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Abstract Mercaptopurine intolerance is an adverse effect of mercaptopurine administration in pediatric patients with acute lymphoblastic leukemia (ALL). NUDT15 variants have emerged as major determinants of mercaptopurine intolerance, especially in the Asian population. Two variants, c.55_56insGAGTCG in exon 1 and c.415C > T in exon 3, were commonly detected in the same allele, named NUDT15*1/*2. Although rare, compound heterozygous mutations also occur, with the two variants on different alleles (NUDT15*3/*6), which may confer tolerance to considerably lesser mercaptopurine dosage. Sanger sequencing or pyrosequencing can determine the NUDT15 variants but not the phase. Here, we designed an allele-specific PCR (AS-PCR) with locked nucleic acid-modified primers. A cohort of 63 patients harboring heterozygous c.55_56insGAGTCG and c.415C > T NUDT15 variations was selected for haplotyping using AS-PCR. Of the 63 patients, 60 harbored the NUDT15*1/*2 variant and three harbored compound heterozygous mutations, including two NUDT15*3/*6 and one NUDT15*2/*7 variants. These findings suggest that AS-PCR can determine NUDT15 diplotype and identify patients with compound heterozygous NUDT15 variants, which may enable precise genetic diagnosis of NUDT15. Nevertheless, a larger clinical trial is required to understand the clinical significance of NUDT15*3/*6 in pediatric patients with ALL because of its low incidence rate and challenges in detecting this variant.

Abstract Neuroblastoma (NB) is a childhood tumor derived from the sympathoadrenal lineage of the neural crest progenitor cells. Core 1 β1,3-galactosyltransferase (C1GALT1) controls the crucial step of GalNAc-type O-glycosylation, and its altered expression affects cancer behaviors. However, the role of C1GALT1 in NB tumors remains unclear. Our data showed that C1GALT1 expression was significantly associated with differentiated tumor histology, correlated with TrkA expression, and predicted good prognosis independently in NB. Downregulation of C1GALT1 promotes malignant behaviors of NB cells in vitro and in vivo. Mechanistic investigation showed that knockdown of C1GALT1 in NB cells increased TrkA pulled down through Vicia villosa agglutinin beads, indicating the modulation of O-glycans on TrkA by C1GALT1, and silencing C1GALT1 suppressed the TrkA expression on the NB cell surface. Overexpression of C1GALT1 increased the protein levels of TrkA and promoted the differentiation of NB cells, whereas knockdown of TrkA inhibited C1GALT1-induced neuronal differentiation. Moreover, the inhibitory effects of migration and invasion in C1GALT1-overexpressing NB cells were blocked by TrkA downregulation. C1GALT1 knockdown enhanced AKT phosphorylation but attenuated ERK phosphorylation, and these properties were consistent in C1GALT1-overexpressing NB cells with TrkA knockdown. Taken together, our data provided the first evidence for the existence of GalNAc-type O-glycans on TrkA and altered O-glycan structures by C1GALT1 can regulate TrkA signaling in NB cells. This study sheds light on the novel prognostic role of C1GALT1 in NB and provides new information of C1GALT1 and TrkA on the pathogenesis of NB.

Background: Patients with childhood cancer are at increased risk for the development of second cancers. Methods: A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. Results: We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. Conclusion: Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.

Genetic changes in juvenile myelomonocytic leukemia (JMML) determine distinct subtypes, treatments, and outcomes. JMML with germline CBL mutation and somatic NRAS mutation possibly achieves spontaneous remission, but hematopoietic stem cell transplantation is indicated for other subtypes of JMML. We hereby report a child with JMML harboring a germline CBL mutation (c.1111T>C) and an NF1 variant (c.3352A>G) concurrently. After evaluation, we considered that the NF1 variant was not the major contributor. After one year of observation, this case had no signs of disease progression. This case highlights the importance of combining available evidence and clinical findings in caring for patients with unusual genomic variations.

