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1.  Trends in the Aggressiveness of End-of-Life Care for Korean Pediatric Cancer Patients Who Died in 2007–2010 
PLoS ONE  2014;9(6):e99888.
Background
In light of the Korean Supreme Court's 2009 ruling favoring a patient's right to die with dignity, we evaluated trends in aggressive care in a cohort of pediatric cancer patients.
Methods We conducted a population-based retrospective study that used administrative data for patients who died in 2007–2010 among the 5,203 pediatric cancer patients registered at the Korean Cancer Central Registry (KCCR) during 2007–2009.
Results
In the time period covered, 696 patients died. The proportion who had received chemotherapy in the last 30 days of life decreased from 58.1% to 28.9% (P<0.001), those who received new chemotherapy in the same time period decreased from 55.2% to 15.1% (P<0.001), and those who received treatment in the last 2 weeks of life decreased from 51.4% to 21.7% (P<0.001). In the last 30 days of life, the proportion of patients whose hospital admission period was over 14 days increased from 70.5% to 82.5% (P = 0.03), the proportion who received cardiopulmonary resuscitation decreased from 28.6% to 9.6% (P<0.001), and we found no statistically significant trends in the proportion of emergency department visits, intensive care unit admissions, or mechanical ventilation.
Conclusions
In this study, in contrast with earlier ones, the aggressiveness of end-of-life care of Korean pediatric cancer patients decreased dramatically.
doi:10.1371/journal.pone.0099888
PMCID: PMC4055703  PMID: 24923320
2.  Cross-Cultural Adaptation of the Korean Version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form 
Journal of Korean Medical Science  2013;28(12):1788-1795.
We verified the reliability and validity of the Korean version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form (KMMQL-AF) among Korean childhood cancer survivors. A total of 107 childhood cancer patients undergoing cancer treatment and 98 childhood cancer survivors who completed cancer treatment were recruited. To assess the internal structure of the KMMQL-AF, we performed multi-trait scaling analyses and exploratory factor analysis. Additionally, we compared each domains of the KMMQL-AF with those of the Karnofsky Performance Status Scale and the Revised Children's Manifest Anxiety Scale (RCMAS). Internal consistency of the KMMQL-AF was sufficient (Cronbach's alpha: 0.78-0.92). In multi-trait scaling analyses, the KMMQL-AF showed sufficient construct validity. The "physical functioning" domain showed moderate correlation with Karnofsky scores and the "psychological functioning" domain showed moderate-to-high correlation with the RCMAS. The KMMQL-AF discriminated between subgroups of different adolescent cancer survivors depending on treatment completion. The KMMQL-AF is a sufficiently reliable and valid instrument for measuring quality of life among Korean childhood cancer survivors.
doi:10.3346/jkms.2013.28.12.1788
PMCID: PMC3857376  PMID: 24339710
Quality of Life; Questionnaires; Validation Studies; Child Psychology; Neoplasms; Survivors
3.  Clinical Characteristics of Pediatric Thalassemia in Korea: A Single Institute Experience 
Journal of Korean Medical Science  2013;28(11):1645-1649.
Few literatures have elaborated on the clinical characteristics of children with thalassemia from low-prevalence areas. A retrospective analysis was conducted on children genetically confirmed with thalassemia at Seoul National University Children's Hospital in Korea. Nine children (1α thalassemia trait, 6β thalassemia minor, 2β thalassemia intermedia) were diagnosed with thalassemia at median age of 4.3 yr old with median hemoglobin of 9.7 g/dL. Seven (78%) children were incidentally found to be anemic and only 2 with β thalassemia intermedia had presenting symptoms. Five children (56%) were initially misdiagnosed with iron deficiency anemia. Despite the comorbidities due to α thalassemia mental retardation syndrome, the child with α thalassemia trait had mild hematologic profile. Children with β thalassemia intermedia had the worst phenotypes due to dominantly inherited mutations. None of the children was transfusion dependent and most of them had no complications associated with thalassemia. Only 1 child (11%) with codon 60 (T→A) mutation of the HBB gene needed red blood cell transfusions. He also had splenomegaly, cholelithiasis, and calvarial vault thickening. Pediatricians in Korea must acknowledge thalassemia as a possible diagnosis in children with microcytic hypochromic hemolytic anemia. High level of suspicion will allow timely diagnosis and managements.
doi:10.3346/jkms.2013.28.11.1645
PMCID: PMC3835508  PMID: 24265529
α-Thalassemia; β-Thalassemia; Genotype; Phenotype; Child; Korea
4.  Pharmacogenetic Study of Deferasirox, an Iron Chelating Agent 
PLoS ONE  2013;8(5):e64114.
Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing −1774 del and/or −24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79–28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7–43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34–150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.
doi:10.1371/journal.pone.0064114
PMCID: PMC3667856  PMID: 23737969
5.  Growth after Hematopoietic Stem Cell Transplantation in Children with Acute Myeloid Leukemia 
Journal of Korean Medical Science  2013;28(1):106-113.
Previous studies have shown that hematopoietic stem cell transplantation (HSCT) may result in growth impairment. The purpose of this study was to evaluate the growth during 5 yr after HSCT and to determine factors that influence final adult height (FAH). We retrospectively reviewed the medical records of acute myeloid leukemia (AML) patients who received HSCT. Among a total of 37 eligible patients, we selected 24 patients who began puberty at 5 yr after HSCT (Group 1) and 19 patients who reached FAH without relapse (Group 2). In Group 1, with younger age at HSCT, sex, steroid treatment, hypogonadism and hypothyroidism were not significantly associated with growth impairment 5 yr after HSCT. History of radiotherapy (RT) significantly impaired the 5 yr growth after HSCT. Chronic graft-versus-host disease (cGVHD) only temporarily impaired growth after HSCT. In Group 2, with younger age at HSCT, steroid treatment and hypogonadism did not significantly reduce FAH. History of RT significantly reduced FAH. Growth impairment after HSCT may occur in AML patients, but in patients without a history of RT, growth impairment seemed to be temporary and was mitigated by catch-up growth.
doi:10.3346/jkms.2013.28.1.106
PMCID: PMC3546088  PMID: 23341720
Hematopoietic Stem Cell Transplantation; Growth; Radiotherapy; Total Body Irradiation; Acute Myeloid Leukemia
6.  Respiratory Viral Infections after Hematopoietic Stem Cell Transplantation in Children 
This study was performed to characterize respiratory viral infections in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Study samples included 402 respiratory specimens obtained from 358 clinical episodes that occurred in the 116 children of the 175 consecutive HSCT cohort at Seoul National University Children's Hospital, Korea from 2007 to 2010. Multiplex reverse-transcription polymerase chain reactions were performed for rhinovirus, respiratory syncytial virus (RSV), parainfluenza viruses (PIVs), adenovirus, human coronavirus (hCoV), influenza viruses and human metapneumovirus. Viruses were identified in 89 clinical episodes that occurred in 58 patients. Among the 89 clinical episodes, frequently detected viruses were rhinovirus in 25 (28.1%), RSV in 23 (25.8%), PIV-3 in 16 (18.0%), adenovirus in 12 (13.5%), and hCoV in 10 (11.2%). Lower respiratory tract infections were diagnosed in 34 (38.2%). Neutropenia was present in 24 (27.0%) episodes and lymphopenia was in 31 (34.8%) episodes. Sixty-three percent of the clinical episodes were hospital-acquired. Three patients died of respiratory failure caused by respiratory viral infections. Respiratory viral infections in pediatric patients who have undergone HSCT are common and are frequently acquired during hospitalization. Continuous monitoring is required to determine the role of respiratory viruses in immunocompromised children and the importance of preventive strategies.
doi:10.3346/jkms.2013.28.1.36
PMCID: PMC3546101  PMID: 23341709
Hematopoietic Stem Cell Transplantation; Respiratory Virus; Respiratory Infections
7.  Successful Treatment of Primary Central Nervous System Lymphoma without Irradiation in Children: Single Center Experience 
Journal of Korean Medical Science  2012;27(11):1378-1384.
