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Abstract: An abnormal immune response to common infection(s) may be a plausible etiological mechanism in childhood leukemia. We investigated whether 931 tagging single nucleotide polymorphisms (SNPs) selected in gene regions related to immune response are associated with childhood leukemia susceptibility in a hospital-based case–control study (63 cases and 148 controls) conducted among Korean children. The AT or TT genotype of rs7939734 in Fas-associated protein with death domain (FADD) was associated with increased risk of childhood leukemia compared with the AA genotype (odds ratio [OR] = 2.26, 95% confidence interval [95% CI] = 1.20–4.25, p trend = 0.0007, min p = 0.002, false discovery rate [FDR] p = 0.17). The CG or GG genotype of rs2301696 in TRPM5 was associated with decreased risk of childhood leukemia compared with the CC genotype (OR = 0.30, 95% CI = 0.14–0.63, p trend = 0.002, min p = 0.004, FDR p = 0.17). Our findings suggest that genetic polymorphisms in immune response genes might play a role in childhood leukemia development with limited biologic evidence. [Copyright &y& Elsevier]

Abstract: Background: Epidemiologic studies of human adenovirus (HAdV) in allogeneic hematopoietic cell transplantation (HCT) recipients have been conducted mostly in European countries where HAdV 2 (species C) has been most prevalent in the community. The main objective of this study was to investigate the epidemiology and the characteristics of HAdV infection in Korean allogeneic HCT recipients (<19 years). Methods: In a prospective study from April 2012 to September 2015, HAdV in blood, urine, and stool specimens were monitored weekly from transplantation to day 100 or after if clinically suspected. HAdV infection was defined as positive HAdV PCR result in any specimens regardless of symptoms. Results: A total of 1734 specimens were collected from 57 consecutively enrolled recipients. The cumulative incidence of HAdV infection at day 100, and 1 year was 10%, and 20%, and the incidence of viremia was 2% and 6%, respectively. The median onset time from HCT to viremia was 221 days (range, 7‐596 days). All viremia cases were caused by only HAdV 3 (species B), whereas several types were detected in stool. Among patients with HAdV infection, lower absolute lymphocyte counts and extensive chronic graft‐vs‐host disease were associated with viremia (P = .028 and P = .006, respectively). Conclusions: Compared to western studies, this study demonstrated a lower incidence and delayed onset of HAdV infections and HAdV 3 was most prevalent in Korea. [ABSTRACT FROM AUTHOR]

Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E−06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed. [ABSTRACT FROM AUTHOR]

Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E−06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality post cord blood transplantation (CBT). It has been suggested that the graft-versus-host disease (GVHD) and immunosuppressants have an impact on CMV infection. This study evaluated the incidence, outcomes, and risk factors of CMV infection, while focusing on GVHD and the use of immunosuppressants, in 103 children who had received CBT. Among the patients, 92.2% were positive for CMV serology, while CMV antigenemia was observed in 68.9% and CMV disease developed in 26.2%. CMV enterocolitis was the most common, followed by retinitis and pneumonia. Patients with positive CMV serology and grade II to IV GVHD were independently associated with CMV antigenemia. Recurrent CMV antigenemia was observed significantly more frequently in patients with extensive chronic GVHD. Patients with CMV disease showed significantly worse overall survival, relapse-free survival, and non-relapse mortality than those without CMV disease. In conclusion, CMV infection is common post-CBT in countries with a high rate of CMV seropositivity in the general population and is related to worse outcomes. GVHD severity is associated with the development and recurrence of CMV infection. Thus, efforts need to be made to prevent CMV infection in children post-CBT. [ABSTRACT FROM AUTHOR]

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients. [ABSTRACT FROM AUTHOR]

Background: Large inter-individual variations in drug metabolism pose a challenge in determining 6-mercaptopurine (6MP) doses. As the last product of 6MP metabolism, DNA-thioguanine nucleotide (DNA-TGN) could reflect the efficacy of 6MP, especially in patients harboring variants in the 6MP metabolism pathway. The aim of this study was to investigate the clinical significance of DNA-TGN monitoring in Korean pediatric acute lymphoblastic leukemia (ALL) patients, focusing on the NUDT15 genotype. Methods: The subjects of this study were patients who underwent ALL treatment with 6MP. Tests for the NUDT15 and TPMT genotypes were performed, and prospective DNA-TGN and erythrocyte TGN samples were collected after two weeks or more of 6MP treatment. DNA-TGN was quantified using the liquid chromatography-tandem mass spectrometry method. Results: A total of 471 DNA-TGN measurements in 71 patients were analyzed, which ranged from 1.0 to 903.1 fmol thioguanine/μg DNA. The 6MP intensity demonstrated a significant relationship with DNA-TGN concentration (P<0.001). Patients harboring NUDT15 variants were treated with a lower dose of 6MP (P<0.001); however, there was no significant difference in DNA-TGN concentration when compared to patients carrying wild-type NUDT15 (P = 0.261). These patients also presented higher variation in DNA-TGN levels (P = 0.002) and DNA-TGN/6MP intensity (P = 0.019) compared to patients carrying wild-type NUDT15. DNA-TGN concentration did not show a significant correlation with WBC count (P = 0.093). Conclusions: Patients harboring NUDT15 variants demonstrated similar DNA-TGN concentrations even at low doses of 6MP and showed high variability in DNA-TGN. Particularly in patients with NUDT15 variants who need a reduced 6MP dose, DNA-TGN could be applied as a useful marker to monitor the therapeutic effect of 6MP. [ABSTRACT FROM AUTHOR]

Background: MYCN amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification. Methods: Fifty-eight whole exome sequencing (WES) and forty-eight whole transcriptome sequencing (WTS) samples of MYCN non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs. Results: In the MYCN non-amplified NB WES data, maximum recurrent mutations were found in MUC4 (26%), followed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32-CBX3 (10%) and SAMD5-SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients. Conclusions: This study provides novel insights into the genomic background of MYCN non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB. [ABSTRACT FROM AUTHOR]

Purpose: We performed a prospective single-arm trial (NCT02782754) to explore the feasibility of reducing radiation therapy (RT) dose when induction chemotherapy is combined in the treatment of intracranial germinoma with beta-human chorionic gonadotropin levels <200 mIU/mL.Methods and Materials: All patients aged 3 to 35 years from November 2012 to June 2018 were eligible for this study. Four cycles of induction chemotherapy were given before RT. Carboplatin/etoposide and cyclophosphamide/etoposide regimens were used in alternation every 3 weeks. A dose of 18 Gy of craniospinal RT for metastatic tumors, whole brain RT for basal ganglia tumors, or otherwise whole ventricular RT followed by 12.6 Gy of boost RT to the primary tumor bed was administered after induction chemotherapy. The primary endpoint of this study was progression-free survival.Results: A total of 41 consecutive patients were enrolled (location: suprasellar in 12, pineal in 12, both suprasellar and pineal in 11, and basal ganglia in 6 patients). Eleven patients had leptomeningeal seeding. Toxicity during chemotherapy was mild, except for bone marrow suppression. Tumor status after induction chemotherapy was complete response in 33 patients and partial response in 8. All but 2 patients completed the scheduled treatment. All patients but 1 remained event free during a median follow-up of 3.4 (range, 0.3-7.0) years from diagnosis. The 1 patient experienced relapse and died of tumor bleeding. Late effects were not significant except for neuroendocrine dysfunction already present at diagnosis. Vertical growth and cognitive function were not significantly disturbed by treatment.Conclusions: This study showed the feasibility of reducing RT dose/volume with induction chemotherapy in pathologically pure germinoma with elevated beta-human chorionic gonadotropin levels up to 200 mIU/mL. [ABSTRACT FROM AUTHOR]