Background/Purpose: Hemophagocytic lymphohistiocytosis (HLH), a rarely occurring syndrome with various triggers, is associated with early mortality. Owing to a lack of sufficient corresponding data in Taiwan, this study aimed to identify the outcome and potential factors associated with 180-day mortality in pediatric HLH. Methods: This retrospective study analyzed clinical and laboratory data on pediatric patients diagnosed with HLH at our institute (1995–2019). Logistic regression analysis was conducted to determine the associations between various factors and 180-day mortality. Results: Overall, 48 patients had HLH; their median age at diagnosis was 5 years (interquartile range: 2–11 years). Clinical presentations and laboratory parameters required for diagnosis included fever (98%), splenomegaly (79%), hyperferritinemia (98%), hemophagocytosis (94%), thrombocytopenia (90%), anemia (63%), hypertriglyceridemia (68%), and neutropenia (57%). The 5-year overall survival (OS) rate was 49%. Of 22 patients who had died at the last follow-up, 15 (68%) died within 180 days after diagnosis. In the multivariate analysis, hemoglobin (odds ratio [OR]: 0.564, p = 0.024) and triglyceride (OR: 1.004, p = 0.049) were significantly associated with 180-day mortality. Higher triglyceride levels at diagnosis were related to significantly lower 180-day OS rates (52.9% vs. 86.1%, p = 0.018). Conclusion: The overall outcome in our cohort was similar to that reported in some of the largest international cohorts. Hypertriglyceridemia and anemia may be indicative of poor prognoses in pediatric HLH patients independently and may be used to guide treatment strategy formulations for better outcomes.

Abstract Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.

Abstract Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0–18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996–December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008–2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996–2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1–RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008–2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008–2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008–2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents’ use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan.

Background/Purpose: The Taiwan Pediatric Oncology Group (TPOG) initiated two consecutive protocols for treating pediatric patients with Langerhans cell histiocytosis (LCH) since 1994. However, the results have not been analyzed and reported. This study aimed to investigate the survival outcomes of childhood LCH at the National Taiwan University Hospital over the past 20 years. Methods: Treatment of pediatric patients with LCH according to TPOG protocols at the National Taiwan University Hospital began in 1994. During 1994–2003, patients were treated using the TPOG LCH-94 protocol. After 2003, patients were treated using the TPOG LCH-2003 protocol. Clinical data of these patients were obtained retrospectively by reviewing electronic medical records. Patients were followed up until July 31, 2018. Results: Fifty-three newly diagnosed pediatric patients with LCH were treated at National Taiwan University Hospital during 1994–2015. Twenty-nine (54.7%) were treated with the TPOG LCH-94 protocol, and 24 (45.3%) were treated with the TPOG LCH-2003 protocol. The 5-year event-free survival and overall survival rates were 96.2 ± 2.6% standard error (SE) and 98.1 ± 1.9% (SE), respectively. Overall survival and 5-year event-free survival between patients treated with the TPOG LCH-94 and TPOG LCH-2003 protocols showed no significant difference. Multisystem, liver, or spleen diseases were associated with significantly bad survival outcomes. Among at-risk-organ involvement in LCH, liver involvement was an independent factor for poor prognosis. Conclusion: Clinical outcomes of children with LCH in Taiwan was good. The results of this study may help in the better classification of risk grouping for protocol designs in the future.

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple genetic alterations. To determine the frequency of common genetic mutations and possible prognostic markers in childhood T-ALL, we performed targeted sequencing of 67 genes across 64 cases treated according to Taiwan Pediatric Oncology Group protocols between January 2002 and December 2015. Together, 302 variants were identified in 60 genes including 233 single nucleotide variants and 69 indels. Sixty-four samples had a median number of six genetic lesions each (range 1–17). Thirteen genes had mutation frequencies > 10%, and 5 were > 20%, with the highest being NOTCH1 (70.31%). Protocadherins FAT1 (32.81%) and FAT3 (17.19%), and the ubiquitin ligase component FBXW7 (28.13%) had higher mutation frequencies than previously reported. Other mutation frequencies (PHF6, DNM2, DNMT3A, CNOT3, and WT1) were within previously reported ranges. Three epigenetic-related genes (KMT2D, DNMT3A, and EZH2) were mutated in our cohort. JAK-STAT signaling pathway genes had mutation frequencies of 3–13% and were observed in 23 cases (35.94%). Changes to genes in the ErbB signaling pathway were detected in 20 cases (31.25%). Patients with NOTCH1/FBXW7 mutations and RAS/PTEN germline exhibited better 5-year overall survival rates.