Primary CNS lymphoma (PCNSL) is a very uncommon disease in children, and usually treated by chemotherapy, combined with focal or craniospinal radiotherapy (RT). However, adverse effects of RT are a concern. We evaluated the outcomes of childhood PCNSL, treated with systemic and intrathecal chemotherapy, but without RT. For fifteen years, six patients among 175 of non-Hodgkin lymphoma were diagnosed as PCNSL in Seoul National University Children's Hospital and we analyzed their medical records retrospectively. Their male:female ratio was 5:1, and median age was 10.1 yr. The primary sites were the sellar area in three patients, parietal area in one, cerebellum in one, and multiple areas in one. Their pathologic diagnoses were diffuse large B-cell lymphoma in three patients, Burkitt lymphoma in two, and undifferentiated B-cell lymphoma in one. Five were treated with the LMB96 treatment protocol, and one was treated with the CCG-106B protocol. None had RT as a first-line treatment. One patient had a local relapse and received RT and salvage chemotherapy, without success. No patient had treatment-related mortality. Their estimated 5-yr event-free and overall survival rates were both 83.3%. In conclusion, PCNSL is a rare disease in childhood, but successfully treated by chemotherapy without RT.
doi:10.3346/jkms.2012.27.11.1378
PMCID: PMC3492674  PMID: 23166421
Primary CNS Lymphoma; Children; Irradiation
8.  Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism 
PLoS ONE  2012;7(9):e45558.
Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations.
doi:10.1371/journal.pone.0045558
PMCID: PMC3454425  PMID: 23029095
9.  A Case Report of Fanconi Anemia Diagnosed by Genetic Testing Followed by Prenatal Diagnosis 
Annals of Laboratory Medicine  2012;32(5):380-384.
Fanconi anemia (FA) is a rare genetic disorder affecting multiple body systems. Genetic testing, including prenatal testing, is a prerequisite for the diagnosis of many clinical conditions. However, genetic testing is complicated for FA because there are often many genes that are associated with its development, and large deletions, duplications, or sequence variations are frequently found in some of these genes. This study describes successful genetic testing for molecular diagnosis, and subsequent prenatal diagnosis, of FA in a patient and his family in Korea. We analyzed all exons and flanking regions of the FANCA, FANCC, and FANCG genes for mutation identification and subsequent prenatal diagnosis. Multiplex ligation-dependent probe amplification analysis was performed to detect large deletions or duplications in the FANCA gene. Molecular analysis revealed two mutations in the FANCA gene: a frameshift mutation c.2546delC and a novel splice-site mutation c.3627-1G>A. The FANCA mutations were separately inherited from each parent, c.2546delC was derived from the father, whereas c.3627-1G>A originated from the mother. The amniotic fluid cells were c.3627-1G>A heterozygotes, suggesting that the fetus was unaffected. This is the first report of genetic testing that was successfully applied to molecular diagnosis of a patient and subsequent prenatal diagnosis of FA in a family in Korea.
doi:10.3343/alm.2012.32.5.380
PMCID: PMC3427829  PMID: 22950077
Fanconi anemia; FANCA; Molecular diagnosis; Prenatal diagnosis
10.  Chronic graft versus host disease with small bowel obstruction after unrelated hematopoietic stem cell transplantation in a patient with acute myeloid leukemia 
The Korean Journal of Hematology  2012;47(2):142-145.
Chronic graft versus host disease (GVHD) is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT), but simultaneous small bowel obstruction is rare. Here, we report a child with acute myeloid leukemia who received an allogeneic HSCT from an unrelated matched donor. After HSCT, the patient developed severe chronic GVHD involving the small intestine, leading to obstruction of the terminal ileum. Small bowel resection was performed, and the symptoms improved without severe complications. Bowel obstruction should be considered as a possible complication of chronic GVHD; surgery may be a valuable corrective measure.