Background: In this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB). Methods: Newly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues. Results: In all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common. Conclusions: The strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study. [ABSTRACT FROM AUTHOR]

• Even long-term antiviral prophylaxis in hematopoietic cell transplantation (HCT) recipients was recommend as standard preventive stratagem for varicella zoster virus (VZV) infection, epidemiology of VZV infection in pediatric autologous HCT recipients is uncertain. • The incidence of VZV infection differs by age. • Difference of VZV infection was evaluated between single and tandem autologous HCTs. • We explored the risk factors for severe VZV infection in the pediatric autologous HCT population. Although long-term antiviral prophylaxis is recommended to prevent varicella zoster virus (VZV) infection in seropositive recipients of allogeneic and autologous (auto-) hematopoietic cell transplantation (HCT), studies of VZV infections in pediatric auto-HCT recipients are rare. This study aimed to investigate the incidence and characteristics of VZV infection in pediatric auto-HCT recipients and explore the risk factors of VZV infection and its effect on survival outcomes. This study included all pediatric patients who underwent auto-HCT at Samsung Medical Center, Seoul, Korea, between January 1998 and December 2013. Before 2006, short-term acyclovir prophylaxis was provided until neutrophil engraftment; thereafter, routine prophylaxis was not provided. Patients who developed either herpes zoster or chickenpox within 2 years from transplantation were identified, and a chart review was performed. A total of 413 recipients and 698 auto-HCTs were included. Sixty-one episodes of VZV infections were identified in 54 patients. Fourteen cases of VZV infection (23%; 14 of 61) occurred within 30 days after auto-HCT. The cumulative incidence of the first episode of VZV infection at 2 years after transplantation was 14% (95% confidence interval [CI], 7.9% to 22.8%) in all recipients and 9% (95% CI, 1.0 to 26.6) in VZV-seronegative patients. Notably, the VZV infection rate increased with age and the VZV infection rate in patients age 15 to 19 years was almost three times higher than in patients age 0 to 4 years (28% versus 10%; P =.003). However, there was no difference in the VZV infection rate between recipients of single auto-HCT and recipients of tandem auto-HCT. Two patients died of disseminated VZV infection. VZV infection is a considerable risk in auto-HCT recipients with or without short-term prophylaxis. Universal antiviral prophylaxis might be considered, particularly in older children, regardless of VZV serologic results. To our knowledge, this is the largest study of VZV infection in pediatric auto-HCT recipients reported to date. [ABSTRACT FROM AUTHOR]

Introduction: Under the hypothesis that early natural killer cell infusion (NKI) following haploidentical stem cell transplantation (haplo-SCT) will reduce relapse in the early post-transplant period, we conducted a pilot study to evaluate the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed previous tandem high-dose chemotherapy and autologous SCT. Methods: We used the high-dose 131I-metaiodobenzylguanidine and cyclophosphamide/fludarabine/anti-thymocyte globulin regimen for conditioning and infused 3 × 107/kg of ex-vivo expanded NK cells derived from a haploidentical parent donor on days 2, 9, and 16 post-transplant. Interleukin-2 was administered (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20 post-transplant. Results: Seven children received a total of 19 NKIs, and NKI-related acute toxicities were fever (n = 4) followed by chills (n = 3) and hypertension (n = 3); all toxicities were tolerable. Grade ≥II acute GVHD and chronic GVHD developed in two and five patients, respectively. Higher amount of NK cell population was detected in peripheral blood until 60 days post-transplant than that in the reference cohort. Cytomegalovirus and BK virus reactivation occurred in all patients and Epstein-Barr virus in six patients. Six patients died of relapse/progression (n = 5) or treatment-related mortality (n = 1), and one patient remained alive. Conclusion: NKI following haplo-SCT was relatively safe and feasible in patients with recurrent neuroblastoma. Further studies to enhance the graft-versus-tumor effect without increasing GVHD are needed. [ABSTRACT FROM AUTHOR]

Advances in genomic technologies and the development of targeted therapeutics are making the use of precision medicine increasingly possible. In this study, we explored whether precision medicine can be applied for the management of refractory/relapsed pediatric solid tumors by discovering actionable alterations using targeted panel sequencing. Samples of refractory/relapsed pediatric solid tumors were tested using a targeted sequencing panel covering the exonic DNA sequences of 381 cancer genes and introns across 22 genes to detect clinically significant genomic aberrations in tumors. The molecular targets were tiered from 1 to 5 based on the presence of actionable genetic alterations, strength of supporting evidence, and drug availability in the Republic of Korea. From January 2016 to October 2018, 55 patients were enrolled. The median time from tissue acquisition to drug selection was 29 d (range 14–39), and tumor profiling was successful in 53 (96.4%) patients. A total of 27 actionable alterations in tiers 1–4 were detected in 20 patients (36.4%), and the majority of actionable alterations were copy number variations. The tiers of molecular alterations were tier 1 (clinical evidence) in 4 variants, tier 2 (preclinical evidence) in 8 variants, tier 3 (consensus opinion) in 2 variants, and tier 4 (actionable variants with a drug that is available in other countries but not in the Republic of Korea) in 9 variants. In one patient with relapsed neuroblastoma with ALK F1174L mutation and ALK amplification, lorlatinib was used in a compassionate use program, and it showed some efficacy. In conclusion, using a targeted sequencing panel to discover actionable alterations in relapsed/refractory pediatric solid tumors was practical and feasible. [ABSTRACT FROM AUTHOR]