Backgorund: Hepatoblastoma is the most common primary liver malignancy in young children. Methods: To identify predictors of the clinical outcomes of hepatoblastoma, we retrospectively reviewed the medical records of 45 children with hepatoblastoma in the National Taiwan University Hospital from 1998 to 2018. All of the children were classified as high risk according to the pretreatment extent of disease (PRETEXT) staging system. The patients’ clinical data (sex, age at diagnosis, PRETEXT status, presence of metastasis or tumor rupture, tumor pathologic type, and clinical outcomes) were analyzed. Results: A total of 45 children with high-risk hepatoblastoma were diagnosed at an average age of 3.2 years. The survival analysis showed that the event-free survival duration was significantly longer in patients aged ≤1.25 years at diagnosis than those >1.25 years (hazard ratio = 2.86, p = 0.036). The absence of initial tumor rupture was associated with longer event-free survival (hazard ratio = 2.74, p = 0.039). Diagnosis at age >1.25 years was correlated with the presence of multifocal liver tumors (p = 0.0002) and tumor rupture at diagnosis (p = 0.02). There was no significant difference in event-free survival between the groups classified as intermediate versus high risk according to the Children's Hepatic tumors International Collaboration hepatoblastoma stratification system (p = 0.13). Conclusions: Diagnosis at ≤ 1.25 years of age and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma.

Background: Post-transplantation lymphoproliferative disorder (PTLD) is a heterogeneous, potentially life-threatening complication after liver transplantation in children. In this study, the disease characteristics, outcomes, and prognostic factors of PTLD were investigated. Methods: A retrospective, observational study was conducted on 16 pediatric liver transplant (LT) recipients who developed PTLD between February 2001 and December 2013 at a tertiary referral center in Taiwan. The disease characteristics and treatment outcomes of the patients were analyzed. Results: The median time from liver transplantation to the development of PTLD was 8 months. Early onset (

Background: Taiwan Pediatric Oncology Group (TPOG) initiated two consecutive protocols for treating pediatric patients with rhabdomyosarcoma since 1995. However, the results have not been analyzed and reported yet. The aim of this study is to investigate the treatment results of these two protocols in our hospital and to assess whether the results are comparable to other large-scaled studies. Methods: Treatment of pediatric patients with rhabdomyosarcoma according to TPOG protocols at National Taiwan University Hospital began in 1995. Between 1995 and 2006, patients were treated by TPOG RMS 95 protocol, which was based on IRS-III/IV. After 2007, patients were treated by TPOG RMS 2007 protocol which was adapted from IRS-V study. The clinical data of patients were obtained retrospectively by reviewing medical records. The date of the latest follow-up was December 31, 2016. Results: Thirty-seven patients were enrolled in this study. The 5-year overall survival (OS) and event-free survival rates of them were 54.7 ± 8.8% and 48.5 ± 8.6%, respectively. The 5-year OS rates for patients treated by TPOG RMS 95 and TPOG RMS 2007 protocols were 55.0 ± 11.1% and 55.9 ± 14.0%, respectively. Age at diagnosis of less than ten years old and receiving operation with gross total or subtotal tumor resection were identified as independent prognostic factors that predicted better outcomes in the multivariate analysis. Conclusion: The clinical outcomes of pediatric patients with rhabdomyosarcoma in Taiwan improved dramatically after incorporating two consecutive protocols from TPOG. In addition, the treatment results of these two protocols were comparable to large-scale studies of other countries. Keywords: Chemotherapy, Clinical outcomes, Pediatric patients, Rhabdomyosarcoma, Taiwan