doi:10.5045/kjh.2012.47.2.142
PMCID: PMC3389064  PMID: 22783362
Acute myeloid leukemia; Hematopoietic stem cell transplantation; Graft versus host disease; Intestinal obstruction
11.  Successful mobilization using a combination of plerixafor and G-CSF in pediatric patients who failed previous chemomobilization with G-CSF alone and possible complications of the treatment 
Peripheral blood stem cell (PBSC) mobilization, which uses plerixafor (AMD 3100), a newly developed specific inhibitor of the CXCR4 receptor, in combination with granulocyte-colony stimulating factor(G-CSF), has been shown to enhance the stem cell mobilization in adult patients, but pediatric data are scarce. We documented our experience with this drug in 6 Korean pediatric patients who had failed in chemomobilization, using G-CSF, alone. All patients were mobilized CD34+ cells (median, 11.08 × 106/kg: range, 6.34-28.97 × 106/kg) successfully within 2 to 3 cycles of apheresis, without complications. A total of 7 autologous transplantations were performed, including 1 tandem transplantation. However, 2 patients with brain tumors showed severe pulmonary complications, including spontaneous pneumomediastinum. This is the first study of PBSC mobilization with plerixafor in Asian pediatric patients. Furthermore our study suggests that mobilization with plerixafor may be effective in Korean pediatric patients, who have previously been heavily treated and have failed PBSC mobilization with classical chemomobilization, using G-CSF. However, further studies are needed to examine the possible complications of autologous transplantation, using a mobilized plerixafor product in children.
doi:10.1186/1756-8722-5-14
PMCID: PMC3361468  PMID: 22458355
Plerixafor; Hematopoietic Stem Cell Mobilization; Pediatrics; Complications; Interstitial Lung Diseases
12.  Treatment outcomes in children with Burkitt lymphoma and L3 acute lymphoblastic leukemia treated using the lymphoma malignancy B protocol at a single institution 
The Korean Journal of Hematology  2011;46(2):96-102.
Background
We compared the outcomes of patients with Burkitt lymphoma and French-American-British (FAB) L3 acute lymphoblastic leukemia treated using Lymphoma Malignancy B (LMB) or other treatment protocols.
Methods
Thirty-eight patients diagnosed between July 1996 and December 2007 were treated using LMB 96, and 22 patients diagnosed between January 1991 and May 1998 (defined as the early period) were treated using the D-COMP or CCG-106B protocols. We retrospectively reviewed their medical records and analyzed cumulative survival according to the treatment period by using Kaplan-Meier analysis.
Results
There were no intergroup differences in the distribution of age, disease stage, or risk group. The median follow-up period of the 33 live patients in the LMB group was 72 months (range, 36-170 months). Overall survival (OS) and event-free survival (EFS) of patients treated using LMB 96 were 86.8%±5.5% and 81.6%±6.3%, respectively, whereas OS and EFS of patients treated in the early period were 72.7%±9.6% and 68.2%±9.9%, respectively. In the LMB 96 group, OS of cases showing non-complete response (N=8) was 62.5%±17.1%, and OS of relapsed or primary refractory cases (N=6) was 33.3%±19.3%. Central nervous system (CNS) disease, high lactate dehydrogenase levels at diagnosis, and treatment response were significant prognostic factors.
Conclusion
Survival outcome has drastically improved over the last 2 decades with short-term, dose-intensive chemotherapy. However, CNS involvement or poor response to chemotherapy was worse prognostic factors; therefore, future studies addressing this therapeutic challenge are warranted.
doi:10.5045/kjh.2011.46.2.96
PMCID: PMC3128907  PMID: 21747881
Burkitt lymphoma; L3 lymphocytic leukemia; Treatment outcome; Prognosis
13.  The impact of HLA matching on unrelated donor hematopoietic stem cell transplantation in Korean children 
Background
The impact of HLA matching on outcomes of unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) varies in different racial or ethnic groups. Since little is known about the impact of such matching on URD HSCT in Korean children, we analyzed this issue.
Methods
We analyzed the outcomes of 142 patients who underwent URD HSCT at 4 Korean medical centers. All patient donor pairs were fully typed for HLA-A, -B, -C, and -DR alleles.