The role of unrelated donor HSCT for children with de novo AML in CR1 is controversial. We performed this study to investigate the feasibility of unrelated donor HSCT who initially had intermediate‐ or high‐risk cytogenetics. We retrospectively reviewed medical records of patients with AML who received unrelated HSCT in CR1 at Samsung Medical Center between November 2001 and January 2012. Patients were allocated based on karyotype at diagnosis as follows: (a) low‐risk: inv(16), t(16;16), t(8;21), and t(15;17); (b) high‐risk: ‐5, 5q‐, ‐7, 3q abnormalities, t(8;16), t(6;9), t(6;11), t(6;21), t(10;11), complex karyotype (≥3 abnormalities), and acute megakaryocytic leukemia without t(1;22); and (c) IR: all the other karyotypes including normal. Patients in intermediate‐ or high‐risk group who were transplanted with either unrelated CB or matched unrelated BM/mobilized PB in their CR1 were included in this study. The projected OS and EFS rates were 74.9% and 71.1%, respectively, with a median follow‐up of 87.3 months after transplantation. The EFS was 70.1%, 80.7%, and 73.9% for CB, BM, and mobilized PB groups, respectively (P = 0.89), and 73.9% and 70.6% for IR and high‐risk groups (P = 0.76). The leading cause of death was relapse (n = 8), and only one patient died from non‐relapse cause. Unrelated donor HSCT seems a feasible approach for children with intermediate‐ or high‐risk AML in CR1. Relapse remains the leading cause of treatment failure among these patients. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea. Methods: From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6‐mercaptopurine were included in the study. One hundred and twenty‐three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction‐restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses. Results: The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine‐related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05). Conclusions: Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to explore the roles of N‐myc and caspase‐8 in TRAIL‐resistant IMR‐32 cells which exhibit MYCN oncogene amplification and lack caspase‐8 expression. Materials and methods: We established N‐myc–downregulated IMR‐32 cells using shRNA lentiviral particles targeting N‐myc and examined the effect the N‐myc inhibition on TRAIL susceptibility in human neuroblastoma IMR‐32 cells expressing caspase‐8. Results: Cisplatin treatment in IMR‐32 cells increased the expression of death receptor 5 (DR5; TRAIL‐R2), but not other receptors, via downregulation of NF‐κB activity. However, the cisplatin‐mediated increase in DR5 failed to induce cell death following TRAIL treatment. Furthermore, interferon (IFN)‐γ pretreatment increased caspase‐8 expression in IMR‐32 cells, but cisplatin failed to trigger TRAIL cytotoxicity. We downregulated N‐myc expression in IMR‐32 cells using N‐myc–targeting shRNA. These cells showed decreased growth rate and Bcl‐2 expression accompanied by a mild collapse in the mitochondrial membrane potential as compared with those treated with scrambled shRNA. TRAIL treatment in N‐myc–negative cells expressing caspase‐8 following IFN‐γ treatment significantly triggered apoptotic cell death. Concurrent treatment with cisplatin enhanced TRAIL‐mediated cytotoxicity, which was abrogated by an additional pretreatment with DR5:Fc chimera protein. Conclusions: N‐myc and caspase‐8 expressions are involved in TRAIL susceptibility in IMR‐32 cells, and the combination of treatment with cisplatin and TRAIL may serve as a promising strategy for the development of therapeutics against neuroblastoma that is controlled by N‐myc and caspase‐8 expression. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to report our single-center experience of allogeneic hematopoietic cell transplantation (HCT), which has been the only curative option for certain patients with lethal primary immunodeficiencies (PIDs).Methods: We summarized the results of HCT performed for patients with PIDs for 11 consecutive years from 2006 to 2016 at Samsung Medical Center, Seoul, Korea. Twenty-six patients with PIDs received HCT. Most had chronic granulomatous disease (42.3%), Wiskott Aldrich syndrome (15.4%), or severe combined immunodeficiency (11.5%).Results: Nine patients (34.6%) received HCT during the former half period and 17 patients (65.4%) during the latter half period. Donor types were categorized as: matched sibling donor (n = 5), unrelated donor (n = 17), and familial mismatched donor (FMMD) (n = 4). Unrelated HCT and FMMD transplantation were increasingly performed in the latter half period compared to the first (5 vs. 16, P = 0.034). Five patients experienced initial engraftment failure, but all of them were eventually engrafted after additional HCTs. The 3-year probability of overall survival was 72.0%. Seven patients (26.9%) died, and the causes of death were bacterial sepsis (n = 4), pneumonia (n = 1), chronic graft-versus-host disease (GVHD) (n = 1), and diffuse alveolar hemorrhage (n = 1). Two patients with bacterial sepsis and a patient with pneumonia also had chronic GVHD. Unrelated HCT and use of methotrexate were associated with poor outcome. Complete chimerism was attained in 85.0% at 1 year after HCT.Conclusion: PID candidates have been increasingly identified for allogeneic HCT in Korea, and the majority of them could be cured by HCT. Establishment of a systematic registry of PID patients for HCT is needed. [ABSTRACT FROM AUTHOR]

In this study, the effect of adipose tissue stem cells (ASCs) on the growth of acute lymphoblastic leukemia (ALL) cells was examined in an in vivo model. We established ALL cell lines expressing firefly luciferase (ALL/fLuc) by lentiviral infection that were injected intraperitoneally to NOD/SCID mice. The luciferase activities were significantly higher in mice co-injected with 105 ALL/fLuc cells and ASCs than in those injected with ALL/fLuc cells alone. Co-injection of 105 ALL/fLuc cells and ASCs in differing ratios into mice gradually increased the bioluminescence intensity in all groups, and mice co-injected with 1 or 2 × 106 ASCs showed higher bioluminescence intensity than those receiving lower numbers. Interestingly, in the mice injected with 105 or 107 ALL/fLuc cells alone, the formation of tumor masses was not observed for at least five weeks. Moreover, co-injection of 107 ALL/fLuc cells and 5 × 105 ASCs into mice increased the bioluminescence intensity in all groups, and showed significantly higher bioluminescence intensity compared to mice co-injected with human normal fibroblast HS68 cells. Overall, ASCs promote the growth of ALL cells in vivo, suggesting that ASCs negatively influence hematologic malignancy, which should be considered in developing cell therapy using ASCs. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we evaluated the results of multimodal treatment that included tandem HDCT/auto‐SCT in children with anaplastic ependymomas. Fourteen patients with anaplastic ependymomas were enrolled from 2006 to 2014. Six cycles of induction chemotherapy were administered to all patients before they underwent tandem HDCT/auto‐SCT. Patients who were older than 3 years of age were administered RT after two cycles of induction chemotherapy. In patients under 3 years of age, RT was either omitted or delayed until they reached 3 years of age, if the patients experienced CR after tandem HDCT/auto‐SCT. All patients, including two who experienced disease progression during induction treatment, underwent the first HDCT/auto‐SCT, and 13 subsequently underwent the second HDCT/auto‐SCT. One patient died from hepatic VOD during the second HDCT/auto‐SCT; other toxicities occurring during tandem HDCT/auto‐SCT were manageable. Relapses or progression occurred in seven patients, and five of seven of them remain alive till date after salvage treatment, including surgery and RT. The 5‐year overall and event‐free survival rates were 85.1% ± 9.7% and 50.0% ± 13.4%, respectively. These findings suggest that multimodal treatment including tandem HDCT/auto‐SCT could be a feasible option for improving survival in children with anaplastic ependymomas. [ABSTRACT FROM AUTHOR]

