also, we examined the paired diagnosis and relapse samples in CBF-AML. CBF-AML accounted for 27% (41/154). c-KIT mutations were detected in 41.5% of CBF-AML at diagnosis (6 in exon 8, 10 in exon 17 and 1 in both exons 8 and 17) , FLT3-TKD 2.7%, N-Ras mutations 7.3% and K-Ras mutations 4.9%. FLT3-LM and CSF1R mutations were not found in CBF-AML. The mutations of RTKs and Ras were mutually exclusive except for one patient who had both c-KIT and N-Ras mutations. Eight of the 41 CBF-AML patients relapsed; four patients retained the identical c-KIT mutation patterns as those at diagnosis, the remaining four without c-KIT mutations at diagnosis did not acquire c-KIT mutations at relapse. Our study showed that 54% of childhood CBF-AML had RTKs and/or Ras mutations; c-KIT but not CSF1R mutations play a role in the leukemogenesis of childhood CBF-AML.

Transplantation of unrelated donor umbilical cord blood utilizing double-unit grafts for five teenagers with transfusion-dependent thalassemia.

To augment graft cell dose, we evaluated the safety of the combined transplantation of two partially HLA-matched umbilical cord blood (UCB) units. Five patients with transfusion-dependent thalassemia, median age 11.1 years (range 10-13.1), received 2 UCB units after myeloablative conditioning. Cord blood units were a 4/6-HLA-match or better with the recipient, and contained a minimum combined pre-freeze CD34 cell dose of 3.0 x 10(5)/kg. All patients engrafted at a median of 15 days (range 12-19). Four patients with durable trilineage engraftment showed acute grade I-III GVHD; none developed extensive chronic GVHD until the date of last contact. The median times to red blood cell transfusion independence and platelet engraftment were 32 and 49 days after transplant, respectively. With a median follow-up of 18.5 months (range 11-32), four patients transplanted with UCB from two different partially HLA-matched donors were transfusion-independent. Therefore, transfusion of two partially HLA-matched UCB units is safe, and may overcome the cell-dose barrier that limits the use of UCB in long-term recipients of multiple transfusions for thalassemia.

CEBPalpha mutations in childhood acute myeloid leukemia.

CEBPalpha: mutations have been described in adult acute myeloid leukemia (AML) and conferred a favorable prognosis. However, CEBPalpha mutation has not been reported in children. We investigated 117 children with de novo AML using DNA PCR assay followed by sequencing for each PCR product. CEBPalpha mutations were detected in seven patients, four had FAB M2, two M1 and one M4. CEBPalpha mutations only occurred in patients with intermediate cytogenetics and not in 56 children with AML1-ETO, CBFbeta-MYH11, PML-RARalpha or MLL rearrangements. Five patients had mutations occurred in both N-terminal part and basic-leucine zipper (bZIP) domain, one had an N-terminal frameshift mutation and the remaining one had an inframe insertion in the bZIP domain. Cloning analysis on five samples carrying more than one mutations demonstrated one homozygous combined mutations and four heterozygous biallelic mutations. Four of seven CEBPalpha mutation(+) patients had cooperating mutations with FLT3-ITD or N-ras mutations compared to 27 in 109 CEBPalpha mutation(-) patients. Our results showed that CEBPalpha mutations occurred in 6% of childhood AML and most exhibited combined mutations in both N-terminal part and bZIP domain.

Efficacy of Helicobacter pylori eradication on platelet recovery in children with chronic idiopathic thrombocytopenic purpura.