Results
At a median follow-up of 22 months, 3-year survival rates for patients with 8, 7, and ≤6 matched alleles were 88.4%, 70.7%, and 53.6%, respectively. A single mismatch (Mm) at HLA-B or -C was associated with lower survival compared with that associated with 8 matched alleles. No significant differences were observed between single-allele and single-antigen Mms with respect to survival rate or acute graft-versus-host disease (aGVHD) incidence rates. HLA disparity had a greater impact on the survival of patients with high-risk malignancy than of those with low-risk malignancy. Among pairs with a single Mm, only locus A showed a significant association and higher risk of grade III-IV aGVHD compared to those in patients with 8 matched alleles.
Conclusion
Disparity in HLA class I, regardless of antigen or allele Mm, adversely affected both survival and grade III-IV aGVHD development. An increased number of HLA Mms was associated with a higher risk of post-transplantation complications. Further investigations using larger cohorts are required to confirm the effects of HLA mismatching on URD HSCT patient outcomes.
doi:10.5045/kjh.2011.46.1.11
PMCID: PMC3065620  PMID: 21461298
URD HSCT; HLA; Korean children
14.  Polymorphisms in innate immunity genes and risk of childhood leukemia 
Human immunology  2010;71(7):727-730.
Objectives
To evaluate whether candidate genes in innate immunity are associated with childhood leukemia, we conducted an association study with the 1,536 SNPs in 203 genes related to innate immunity.
Methods
Incident childhood leukemia cases (n=136) aged from 0 to 18 were recruited from three teaching hospitals in Seoul between 2003 and 2006. Non-cancer controls (n=140) were frequency-matched to cases by age and gender. The information on the characteristics of children and their parents were collected by trained interviewers using structured questionnaire. Candidate genes were selected based on SNP databases (CGAP and SNP500 database), and genotype assay was performed using GoldenGate (Illumina) oligonucleotide pool assay (OPA). False discovery rate (FDR), permutation test, and haplotype analyses were used to identify the SNP with significant association with childhood leukemia. Childhood leukemia risk was estimated as ORs and 95% CIs adjusted for age, gender and birth weight.
Results
Fourteen SNPs in 13 genes (LMAN1, TLR4, STAT4, CCR9, MBP, ZP1, C8B, XDH, C7, C1QG, FGF2, LOC390183, and STAT6) were significantly associated with childhood leukemia risk (FDR p-values <0.05). In particular, LMAN1 rs1127220, TLR4 rs11536897, STAT4 rs13020076, CCR9 rs1471962, and MBP rs10514234 were significant in 5,000 permutation tests (Permutation p-value <0.05). The most significant association with childhood leukemia risk was for the LMAN1 rs1127220 that is in the protein-coding region, this finding was also supported by haplotype analysis.
Conclusions
A number of innate immunity related genes are associated with childhood leukemia, suggesting possible links between the innate immunity system and development of the childhood leukemia.
doi:10.1016/j.humimm.2010.04.004
PMCID: PMC2967770  PMID: 20438785
Childhood Leukemia; Innate Immunity; Single Nucleotide Polymorphism
15.  Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors 
Journal of Korean Medical Science  2010;25(9):1336-1342.
This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8±83.4 mg/m2 in the dexrazoxane group and 266.1±75.0 mg/m2 in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.
doi:10.3346/jkms.2010.25.9.1336
PMCID: PMC2923785  PMID: 20808678
Dexrazoxane; Doxorubicin; Cardiotoxicity; Child; Solid Tumors
16.  Induction of hypoxia-inducible factor-1α inhibits drug-induced apoptosis in the human leukemic cell line HL-60 
The Korean Journal of Hematology  2010;45(3):158-163.
Background
Leukemic cells originate from hypoxic bone marrow, which protects them from anti-cancer drugs. Although many factors that cause drug resistance in leukemic cells have been studied, the effect of hypoxia on drug-induced apoptosis is still poorly understood.
Methods
In this study, we examined the effect of hypoxia on anti-leukemic drug resistance in leukemic cell lines treated with cobalt chloride (CoCl2), a hypoxia-mimetic agent. Cellular proliferation was evaluated using the methyl thiazolyl tetrazolium (MTT) assay. Flow cytometry analysis and western blots were performed to investigate apoptosis-related proteins.