Human mesenchymal stem cells (MSCs) are known for their prostaglandin E2 (PGE2)-mediated immunosuppressive function but the precise molecular mechanisms underlying PGE2 biosynthesis during inflammation have not been completely elucidated. In this study, we have investigated the involvement of PGE2 pathway members in PGE2 production by bone marrow (BM)-MSCs in response to inflammatory stimuli, and their role in immunosuppression mediated by BM-MSCs. We found that IFN-γ and TNF-α increased cyclooxygenase (COX)-2 expression but not that of prostaglandin E synthase (PGES), or PGE2 production. On the other hand, the toll like receptor 3 (TLR3) stimulant poly(I:C) increased expression of both COX-2 and PGES, resulting in a significant increase in PGE2 levels. This effect was reversed upon COX-2 inhibition with indomethacin or PGES downregulation by siRNA. Reduced PGE2 levels decreased MSC’s capacity to inhibit hPBMC proliferation. In addition, administration of MSCs with inhibited PGES expression into mice with graft-versus-host disease (GVHD) did not reduce mortality. In summary, the present study reveals that upregulation of PGES via TLR3 is critical for BM-MSCs-mediated immunosuppression by PGE2 secretion via the COX-2/PGE2 pathway. These results provide a basis for understanding the molecular mechanisms underlying the PGE2-mediated immunosuppressive properties of MSCs. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptor (PPAR) γ, a subtype of PPARs, is a member of the nuclear receptor family. PPARγ and its ligands contribute to various types of diseases including cancer. Given that currently developed therapies against leukemia are not very effective or safe, PPARγ ligands have been shown to be a new class of compounds with the potential to treat hematologic malignancies, particularly leukemia. The capability of PPARγ ligands to induce apoptosis, inhibit proliferation, and promote differentiation of leukemia cells suggests it has significant potential as a drug against leukemia. However, the specific mechanisms and molecules involved are not well-understood, although a number of PPARγ ligands with anti-leukemic effects have been identified. This may explain why PPARγ ligands have not been widely evaluated in clinical trials. To fill the gaps in the lack of understanding of specific anti-leukemic processes of PPARγ ligands and further adapt these molecules as anti-leukemic agents, this review describes previous studies of the anti-leukemic effects of PPARγ ligands. [ABSTRACT FROM AUTHOR]

We reviewed the medical records of five patients with T-B+NK- severe combined immunodeficiency (SCID) who received minimal dose allogeneic hematopoietic cell transplantation (HCT) (total nucleated cell count (TNC) lower than 1.0 × 108/kg). Patients were administered a median of 5.0 mL of bone marrow or peripheral blood without conditioning (in four) or with anti-thymocyte globulin alone (in one). Three patients received HCT from a matched sibling donor, one from unrelated donor, and one from familial mismatched donor. The median TNC and CD34+ cells were 0.54 (0.29–0.84) × 108/kg and 0.61 (0.35–0.84) × 106/kg, respectively. Engraftment was achieved in all. Total T cell, CD4+ cell, and CD8+ cell recovery was obtained within a year in four, and immunoglobulin replacement was discontinued in all. All patients survived, exhibiting stable donor chimerism. We obtained sufficient therapeutic effects with minimal dose transplantation without intensive conditioning in patients with T-B+NK- SCID. • Patients with SCID were administered a median of 5.0 mL of BM or PB grafts. • The median TNC and CD34+ cells were 0.54 × 108/kg and 0.61 × 106/kg, respectively. • Except for one patient, T cell recovery was obtained within a year. • IVIg replacement was discontinued in all patients at a median of 4 months. • All survived without disease recurrence, exhibiting stable donor chimerism. [ABSTRACT FROM AUTHOR]

While a portable microscopic cell counter has been evaluated to enumerate residual white blood cells (WBCs) in red blood cells and platelet concentrates at blood centers, it has not yet been assessed in a hospital blood bank. We investigated the performance of this device and evaluated its accuracy, along with its benefits in time management. Residual WBCs from each of 100 apheresis platelet specimens were measured manually using a Nageotte chamber, along with flow cytometry methods and an ADAM-rWBC automated instrument (NanoEnTek, Seoul, South Korea). The efficiency was calculated by measuring the time required for the analysis of one specimen ten times consecutively. Flow cytometry and the ADAM-rWBC were able to detect four sporadic cases that had residual WBCs exceeding 1/μL that were not detected by the manual method. Analysis time was the shortest with the ADAM-rWBC, followed by flow cytometry and the manual method. Our data suggest that hospital blood banks require quality control of residual WBCs; among the methods evaluated in this study, the portable microscopic cell counter offers the best time efficiency. [ABSTRACT FROM AUTHOR]

Monosomal karyotype (MK) is known as a far end of the unfavorable cytogenetics in adult acute myeloid leukemia (AML), while available data in childhood AML is scarce. In this study, we investigated the prevalence and prognostic value of MK with retrospectively analyzed 119 patients newly diagnosed with childhood de novo AML. Ten patients (8.4%) revealed to have MK. All MK-positive (MK(+)) AML were associated with complex cytogenetic abnormalities and belonged to the cytogenetic adverse-risk group. Nine of MK(+) patients (90%) achieved complete remission. The event-free survival (EFS) and overall survival (OS) of MK(+) adverse group were comparable to the ESF and OS of MK-negative non-adverse group (EFS 60.0 ± 15.5% vs 59.0 ± 5.1%, P = 0.925; OS 70.0 ± 14.5% vs 58.1 ± 5.3%, P = 0.696). In multivariate analysis, MK was not an independent adverse prognostic factor for EFS (hazard ratio 0.45, 95% C.I. 0.13–1.50, P = 0.194). In addition, 7 of 9 MK(+) patients who received allogeneic hematopoietic stem cell transplantation (HSCT) survived event-free, with a median follow-up of 64 months. In conclusion, MK did not act as an adverse prognostic factor in childhood de novo AML. Allogeneic HSCT might have contributed to the excellent outcome of MK(+) childhood de novo AML. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed infectious complications during tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in children and adolescents with high-risk or recurrent solid tumors. A total of 324 patients underwent their first HDCT/auto-SCT between October 2004 and September 2014, and 283 of them proceeded to their second HDCT/auto-SCT (a total of 607 HDCT/auto-SCTs). During the early transplant period of 607 HDCT/auto-SCTs (from the beginning of HDCT to day 30 post-transplant), bacteremia, urinary tract infection (UTI), respiratory virus infection, and varicella zoster virus (VZV) reactivation occurred in 7.1%, 2.3%, 13.0%, and 2.5% of HDCT/auto-SCTs, respectively. The early transplant period of the second HDCT/auto-SCT had infectious complications similar to the first HDCT/auto-SCT. During the late transplant period of HDCT/auto-SCT (from day 31 to 1 year post-transplant), bacteremia, UTI, and VZV reactivation occurred in 7.5%, 2.5%, and 3.9% of patients, respectively. Most infectious complications in the late transplant period occurred during the first 6 months post-transplant. There were no invasive fungal infections during the study period. Six patients died from infectious complications (4 from bacterial sepsis and 2 from respiratory virus infection). Our study suggests that infectious complications are similar following second and first HDCT/auto-SCT in children. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for severe aplastic anemia (SAA); however, the optimal conditioning regimen for HSCT with an unrelated donor has not yet been defined. A previous study using a fludarabine (FLU), cyclophosphamide (Cy), and antithymocyte globulin (ATG) conditioning regimen (study A: 50 mg/kg Cy once daily i.v. on days −9, −8, −7, and −6; 30 mg/m 2 FLU once daily i.v. on days −5, −4, −3, and −2; and 2.5 mg/kg of ATG once daily i.v. on days −3, −2, and −1) demonstrated successful engraftment (100%) but had a high treatment-related mortality rate (32.1%). Therefore, given that Cy is more toxic than FLU, we performed a new phase II prospective study with a reduced-toxicity regimen (study B: 60 mg/kg Cy once daily i.v. on days −8 and −7; 40 mg/m 2 FLU once daily i.v. on days −6, −5, −4, −3, and −2; and 2.5 mg/kg ATG once daily i.v. on 3 days). Fifty-seven patients were enrolled in studies A (n = 28) and B (n = 29), and donor type hematologic recovery was achieved in all patients in both studies. The overall survival (OS) and event-free survival (EFS) rates of patients in study B was markedly improved compared with those in study A (OS: 96.7% versus 67.9%, respectively, P = .004; EFS: 93.3% versus 64.3%, respectively, P = .008). These data show that a reduced-toxicity conditioning regimen with FLU, Cy, and ATG may be an optimal regimen for SAA patients receiving unrelated donor HSCT. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effect of cell density on the proliferation activity of human mesenchymal stem cells (MSCs) derived from adipose tissue (AT-MSCs) over time in culture. Passage #4 (P4) and #12 (P12) AT-MSCs from two donors were plated at a density of 200 (culture condition 1, CC1) or 5000 (culture condition 2, CC2) cells cm−2. After 7 days of incubation, P4 and P12 AT-MSCs cultured in CC1 were thin and spindle-shaped, whereas those cultured in CC2 had extensive cell-to-cell contacts and an expanded cell volume. In addition, P4 and P12 AT-MSCs in CC1 divided more than three times, while those in CC2 divided less than once on average. Flow cytometric analysis using 5(6)-carboxyfluorescein diacetate N-succinimidyl ester dye showed that the fluorescence intensity of AT-MSCs was lower in CC1 than in CC2. Furthermore, expression of proliferation-associated genes, such as CDC45L, CDC20A and KIF20A, in P4 AT-MSCs was higher in CC1 than in CC2, and this difference was also observed in P12 AT-MSCs. These data demonstrated that cell culture density affects the proliferation activity of MSCs, suggesting that it is feasible to design a strategy to prepare suitable MSCs using specific culture conditions. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, is a promising new strategy for the treatment of cancer. However, aberrant PI3K/Akt/mTOR survival signaling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. In the present study, we showed that the Akt/mTOR inhibitor RAD001 (everolimus) induced cell death in a dose-dependent manner and enhanced TRAIL-induced apoptosis in human leukemic Jurkat T cells, which show PI3K/Akt/mTOR pathway activation and basal expression levels of death receptor (DR) 5 (TRAIL-R2). Investigation of the effect of RAD001 treatment on the expression of TRAIL receptors (TRAIL-Rs) in Jurkat T cells showed that RAD001 significantly upregulated DR5 by up to 51.22%, but not other TRAIL-Rs such as DR4 (TRAIL-R1), decoy receptor (DcR) 1 (TRAIL-R3), and DcR2 (TRAIL-R4). Pretreatment with DR5:Fc chimera abrogated the RAD001-induced increase of TRAIL cytotoxicity, indicating that the upregulation of DR5 by RAD001 plays a role in enhancing the susceptibility of Jurkat T cells to TRAIL. Our results indicate that combination treatment with RAD001 and TRAIL may be a novel therapeutic strategy in leukemia. [ABSTRACT FROM AUTHOR]