Background: Invasive fungal infection (IFI) causes significant morbidity and mortality in patients with hematological malignancies, especially those with acute myeloid leukemia (AML), recurrent acute leukemia, high-risk acute lymphoblastic leukemia, and after allogeneic hematopoietic stem cell transplantation. The study aimed to investigate the clinical characteristics and outcome of IFIs in pediatric AML patients in a medical center in Taiwan. Methods: We performed retrospective chart reviews. We enrolled pediatric AML patients who were admitted to National Taiwan University Hospital between January 2005 and December 2014. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group 2008 consensus criteria. Results: In total, 78 patients were included for analysis. Twenty two episodes of IFIs were identified in 16 patients. The incidence for IFIs was 20.5% (16/78), and no specific trend of increase or decrease was observed through the study period (p=0.374). Candida species caused the majority (59.1%) of IFIs. Prolonged neutropenia and elevated alanine aminotransferase and creatinine values were factors associated with IFIs (p

Abstract Background Hepatoblastoma, a leading primary hepatic malignant tumor in children, is originated from primitive hepatic stem cells. We aimed to elucidate the relationships between the histological distribution of β-catenin and hepatic stem cell markers with the clinical outcomes of hepatoblastoma. Methods Immunohistochemistry was applied to detect β-catenin and hepatic stem cell markers expression in 31 hepatoblastoma tumors. We analyzed the relationship between the stem cell markers and the clinical course of hepatoblastoma. Results Thirty-one hepatoblastoma patients were diagnosed at a mean age of 2.58 ± 3.78 years, and 7 (22.58%) died. A lack of anticipated decrease in alpha-fetal protein levels after neoadjuvant chemotherapy indicated a higher mortality rate. Nuclear β-catenin expression was significantly associated with membranous epithelial cell adhesion molecule (EpCAM) expression in hepatoblastoma tumor specimens. The co-expression of nuclear β-catenin and membranous EpCAM together with an age at diagnosis ≤1.25 years were predictive of an alpha-fetoprotein level

Background: Cytomegalovirus (CMV) is a major pathogen causing significant mortality and morbidity in immunocompromised hosts. It is important to find risk factors associated with CMV viremia and its outcome. Methods: We investigated the incidence, time of onset, risk factors for CMV viremia, and characteristics of CMV diseases in 57 pediatric patients receiving hematopoietic stem cell transplantation (HSCT). Between August 2011 and March 2014, cases of pediatric HSCT patients at the National Taiwan University Children's Hospital were reviewed. Viremia was identified by plasma CMV real-time polymerase chain reaction (RT-PCR) assay. Results: Eighteen (32%) of the 57 patients developed CMV viremia at a median of 23 days post-HSCT (range −3 to +721 days). Eighty-nine percent (16/18) of CMV viremia occurred within 100 days posttransplantation. Four patients finally had CMV diseases (1 with CMV colitis and 3 with CMV pneumonitis) and one patient died of CMV pneumonitis complicated with pulmonary hemorrhage and sepsis. Significant risk factors associated with CMV viremia via univariate analysis include older age (p = 0.03), leukemic patients [odds ratio (OR): 5.2, 95% confidence interval (CI): 1.52∼17.7, p = 0.008), allogeneic HSCT (OR: 14.57, 95% CI: 1.76∼120.5, p = 0.002), antithymoglobulin (ATG) use before transplantation (OR: 5.09, 95% CI: 1.52∼16.9, p = 0.007), graft-versus-host disease (GvHD) (OR: 10.1, 95% CI: 2.7∼38.7, p

Mutations in the tet oncogene family member 2 gene (TET2) are frequently found in adult patients with acute myeloid leukemia (AML). Reports of TET2 mutations in children are limited. We assessed the prevalence of TET2 mutations in Taiwanese children with AML and analyzed their prognosis. Methods: Between 1997 and 2010, a total of 69 consecutive children with AML were enrolled at the National Taiwan University Hospital. The analysis for TET2 mutations was performed using direct sequencing. Clinical characteristics and overall survival (OS) were compared between patients with and without TET2 alterations. Results: Intronic and missense mutations were identified. No nonsense or frameshift mutations were observed. Two putative disease-causing missense mutations (S609C and A1865G) were identified in one patient. We estimated the prevalence of TET2 mutations in the current patient population to be 1.4%. The most common polymorphism was I1762V (45%), followed by V218M (12%), P29R (6%), and F868L (6%). Patients with polymorphism I1762V had an increased 10-year survival rate compared with patients without I1762V (48.4% vs. 25.7%, p = 0.049) by Chi-square test; OS was not different when examined using the Kaplan–Meier method (p = 0.104). Conclusion: The prevalence of TET2 mutations in children with AML compared with adults with AML was lower and less complex. Patient prognosis associated with TET2 mutations in children requires further investigation.