Results
Unlike its previously known apoptotic effect, the expression of HIF-1α increased the survival rate of human promyelocytic leukemia HL-60 cells when these cells were exposed to anti-leukemic drugs; these effects were mediated by heat-shock protein HSP70 and the pro-apoptotic protein Bax.
Conclusion
These findings may provide new insights for understanding the mechanisms underlying hypoxia and for designing new therapeutic strategies for acute myeloid leukemia.
doi:10.5045/kjh.2010.45.3.158
PMCID: PMC2983039  PMID: 21120203
Hypoxia; Arsenic trioxide; HIF-1α; Cobalt chloride; Bax; HSP70
17.  Efficacy of High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Relapsed Medulloblastoma: A Report on The Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 Study 
Journal of Korean Medical Science  2010;25(8):1160-1166.
The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma.
doi:10.3346/jkms.2010.25.8.1160
PMCID: PMC2908784  PMID: 20676326
Recurrence; Medulloblastoma; Transplantation, Autologous; Tandem; Hematopoietic Stem Cell Transplantation
18.  High Transcript Level of FLT3 Associated with High Risk of Relapse in Pediatric Acute Myeloid Leukemia 
Journal of Korean Medical Science  2010;25(6):841-845.
Identification of prognostic factors and risk-based post-remission therapy was proposed to improve the outcomes of acute myeloid leukemia (AML) and a mutation of FLT3 has been reported to be a risk factor, especially for pediatric patients. Recently, FLT3 expression level was implicated to have prognostic significance in adults, but little is known for childhood AML. To define the prognostic significance, transcript level of FLT3 was analyzed in 52 pediatric AML patients. The median copy number of FLT3 was 4.6×103 (40-5.9×107 copies)/1.0×106 GAPDH copy, and the relapse free survival of patients with high transcript level of FLT3 (>106 copy number) (0%) was significantly lower than that of the others (53.2%). High transcript level of FLT3 was associated with a markedly high risk of relapse. The development of new therapeutic scheme such as a frontline allogeneic stem cell transplantation or administration of FLT3 inhibitor is needed to improve outcomes.
doi:10.3346/jkms.2010.25.6.841
PMCID: PMC2877222  PMID: 20514303
FLT3; Transcript Level; Leukemia, Myeloid, Acute; Pediatric Age
19.  Reduced-dose craniospinal radiotherapy followed by high-dose chemotherapy and autologous stem cell rescue for children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuroectodermal tumor 
The Korean Journal of Hematology  2010;45(2):120-126.
Background
In this study, we investigated the effects of reduced-dose craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in children with a newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET).
Methods
Between March 2005 and April 2007, patients older than 3 years with a newly diagnosed high-risk MB or sPNET were enrolled. The patients received two cycles of pre-RT chemotherapy consisting of cisplatin, etoposide, vincristine, and cyclophosphamide (cycle A), and carboplatin, etoposide, vincristine, and ifosphamide (cycle B), followed by CSRT with 23.4 Gy and local RT with 30.6 Gy. After four cycles of post-RT chemotherapy (cycles A, B, A, and B), tandem double HDCT with ASCR was performed.
Results
A total of 13 patients (MB=11, sPNET=2) were enrolled. Of these, one patient progressed, one patient died of septic shock after the second cycle of B, and one patient relapsed after the third cycle of B. The 3-year event-free survival (EFS) rate of the patients intended for HDCT was 76.9%, whereas the 3-year EFS rate of the patients who received HDCT was 100%. No treatment-related mortality occurred during HDCT.
Conclusion
Although the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by HDCT and ASCR warrant further exploration in a larger study population.
doi:10.5045/kjh.2010.45.2.120
PMCID: PMC2983022  PMID: 21120191
Radiotherapy; High-dose chemotherapy; Autologous stem cell transplantation; Medulloblastoma; Supratentorial primitive neuroectodermal tumor; Children
20.  Efficacy of Tandem High-Dose Chemotherapy and Autologous Stem Cell Rescue in Patients Over 1 Year of Age with Stage 4 Neuroblastoma: The Korean Society of Pediatric Hematology-Oncology Experience Over 6 Years (2000-2005) 
Journal of Korean Medical Science  2010;25(5):691-697.