To evaluate the optimal timing of mesenchymal stem cell (MSC) transplantation following stroke, rats were transplanted with MSCs at 1 (D1), 4 (D4), and 7 days (D7) after middle cerebral artery occlusion (MCAo). Rats in the D1 group showed a better functional recovery than those in the D4 or D7 groups after MCAo. MSCs preferentially migrated to the cortex in the D1 group, while the MSCs in the D4 or D7 groups preferentially migrated to the striatum. Interestingly, the level of monocyte chemotactic protein-1 (MCP-1) in the cortex was highest at 1 day after MCAo, while the level of stromal cell-derived factor-1 (SDF-1) in the striatum was lowest at 1 day after MCAo and then increased over time. The pattern of MCP-1 and SDF-1 level changes according to the time after MCAo was consistent with in vivo and in vitro migration patterns of MSCs. The results suggest that an earlier MSC transplantation is associated with a better functional recovery after stroke, which could be explained by the preferential migration of MSCs to the cortex in the early transplantation group. The time-dependent differential expression of MCP-1 and SDF-1 between ischemic regions seemed to mediate the differential migration of MSCs. Highest level of MCP-1 at one day of stroke may induce preferential migration of MSCs to the cortex, then better functional improvement. [ABSTRACT FROM AUTHOR]

Neurologic complications are serious complications after hematopoietic stem cell transplantation (HSCT) and significantly contribute to morbidity and mortality. The purpose of this study was to investigate the clinical features and prognosis in pediatric patients who had neurologic complications after allogeneic HSCT. We retrospectively reviewed the medical records of children and adolescents (19 years old or younger) who underwent allogeneic HSCT at our institution from 2000 to 2012. A total of 383 patients underwent 430 allogeneic transplantations. Among them, 73 episodes of neurologic complications occurred in 70 patients. The cumulative incidence of neurologic complications at day 400 was 20.0%. Almost two thirds of the episodes (63.0%, 46 of 73) occurred within 100 days after transplantation. Calcineurin inhibitor–related neurotoxicity was observed as the most common cause of neurotoxicity (47.9%, 35 of 73) and was significantly associated with earlier onset neurologic complications, seizure, and tremor. It also showed a significant association with lower probability of headache, abnormality of cranial nerve, and neurologic sequelae. In a multivariate analysis, days to neutrophil engraftment after HSCT, extensive chronic graft-versus-host disease (GVHD) and the existence of neurologic sequelae were identified as risk factors for mortality in patients who had neurologic complications (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.02 to 1.15; P = .011; HR, 5.98; 95% CI, 1.71 to 20.90; P = .005; and HR, 4.37; 95% CI, 1.12 to 17.05; P = .034, respectively). However, there was no significant difference in the 5-year overall survival between the patients who had neurologic complications without sequelae and the patients who did not have any neurologic complications (57.3% versus 61.8%, P = .906). In conclusion, we found that the major significant risk factors for mortality in pediatric recipients with neurologic complications were the existence of neurologic sequelae and extensive chronic GVHD. [ABSTRACT FROM AUTHOR]