Although Down syndrome (DS) patients have a higher risk of developing transient myeloproliferative disorder (TMD) and acute leukemia, very little data is available on long-term outcome in Taiwanese patients. The current study was designed to determine the clinical characteristics and treatment outcome of DS patients with TMD or acute leukemia (AL). Methods: In 25 consecutive DS patients with TMD or AL enrolled from 1990 to 2012, clinical manifestations and treatment protocols were investigated and GATA1 (GATA binding protein 1) mutations were identified. Among 16 DS-acute myeloid leukemia (DS-AML) patients, clinical outcomes were compared between survivors and nonsurvivors. Results: Most of our DS patients had TMD (32%), acute megakaryoblastic leukemia (24%), or acute erythromegakaryoblastic leukemia (16%). The median follow-up time was 22.5 months (1–230 months). The age was younger and the hemoglobin (Hb) level and platelet count were higher in TMD patients than in leukemia patients. Among DS-AML patients, the Hb level was higher in survivors than nonsurvivors (8.8 ± 2.7 g/dL vs. 5.8 ± 2.4 g/dL; p = 0.044) and the age was older in relapsed patients than in nonrelapsed patients (43.8 ± 18 months old vs. 21.6 ± 8.6 months old; p = 0.025). The 3-year overall survival (OS) rate was 44%, higher in patients receiving appropriate chemotherapy than in those receiving inadequate treatment (63.6% vs. 0%, p = 0.001), and higher in those diagnosed with TMD or AL after 2008 than before 2008 (33.3% vs. 75%; p = 0.119). Conclusion: Outcome in DS-AML patients is optimal if appropriate treatment is provided. With modification of the treatment strategy in 2008, OS increased in Taiwan.

Human chorionic gonadotropin (HCG)-secreting germ cell tumors (GCTs) are rare childhood malignancies with unique clinical manifestations but delayed diagnosis is common. The purpose of this study is to investigate the clinical manifestations and endocrine dysfunction of Taiwanese children with HCG-secreting GCTs. Methods: From 1991 to 2011, 24 children (19 boys and five girls) with HCG-secreting GCTs were evaluated for their clinical findings and endocrine functions. Results: The mean age at diagnosis of the study patients was 10.8 ± 3.1 years. Of the 24 patients, 20 had central nervous system (CNS) GCTs and four had primary mediastinal GCTs (PMGCTs). The most common pathologic findings were germinomas and mixed type GCTs. The common initial symptoms and signs included polyuria, polydipsia, rapid growth, neurologic deficit,sexual precocity, and growth retardation. There was a delay in diagnosis in about 60% of patients. Diabetes insipidus and hypopituitarism were common endocrine dysfunctions in patients with CNSGCTs. Twelve boys had gonadotropin-independent puberty upon diagnosis, which were related to their high serum β-hCG levels. None of the five girls had this disorder despite their high serum β-hCG levels. Three of the four PMGCTs patients had the classic form of Klinefelter syndrome. Conclusion: Taiwanese children with HCG-secreting GCTs often have clinical manifestations related to endocrine dysfunction. High index of suspicion is important to avoid delayed diagnosis in these children.