The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival±95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2±12.4% vs. 31.3±11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients.
doi:10.3346/jkms.2010.25.5.691
PMCID: PMC2858826  PMID: 20436703
Neuroblastoma; High-dose Chemotherapy; Transplantation, Autologous
21.  Idarubicin Plus Behenoyl Cytarabine and 6-thioguanine Compares Favorably with Idarubicin Plus Cytarabine-based Regimen for Children with Previously Untreated Acute Myeloid Leukemia: 10-Year Retrospective, Multicenter Study in Korea 
We investigated the outcome of idarubicin plus N4-behenoyl-1-β-D-arabinofuranosyl cytosine (BHAC)-based chemotherapy (BHAC group, n=149) compared to idarubicin plus cytarabine-based chemotherapy (cytarabine group, n=191) for childhood acute myeloid leukemia (AML). Between January 1996 and December 2005, 340 children with AML from 5 university hospitals in Korea received the BHAC-based or cytarabine-based chemotherapy, with or without hematopoietic stem cell transplantation. After induction therapy, 264 (77.6%) of 340 children achieved a complete remission (CR) and 43 (12%) achieved a partial remission (PR). The CR rate in the BHAC group was higher than in the cytarabine group (85.2% vs. 71.7%, P=0.004). However, the overall response rate (CR+PR) was not different between the two groups (93.3% vs. 87.9%, P=0.139). The 5-yr estimates of overall survival (OS) of children in the two groups were similar (54.9% for the BHAC group vs. 52.4% for the cytarabine group, P=0.281). Although the results were analyzed according to the treatment type and cytogenetic risk, the OS showed no significant difference between the BHAC group and the cytarabine group. In the present study, the clinical outcomes of the BHAC-based chemotherapy, consisting of BHAC, idarubicin, and 6-TG, are comparable to that of the cytarabine-based chemotherapy for childhood AML.
doi:10.3346/jkms.2010.25.1.9
PMCID: PMC2800026  PMID: 20052341
Leukemia, Myeloid, Acute; Enocitabine; Childhood
22.  Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk 
Leukemia research  2008;33(2):250-258.
We conducted a case–control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (–17961T>C, –9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8, 95% CI = 1.1–2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2–3.4). An increasing trend in risk was observed for pack-years smoked after birth (Ptrend = 0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (Ptrend = 0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5–5.3) and the presence of at least one smoker in the home (2.3, 1.2–4.4), and the test for interaction was significant (Pinteraction = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04–1.24) and smoking before the pregnancy of the child (1.12, 1.04–1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.
doi:10.1016/j.leukres.2008.06.031
PMCID: PMC2787091  PMID: 18691756
Childhood leukemia; Paternal smoking; CYP1A1; Interaction; Haplotype
23.  Successful Salvage Unrelated Umbilical Cord Blood Transplantation with Two Units After Engraftment Failure with Single Unit in Severe Aplastic Anemia 
Journal of Korean Medical Science  2009;24(4):744-746.
Severe aplastic anemia (SAA) patients without an HLA-matched sibling donor need alternative treatment options. Umbilical cord blood transplantation (UCBT) has become an alternative means for treating various diseases, but it has not been proved to be a satisfactory method to treat SAA. Here, we report the case of a girl who underwent successful two-unit UCBT after engraftment failure with a single unit. Two-unit UCBT is proposed to have better engraftment potential and to offer a better chance of survival, according to some reports. Increased cell dose and graft-versus-graft reaction could contribute to these advantages. With this promising result, two-unit UCBT could be an alternative treatment option for patients with SAA without an HLA-matched donor.
doi:10.3346/jkms.2009.24.4.744
PMCID: PMC2719196  PMID: 19654963
Anemia, Aplastic; Cord Blood Stem Cell Transplantation; Two-unit
24.  Improvement of Induction Remission Rate by Modifying the Dose of Idarubicin for Relapsed Childhood Acute Lymphoblastic Leukemia 
Journal of Korean Medical Science  2009;24(2):281-288.
Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL), yet there is no established treatment for relapsed ALL. To improve the induction remission rate, we modified the dose of idarubicin in the original Children's Cancer Group (CCG)-1884 protocol, and retrospectively compared the results. Twenty-eight patients diagnosed with relapsed ALL received induction chemotherapy according to the CCG-1884 protocol. Complete remission (CR) rate in all patients after induction chemotherapy was 57%. The idarubicin 10 mg/m2/week group showed CR rate of 74%, compared with the 22% CR rate of the idarubicin 12.5 mg/m2/week group (p=0.010). Remission failure due to treatment-related mortality (TRM) was 44% and 5.2% in the idarubicin 12.5 mg/m2/week and 10 mg/m2/week groups, respectively (p=0.011). Overall survival (OS) and 4-yr event-free survival (EFS) were 12.8% and 10.3%, respectively. OS and 4-yr EFS were higher in the idarubicin 10 mg/m2/week group (19.3% and 15.6%) than in the 12.5 mg/m2/week group (0% and 0%). In conclusion, a modified dose of idarubicin from 12.5 mg/m2/week to 10 mg/m2/week resulted in an improved CR rate in the treatment of relapsed ALL, which was due to lower TRM. However, despite improved CR rate with modified dose of idarubicin, survival rates were unsatisfactory.
doi:10.3346/jkms.2009.24.2.281
PMCID: PMC2672129  PMID: 19399271
Idarubicin; Remission Induction; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma
25.  Clinical Results of Chemotherapy based Treatment in Retinoblastoma Patients: A Single Center Experience 
Purpose
Retinoblastoma is the most common intraocular malignancy in children. Since the 1990s, chemotherapy was indicated for intraocluar disease to reduce the frequency of enucleation and spare the complications associated with external beam radiation. In this study, we analyzed treatment results of retinoblastoma in our institute.
Materials and Methods
Datas from children diagnosed with retinoblastoma and treated at Seoul National University Children's Hospital between 1986 and 2008 were analyzed retrospectively. We utilized cyclophosphamide, vincristine, adriamycin, and methotrexate (CVAM) for OPD-based adjuvant chemotherapy. From 1990, primary chemotherapy was administered to patients with intraocular disease for eyeball-saving and patients received a combination of etoposide, vincristine, cisplatin (or ifosfamide) as a moderately intensive regimen, or a combination of cisplatin, doxorubicin, etoposide, and cycophosphamide (CDEC) as a highly intensive regimen.
Results
One hundred eighteen children were analyzed. There were 68 unilateral and 50 bilateral diseases. The median age at diagnosis was 1 year and Reese-Ellsworth stage V was the most common stage at the time of diagnosis. All patients were treated by chemotherapy-based multimodality methods, and primary chemotherapy was administered to 80 patients. The 10-year overall and event-free survival rate of all patients were 93.9% and 91.6%, respectively. Two patients who died were in the CDEC regimen group, but there was no significant statistical difference in survival rates by chemotherapy regimens. Fifty-six of 114 eyeballs were saved after primary chemotherapy-based treatment, and the eyeball-saving rate was 49.1%. Six patients relapsed after enucleation and 2 patients were treated successfully after autologous PBSCT. Osteosarcoma occurred in 2 patients as a secondary malignancy, and facial asymmetry after radiotherapy was the most common long-term sequelae.
Conclusions
In this study, the overall and event-free survival rates of retinoblastoma were satisfactory and eye-saving was possible with primary chemotherapy. Development of new chemotherapeutic regimens and a team approach are necessary to improve the eyeball-saving rate.
doi:10.4143/crt.2008.40.4.164
PMCID: PMC2697477  PMID: 19688125
Retinoblastoma; Chemotherapy; Radiotherapy; Enucleation; Survival rate; Eyeball-saving

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