Background We analyzed a nationwide registry of pediatric patients with hemophagocytic lymphohistiocytosis ( HLH) in Korea to assess the clinical and genetic features and treatment outcomes in pediatric HLH. Methods The Korea Histiocytosis Working Party retrospectively analyzed data on 251 pediatric patients diagnosed with HLH between 1996 and 2011. Results In the study cohort, 25 cases were categorized with familial HLH, 64 with presumed secondary HLH, and 162 with unspecified HLH. Of 217 evaluable patients, 91 (42%) had concomitant Epstein-Barr virus infection. Of 238 evaluable patients, central nervous system ( CNS) involvement, which was more frequent in the familial group, was evident in 81 cases (34%). Genetic tests revealed a predominant UNC13D mutation with a high incidence of two recurrent splicing mutations (c.118-308C>T and c.754-1G>C). The 5-yr overall survival rate was 68% (38% in the familial group and 81% in the presumed secondary group). The 5-yr overall survival rate among 32 patients who underwent allogeneic hematopoietic stem cell transplantation was 64%. In multivariate analysis, a younger age at diagnosis, severe transaminasemia, and a coagulation abnormality were independent prognostic factors for survival. Responses during initial treatments were also significant indicators of outcome. Conclusion Our study showed the unique predominance of a UNC13D mutation and vulnerability to Epstein-Barr virus infection in Korean children with HLH and emphasizes the prognostic significance of age, liver dysfunction, and treatment responses in this disease. A multicenter prospective trial that builds on the present results is warranted to identify subgroups of patients with a poor prognosis and identify optimal treatments. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between volume-based PET parameters and prognosis in patients with soft tissue sarcoma (STS).Methods: We retrospectively reviewed 55 patients with pathologically proven STS who underwent pretreatment with (18) F-Fluorodeoxyglucose ((18)F-FDG) PET/CT. The maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of primary tumors were measured using a threshold SUV as liver activity for determining the boundary of tumors. Univariate and multivariate survival analyses for overall survival were performed according to the metabolic parameters and other clinical variables.Results: Cancer-related death occurred in 19 of 55 patients (35 %) during the follow-up period (29 ± 23 months). On univariate analysis, AJCC stage (stage IV vs. I-III, hazard ratio (HR) = 2.837, p = 0.028), necrosis (G2 vs. G0-G1, HR = 3.890, p = 0.004), SUVmax (1 unit - increase, HR = 1.146, p = 0.008), SUVavg (1 unit - increase, HR = 1.469, p = 0.032) and treatment modality (non-surgical therapy vs. surgery, HR = 4.467, p = 0.002) were significant predictors for overall survival. On multivariate analyses, SUVmax (HR = 1.274, p = 0.015), treatment modality (HR = 3.353, p = 0.019) and necrosis (HR = 5.985, p = 0.006) were identified as significant independent prognostic factors associated with decreased overall survival.Conclusions: The SUVmax of the primary tumor is a significant independent metabolic prognostic factor for overall survival in patients with STS. Volume-based PET parameters may not add prognostic information outside of the SUVmax. [ABSTRACT FROM AUTHOR]

No abstract available [ABSTRACT FROM AUTHOR]

This study analyzes the data reported to the Korean Cord Blood Registry between 1994 and 2008, involving children and adolescents with non-malignant diseases. Sixty-five patients were evaluated in this study: SAA (n = 24), iBMFS, (n = 16), and primary immune deficiency/inherited metabolic disorder (n = 25). The CI of neutrophil recovery was 73.3% on day 42. By day 100, the CI of acute grade II-IV graft-versus-host disease was 32.3%. At a median follow-up of 71 months, five-yr OS was 50.7%. The survival rate (37.5%) and CI of neutrophil engraftment (37.5%) were lowest in patients with iBMFS. Deaths were mainly due to infection, pulmonary complications, and hemorrhage. In a multivariate analysis, the presence of >3.91 × 105/kg of infused CD34 + cells was the only factor consistently identified as significantly associated with neutrophil engraftment (p = 0.04) and OS (p = 0.03). UCBT using optimal cell doses appears to be a feasible therapy for non-malignant diseases in children and adolescents for whom there is no appropriate HLA-matched related donor. Strategies to reduce transplant-related toxicities would improve the outcomes of UCBT in non-malignant diseases. [ABSTRACT FROM AUTHOR]

Previous studies conducted cell expansion ex vivo using low initial plating densities for optimal expansion and subsequent differentiation of mesenchymal stem cells (MSCs). However, MSC populations are heterogeneous and culture conditions can affect the characteristics of MSCs. In this study, differences in gene expression profiles of adipose tissue (AT)-derived MSCs were examined after harvesting cells cultured at different densities. AT-MSCs from three different donors were plated at a density of 200 or 5,000 cells/cm2. After 7 days in culture, detailed gene expression profiles were investigated using a DNA chip microarray, and subsequently validated using a reverse transcription polymerase chain reaction (RT-PCR) analysis. Gene expression profiles were influenced primarily by the level of cell confluence at harvest. In MSCs harvested at ∼90% confluence, 177 genes were up-regulated and 102 genes down-regulated relative to cells harvested at ∼50% confluence (P<0.05, FC>2). Proliferation-related genes were highly expressed in MSCs harvested at low density, while genes that were highly expressed in MSCs harvested at high density (∼90% confluent) were linked to immunity and defense, cell communication, signal transduction and cell motility. Several cytokine, chemokine and growth factor genes involved in immunosuppression, migration, and reconstitution of damaged tissues were up-regulated in MSCs harvested at high density compared with MSCs harvested at low density. These results imply that cell density at harvest is a critical factor for modulating the specific gene-expression patterns of heterogeneous MSCs. [ABSTRACT FROM AUTHOR]

To overcome the limitations of allogeneic hematopoietic stem cell transplantation (HSCT), we conducted a study to identify a strategy for enhancing hematopoietic stem cell (HSC) engraftment during HSCT. Co-transplantation experiments with mesenchymal stem cells (MSCs) derived from adult human tissues including bone marrow (BM), adipose tissue (AT), and umbilical cord blood (CB) were conducted. We showed that AT-MSCs and CB-MSCs enhanced the engraftment of HSCs as effectively as BM-MSCs in NOD/SCID mice, suggesting that AT-MSCs and CB-MSCs can be used as alternative stem cell sources for enhancing the engraftment and homing of HSCs. CB-MSCs derived from different donors showed different degrees of efficacy in enhancing the engraftment of HSCs. The most effective CB-MSCs showed higher proliferation rates and secreted more MCP-1, RANTES, EGF, and VEGF. Our results suggest that AT-MSCs and CB-MSCs could be alternative stem cell sources for co-transplantation in HSCT. Furthermore, in terms of MSCs’ heterogeneity, characteristics of each population of MSCs are considerable factors for selecting MSCs suitable for co-transplantation with HSC. [ABSTRACT FROM AUTHOR]

Abstract: Pre-engraftment syndrome (PES) is poorly characterized, and its clinical significance and the prognostic impact after unrelated cord blood transplantation (CBT) are unclear. To address these issues, we retrospectively analyzed the incidence, risk factors, and clinical outcomes of PES in unrelated CBT recipients. Data of 381 patients who received unrelated CBT from 18 medical centers in Korea were reviewed. PES was defined as unexplained fever >38.3°C not associated with infection, and/or unexplained skin rash with or without evidence of fluid retention before neutrophil recovery. PES developed in 102 patients (26.8%) at a median of 7 days after CBT. Of these patients, 74 patients (72.5%) received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 95% showed clinical improvement. Risk factors for developing PES included low risk disease, myeloablative conditioning, graft-versus-host disease (GVHD) prophylaxis without methotrexate or corticosteroid, and >5.43 x 107/kg infused nucleated cells. Absence of PES was one of the risk factors for graft failure in multivariate analysis. The cumulative incidence of grade II to grade IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% versus 34.4%, P < .01). PES was not associated with chronic GVHD, treatment-related mortality, relapse, or overall survival. PES seems to be common after CBT and may be associated with enhanced engraftment without significant morbidity. [Copyright &y& Elsevier]