The newly available iron chelator deferasirox (Exjade, Novartis) is expected to provide better long-term clinical outcomes and improved quality of life for patients with thalassemia than its predecessor, deferoxamine (Desferal, Novartis), because of its oral tablet form. Methods: We used the Markov model to estimate total additional lifetime costs and quality-adjusted life years (QALYs) gained with deferasirox versus deferoxamine in patients with transfusion-dependent thalassemia. Patients were assumed to be 2 years of age at initiation of chelation therapy. Clinical outcomes in terms of morbidity and mortality from associated complications and life expectancy for the study population were estimated using the databases of the Bureau of National Health Insurance and the Health and Vital Statistics of Taiwan. Treatment costs were based on analyses of health insurance claims for patients with transfusion-dependent thalassemia. Utilities in terms of quality of life were also included in the model. The incremental cost–utility ratio of deferasirox versus deferoxamine was defined by the ratio of the difference in expected lifetime costs to the difference in QALYs. One-way sensitivity analyses were performed to examine the robustness of the results to key assumptions. Results: Patients treated with deferasirox are expected to experience a lower incidence of associated complications and obtain 2.3 QALYs (discounted) at an additional lifetime cost of US$36,291 per patient (US$15,596 per QALY). Sensitivity analyses showed that the unit drug cost of deferasirox had the greatest impact on the incremental cost–utility ratio. In addition, the incremental cost–utility ratio will increase by delaying the starting age (2 years of age in our study) of chelation therapy. Conclusion: Compared with infusional deferoxamine, oral deferasirox improved clinical outcomes and quality of life in terms of iron chelation in transfusion-dependent patients with thalassemia at a reasonable cost from a healthcare perspective.

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder with diverse response rates to treatments that include corticosteroids, intravenous immunoglobulins (IVIG), and splenectomy. The predisposing causes of this autoimmune disorder, one of which is immunogenetic susceptibility, have not been fully determined. We investigated whether clinical features and human leukocyte antigen (HLA) genotypes influence the occurrence, treatment response, and disease duration of childhood ITP in Taiwan. Methods: We performed HLA genotyping of 70 Taiwanese children with ITP and of 70 healthy controls and compared the data. Demographic data were also collected and evaluated. Results: The frequencies of heterozygous HLA-A11 and the HLA-Cw1 allele were both significantly decreased in the ITP group (p = 0.0160 and p = 0.0089, respectively), whereas the frequency of heterozygous HLA-DQ5 was significantly increased in the ITP group (p = 0.0057). Patients with HLA-DRB1*11 or -DRB1*15 were more likely to respond poorly to corticosteroids than IVIG (p = 0.0446 and p = 0.0008, respectively). In addition, we observed a positive association between HLA-A11 homozygosity and the development of persistent or chronic ITP [odds ratio (OR) = 6.3165, p = 0.0479]. The presence of HLA-DRB1*08 was, however, negatively correlated with the development of persistent or chronic ITP (OR = 0.1729, p = 0.0657). Children with antecedent of preceding illness (API) and with a younger age of onset were more likely to experience a better treatment response and shorter course of ITP. Conclusion: We suggest that API, age of onset, and particular HLA class I and class II alleles, may be involved in and influence the occurrence and disease duration of childhood ITP, as well as responses to different therapeutic approaches.

Childhood acute lymphoblastic leukemia (ALL) with t(12;21), which results in expression of the ETV6/RUNX1 fusion gene, is the most common chromosomal lesion in precursor-B (pre-B) ALL. We identified 17 microRNAs that were downregulated in ETV6/RUNX1+ compared with ETV6/RUNX1- clinical samples. Among these microRNAs, miR-181a-1 was the most significantly reduced (by ~75%; P < 0.001). Using chromatin immunoprecipitation, we demonstrated that ETV6/RUNX1 directly binds the regulatory region of MIR181A1, and knockdown of ETV6/RUNX1 increased miR-181a-1 level. We further showed that miR-181a (functional counterpart of miR-181a-1) could target ETV6/RUNX1 and cause a reduction in the level of the oncoprotein ETV6/RUNX1, cell growth arrest, an increase in apoptosis, and induction of cell differentiation in ETV6/RUNX1+ cell line. Moreover, ectopic expression of miR-181a also resulted in decreased CD10 hyperexpression in ETV6/RUNX1+ primary patient samples. Taken together, our results demonstrate that MIR181A1 and ETV6/RUNX1 regulate each other, and we propose that a double negative loop involving MIR181A1 and ETV6/RUNX1 may contribute to ETV6/RUNX1-driven arrest of differentiation in pre-B ALL.

BACKGROUND: Patients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events. METHODS AND RESULTS: Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values