AIM: Little is known about the influence of environmental factors on the epidemiology of idiopathic thrombocytopenic purpura (ITP). The role of Helicobacter pylori infection in relation to the development and/or persistence of ITP in infected patients remains controversial. Therapy used for eradicating H. pylori has led to a rise in platelet counts in a significant number of adult patients. but few paediatric studies have been undertaken to evaluate such treatment. The aim of this prospective study was to determine the prevalence of H. pylori and to evaluate whether H. pylori eradication can induce chronic ITP regression in children. METHODS: To investigate new, noninvasive techniques for diagnosis of H. pylori infection, an enzyme immunoassay for H. pylori antigens in faeces (HpSA) was evaluated. Patient eligibility criteria included isolated thrombocytopenia (< or = 50 x 10(9) L-(-1)) for more than 6 months without any identifiable cause and either normal or increased marrow megakaryocytes. H. pylori status was monitored before eradication and 4, 12, and 24 mo, after the end of treatment using Premier Platinum HpSA. RESULTS: In this study we evaluated 22 chronic ITP patients, 9 of whom were infected with H. pylori. Using repeated HpSA testing, we demonstrated for eradication of H. pylori after treatment in all infected patients. Five of the nine patients had increased platelet counts that persisted throughout the follow-up period. CONCLUSION: These results should stimulate additional research into the involvement of H. pylori infection in chronic ITP in childhood. This approach may offer an accepted algorithm at least for some of these patients.

Splenic abscess caused by group A beta-haemolytic streptococcus.

UNLABELLED: A case of a pyoderma complicated with splenic abscess and bacteraemia caused by group A streptococcus was treated successfully with antibiotics alone for 4 weeks. To our knowledge, this is the first reported case of splenic abscess associated with group A streptococcal bacteraemia. Advances in antibiotic therapy and imaging techniques have improved the management and outcomes of splenic abscesses. Clinicians should be aware of the possibility of splenic abscess after a pyoderma or a sepsis-like episode. CONCLUSION: Splenic abscesses can be diagnosed by serial ultrasound or CT scan examinations and should be treated with antibiotics for 4-6 weeks.

FLT3-TKD mutation in childhood acute myeloid leukemia.

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation.

Perforation of toxic megacolon in non-typhoid Salmonella enterocolitis spares young infants and is immune-mediated.

Intestinal perforation, a life-threatening complication of toxic megacolon (TM) following non-typhoid Salmonella infection, is relatively uncommon in infants less than 1 year of age. The situation, also found in typhoid fever, appears to be cytokine-mediated. This finding may justify immunotherapy for older children with TM associated with non-typhoid Salmonella infection in order to prevent this complication.

Pitfalls in the diagnosis of idiopathic pulmonary haemosiderosis.

Idiopathic pulmonary haemosiderosis is a very rare but devastating disorder. Diagnosis is sometimes difficult and the clinical course exceedingly variable, as illustrated by this report of a girl, aged 2 years 4 months, with severe iron deficiency anaemia. There was no response to iron therapy and transfusions. Sustained and striking reticulocytosis associated with low haptoglobin mimicked haemolytic anaemia. Positive faecal blood test was documented after repeated testing. There were no pulmonary symptoms. A chest radiograph showed bilateral diffuse alveolar infiltrates. Bronchoalveolar lavage fluid showed numerous siderophages. High resolution computed tomography of the thorax revealed early pulmonary fibrotic changes. Recurrent reticulocytosis appeared to be a very useful sign of recurrent bleeding episodes.

Epstein-Barr virus-associated hemophagocytic syndrome masquerading as lymphoma: a case report.

Virus-associated hemophagocytic syndrome (VAHS) is a non-neoplastic, generalized histiocytic proliferation with prominent hemophagocytosis associated with a systemic viral infection. Although Epstein-Barr virus (EBV) is one candidate virus for this association, thorough serologic and molecular biologic studies to determine the presence of the viral infection have been lacking in many reports. Whereas elevated liver function tests are common findings in patients with VAHS, exudative ascites and abdominal lymphadenopathy are rare. We describe a case of EBV-AHS masquerading as lymphoma in which treatment with intravenous immunoglobulins was associated with complete clinical remission at 2 years and 6 months after the onset. Regardless of the exact mechanism responsible for ascites formation in VAHS, this case adds support to the possible involvement of EBV in patients with abdominal lymphadenopathy and ascites.

Surgical implications of pseudomonas aeruginosa necrotizing fasciitis in a child with acute lymphoblastic leukemia.