BACKGROUND: In patients with high-risk neuroblastoma, the reduction in primary tumor volume was measured during the early phase of induction chemotherapy as an indicator of early tumor response, and the authors investigated whether the degree of tumor volume reduction could predict outcome in these patients. METHODS: Primary tumor volumes were measured both at diagnosis and at the first tumor response evaluation (after 2 or 3 cycles of induction chemotherapy) in 90 patients with high-risk neuroblastoma who had volumetrically evaluable computed tomography or magnetic resonance scans. If the tumor volume at the first response evaluation was >40% of the initial tumor volume, then the patient was categorized as a poor responder; otherwise, the patient was categorized as a good responder. Outcomes were compared according to the degree of tumor volume reduction at the first response evaluation. RESULTS: The tumor volume reduction was greater in patients who remained relapse free than in patients who had a relapsed tumor (median percentage tumor volume, 21% vs 41.5%; P = .037). The 5-year relapse-free survival rate was higher in the good responders than in the poor responders (83% [95% confidence interval, 72%-94%] vs 51% [95% confidence interval, 31%-71%]; P = .002). In a multivariate analysis of relapse-free survival, a poor early response was identified as an independent, unfavorable prognostic factor (hazard ratio, 4.24; 95% confidence interval, 1.59-11.29; P = .004). CONCLUSIONS: A greater reduction in tumor volume reduction the early phase of induction chemotherapy was associated with a better outcome in patients with high-risk neuroblastoma. Tailoring treatment intensity according to the early tumor response to induction chemotherapy may improve patient outcomes. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: We analyzed the characteristics of stored and transplanted cord blood (CB) units from the Korean network for public CB donation (KoreaCORD) to reassess the banking guidelines and optimize CB selection based on cell dose and human leukocyte antigen (HLA) mismatching. STUDY DESIGN AND METHODS: We retrospectively reviewed data, with regard to total nucleated cell (TNC) count and HLA match in the KoreaCORD registry from August 2001 to December 2010. RESULTS: A total of 21,914 CB units have been registered, of which 904 units (4.1%) contained less than 5 × 108 TNCs, which did not meet the present storage criteria for public CB banking in Korea. Although the proportion of stored CBs providing TNC of 5 × 108 to 7.9 × 108 was 45.7%, only 22.0% of all transplanted CBs were derived from these stored CBs. In the single CB transplantation setting, 79% (85/108) of CB units provided 4 × 107 TNCs/kg or more in the transplanted one-mismatch (1-MM) CB units and 51% (19/37) of CBs provided 6 × 107 TNCs/kg or more in the transplanted 2-MM CB units. CONCLUSIONS: The minimal requirement of TNCs for banking of CB units for public banking should be evaluated and increased to support the selection of CB units with higher cell doses, especially for use in the 1- and 2-MM transplant settings. [ABSTRACT FROM AUTHOR]

Abstract: Current evidence suggests that apoptosis and the cell cycle system play an important role in cancer development. To identify susceptible genetic markers in these mechanisms, we did an association study in 63 patients and 148 controls. A total of 304 SNPs in 31 gene regions were selected. We evaluated an association at a gene region level by computing the minimum P-value (minP) and doing the false discovery rate (FDR) test. Both SNP and gene-based analyses presented associations with the risk of childhood leukemia for 5 genes: CASP7, CASP14, CASP8AP2, MYC, and RIPK1 (P trend <0.05). There were statistically significant associations for CASP7 (rs12416109 and rs3814231, P trend =0.002 and 0.009, respectively, minP =0.013, FDR=0.042) and CASP14 (rs8110862, P trend <0.001, minP =0.002, FDR=0.027). This study suggests that genetic polymorphisms in apoptosis and cell cycle related genes might play a role in childhood leukemia development. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPARγ in CGZ-induced cell death was examined. At concentrations of greater than 30μM, CGZ, a synthetic PPARγ agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30μM CGZ effectively induced cell death after pretreatment with 30μM of the PPARγ antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPARγ was down-regulated cells by siRNA, lower concentrations of CGZ (<30μM) were sufficient to induce cell death, although higher concentrations of CGZ (⩾30μM) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPARγ. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPARγ in glioma cells, by down-regulating Akt activity and inducing MMP collapse. [Copyright &y& Elsevier]

Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) enhance the engraftment of human hematopoietic stem cells (HSCs) when they are cotransplanted in animal and human studies. However, the type of MSCs that preferentially facilitate the engraftment and homing of HSCs is largely unknown. The authors categorized UCB-MSCs as the least-effective MSCs (A) or most-effective MSCs (B) at enhancing the engraftment of HSCs, and compared the gene expression profiles of various cytokines and growth factors in the UCB-MSC populations. The most-effective UCB-MSCs (B) secreted higher levels of several factors, including chemokine (C-X-C motif) ligand 12 (CXCL12), regulated upon activation, normal T cells expressed and secreted (RANTES), epithelial growth factor (EGF), and stem cell factor (SCF), which are required for the engraftment and homing of HSCs. By contrast, levels of growth-related oncogene (GRO), insulin-like growth factor-binding protein 1 (IGFBP1), and interleukin-8 (IL-8), which are associated with immune inflammation, were secreted at higher levels in UCB-MSCs (A). In addition, there were no differences between the transcripts of the 2 UCB-MSC populations after interferon-gamma (IFN-γ) stimulation, except for cyclooxygenase (COX)-1. Based on these findings, the authors propose that these chemokines may be useful for modulating these cells in a clinical setting and potentially for enhancing the effectiveness of the engraftment and homing of HSCs. [ABSTRACT FROM AUTHOR]

Lee SH, Paik KH, Sung KW, Son MH, Yoo KH, Koo HH, Kim JY, Cho EJ. Renal function after tandem high-dose chemotherapy and autologous stem cell transplantation in children with Wilms tumor. Pediatr Transplantation 2011: 15: 855-860. © 2011 John Wiley & Sons A/S. Abstract: Despite increasing evidence that tandem HDCT and autoSCT might improve the survival of patients with high-risk solid tumors, patients with Wilms tumor may be at high risk of acute and chronic renal impairment during and after tandem HDCT/autoSCT because they usually have a single kidney. We investigated the feasibility of tandem HDCT/autoSCT in patients with Wilms tumor, focusing on renal function. Six patients with relapsed/progressed Wilms tumor were assigned to undergo tandem HDCT/autoSCT. One patient developed transient ARF during the first HDCT/autoSCT. All other patients underwent the second HDCT/autoSCT as scheduled. Acute renal dysfunction during the second HDCT/autoSCT was transient and manageable. Indicators of glomerular function such as creatinine clearance, serum creatinine, and albumin excretion were in the normal range at three yr after tandem HDCT/autoSCT. Subclinical tubular dysfunctions, such as increased excretion of β- N-acetylglucosaminidase and β2-microglobulin, were identified at one and three yr after tandem HDCT/autoSCT; however, no patient required treatment for these conditions. These results are helpful to consider tandem HDCT/autoSCT as a treatment option in patients with Wilms tumor. Longer duration of follow-up and close monitoring of tubular function are required if tandem HDCT/autoSCT is indicated in patients with Wilms tumor. [ABSTRACT FROM AUTHOR]

In the present study, the authors analyzed the tyrosine hydroxylase (TH) expression in peripheral blood (PB) of neuroblastoma (NB) patients and investigated the clinical implications. From April 2005 to October 2008, a total of 683 PB specimens (64 at diagnosis, 244 during chemotherapy, 355 during off-therapy follow-up, and 20 at relapse) acquired from141 patients were investigated. TH expression was measured by quantitative reverse transcriptase-polymerase chain reaction (RTPCR). TH-positive rate at diagnosis (21.4%) was higher than those during chemotherapy (0.8%) or off-therapy follow-up (1.7%). TH expression at diagnosis was associated with high-risk features (ie, advanced stage, older age, unfavorable pathology, and amplified N-myc) and the probability of 3- year relapse-free survival in the TH-positive patients was lower than in the TH-negative patients (45.8% ± 27.8% versus 95.8% ± 5.7%, P < .001). TH expression was positive in only 6 specimens during off-therapy follow-up. However, tumor relapse occurred in only 2 out of 6 TH-positive patients. In addition, TH expression was negative during previous off-therapy follow-up, prior to relapse, in 8 out of 10 relapsed patients. Whereas TH expression in PB at diagnosis was associated with high-risk features and a poorer outcome, TH expression during off-therapy follow-up had very limited value for the prediction of a subsequent relapse. [ABSTRACT FROM AUTHOR]

Antithymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective for preventing graft-versus-host disease (GVHD) and the rejection of organ transplants. After the promising results of our preliminary study, we conducted a phase II prospective multicenter clinical trial using a fludarabine (Flu), cyclophosphamide (Cy), and thymoglobulin conditioning regimen to allow good engraftment in patients who underwent unrelated transplantation for SAA. Twenty-eight patients underwent bone marrow (N = 15) or mobilized peripheral blood (N = 13) transplantation from HLA-matched unrelated donors with Cy (50 mg/kg once daily intravenously (i.v.) on days −9, −8, −7, and −6), Flu (30 mg/m2 once daily i.v. on days −5, −4, −3, and −2), and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2, and −1). Donor-type hematologic recovery was achieved in all patients. The estimated survival rate (SR) was 67.9%, and all the events were treatment-related mortality (TRM), which included thrombotic microangiopathy (N = 2), pneumonia (N = 1), myocardiac infarction (N = 1), posttransplantation lymphoprolifarative disease (N = 3), and chronic GVHD-associated complications (N = 2). The SR of patients who received bone marrow (60.0%) was not different from that of patients who received mobilized peripheral blood (76.9%) (P = .351), but the SR of patients who received more than 15 units of red blood cells before transplantation (45.5%) was significantly lower than that of the other patients (82.4%) (P = .048). The Flu, Cy, and thymoglobulin conditioning regimen achieved promising results for successful engraftment, but the TRM was high. This study was registered at www.clinicaltrials.gov (NCT00737685), and now we are performing a new multicenter study (NCT00882323) to decrease the TRM by reducing the dose of Cy. [Copyright &y& Elsevier]

Umbilical cord blood transplantation (UCBT) with two units has been conducted with promising results in adults to overcome the limitation of low cell numbers. In an attempt to improve the outcomes, double UCBT was performed in children and adolescents. Sixty-one patients, including 44 acute leukemia, and 17 other hematologic diseases, received double UCBT. Donor-type engraftment achieved in 82% of patients. Except one patient with persistent mixed chimerism of two units, other 49 patients showed dominancy of one unit and only the CFU-GM was significant factor influencing dominancy. The event-free survival (EFS) of leukemia and other hematologic disease were 59% and 53%, respectively, and the EFS of acute leukemia patients who received transplant in first or second CR (68.6%) was significantly better than in those with advanced disease (22.2%) (P = 0.007). Among the factors influencing outcomes, low cell dose difference between two units (TNC difference/TNC of large unit <15%) were associated with higher TRM, relapse, and lower EFS. Double UCBT was a promising modality of transplant in children and adolescence. However, engraftment and other results were not so satisfactory yet. To improve the outcomes, development of new selection guideline, probably including cell dose difference between two units and technology to enhance engraftment and reduce transplantation-related mortality are warranted. [ABSTRACT FROM AUTHOR]

Abstract: We conducted a genome-wide association study of childhood acute lymphoblastic leukemia (ALL) in a case–control study conducted in Korea. Incident childhood ALL cases (n =50) and non-cancer controls (n =50) frequency-matched to cases by age and sex, recruited from three teaching hospitals in Seoul between 2003 and 2008, were genotyped using Affymetrix SNP Array 6.0 platform. ALL risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age and birth weight. The false discovery rate (FDR) was used for adjusting multiple tests. Of these 1 million SNPs, six SNPs in 4 genes (HAO1 rs6140264, EPB41L2 rs9388856, rs9388857, rs1360756, C2orf3 12105972, MAN2A1 rs3776932) were strongly associated with childhood ALL risk (P dominant ≤0.0001 and P trend <0.006). These SNPs remained significant after FDR adjustment (FDR value <0.2). Our genome-wide association study in Korea children identified a few genetic variations as potential susceptibility markers for ALL, warranting further replication studies among various ethnic groups. [ABSTRACT FROM AUTHOR]

Abstract: The immune system plays an important role in the control of cancer development. To investigate possible genetic contribution to childhood leukemia risk in the innate immune system, we performed an association study for the 1214 SNPs in 146 gene regions related to innate immunity using GoldenGate (Illumina) oligonucleotide pool assay (OPA) in 106 case patients and 123 controls. Childhood leukemia risk was estimated as odds ratios and 95% confidence intervals adjusted for age, gender and birth weight. The minP test was used to identify statistically significant association at gene level. Three SNPs (STAT6 rs703817, C1qG rs17433222, and MBP rs3794845) were significantly associated with childhood leukemia risk (p trend < 0.001, minP < 0.01). The most significant association with childhood leukemia risk was for STAT6 rs703817 (GA vs GG: 0.48 (0.26–0.87), AA vs GG: 0.21 (0.07–0.61), p trend = 0.0003, minP = 0.002). Subgroup analysis showed that Ly96 rs78380171 and MBP rs3794845 were significantly associated with the risk of acute lymphoblastic leukemia (p trend < 0.001). Our results suggest that genetic polymorphisms in innate immunity genes might play a role in the genesis of childhood leukemia with limited biologic evidence. Additional, larger studies are needed to identify the mechanism of these genes in childhood leukemia patients. [Copyright &y& Elsevier]

Abstract: Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. In this study, we conducted a comparative analysis of the immunomodulatory properties of MSCs derived from adult human tissues including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton’s jelly (WJ). Using a multiple cytokine detection assay, we showed that there were no significant differences in levels of secreted factors from non-stimulated MSCs. We compared the immunosuppressive effect of BM-MSCs, AT-MSCs, CB-MSCs, and WJ-MSCs on phytohemagglutinin-induced T-cell proliferation. AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed mitogen-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, the expression of hepatocyte growth factor, IL-10, transforming growth factor-β1, cyclooxygenase (COX)-1, and COX-2 were unchanged in MSCs treated with IFN-γ and/or TNF-α, while indoleamine 2,3-dioxygenase (IDO) expression increased. IFN-γ and/or TNF-α produced by activated T-cells were correlated with induction of IDO expression by MSCs, which, in turn, suppressed T-cell proliferation. These findings suggest that MSCs derived from AT, CB, or WJ could be substituted for BM-MSCs for treatment of allogeneic conflicts. [Copyright &y& Elsevier]