Necrotizing fasciitis caused by Pseudomonas aeruginosa is extremely rare. Only 4 cases were reported in the literature. The authors report the occurrence of P aeruginosa necrotizing fasciitis starting out as a vulval abscess in a girl before induction chemotherapy for acute lymphoblastic leukemia. To our knowledge, this is the second case described in association with leukemia. In this case, the outcome was favorable because of early surgical intervention, confirming the diagnosis. J Pediatr Surg 36:948-950.

Acute disseminated encephalomyelitis in autoimmune hemolytic anemia.

A 16-year-old female with chronic autoimmune hemolytic anemia is presented. She was diagnosed with acute disseminated encephalomyelitis by clinical findings and magnetic resonance imaging (MRI), and the condition occurred after a systemic infection with Cryptococcus neoformans. Intravenous immunoglobulin therapy remarkably improved the patient's neurologic deficit and resolved abnormalities evidenced on MRI. To our knowledge, this report is the first of a pediatric patient with autoimmune hemolytic anemia complicated by acute disseminated encephalomyelitis that developed after an apparently successful treatment of cryptococcal meningitis.

Septic arthritis of the hip caused by Salmonella typhi.

We describe septic arthritis of the hip in a child with typhoid fever. The aetiological diagnosis was confirmed by a positive Widal test as well as by isolation of Salmonella typhi from joint aspirate. Treatment with ceftriaxone along with surgical drainage was successful.

Tumor lysis syndrome in an infant with Langerhans cell histiocytosis successfully treated using continuous arteriovenous hemofiltration.

Langerhans cell histiocytosis (LCH) is an enigmatic disease usually occurring in children. Tumor lysis syndrome (TLS) is a clinical syndrome associated with severe metabolic derangement and oliguric acute renal failure. In this report, we present the clinical course of an infant with advanced LCH who had TLS develop after chemotherapy. Treatment with continuous arteriovenous hemofiltration resulted in effective control of serum uric acid, potassium, creatinine, phosphorus, and blood urea nitrogen levels in the blood.

Treatment results of the TPOG-NHL92 protocols for childhood non-Hodgkin's lymphomas in Taiwan: a report from the Taiwan Pediatric Oncology Group (TPOG)

A nation-wide chemotherapeutic trial for childhood non-Hodgkin's lymphoma (NHL) was conducted by the Taiwan Pediatric Oncology Group (TPOG). Four TPOG-NHL92 protocols based on stage and histology were activated in 1992: TPOG-92LD (treatment duration: 8 months) was used for localized (stages I/II) NHL with any histology, 92LB (2 years), 92SNC (5 months), and 92LC (1 year) for advanced (stages III/IV) lymphoblastic (LB), small non-cleaved cell (SNC), and large cell (LC) lymphoma, respectively. From January 1992 through June 1998, 200 children with newly diagnosed NHL from 13 member hospitals of TPOG were enrolled. There were 140 boys and 60 girls. Their ages at diagnosis ranged from 2.4 months to 18.3 years with a median of 8.2 years. There were 54 (27.3%) patients with LB, 94 (47.5%) with SNC including B-cell acute lymphoblastic leukemia (B-ALL), and 50 (25.2%) with LC. Stages I, II, III, and IV (including B-ALL) of the disease comprised 5%, 10%, 43%, and 42% of cases, respectively. There were 176 patients eligible for evaluation of treatment results. The remission rate of induction was 82.4%, induction failed in 22 (12.5%) patients, and nine patients died during induction. As of August 31, 1999, 26 patients relapsed, six died during remission, one patient developed secondary acute myelomonocytic leukemia, and 105 patients remained in continuous remission with a median remission duration of 49 months. The event-free survival (EFS) at 7 years was 63.5%, 61.5% and 65% for LB, SNC, and LC groups (P = 0.8298). The 7-year EFS for stages I/II, III, and IV of the disease was 73%, 68.9%, and 50.3% (P = 0.0212), respectively. We concluded that following the strategy of stratification of therapy, only disease stages had prognostic significance in this study. More efforts are needed to improve our treatment results.