Publications by authors named "Hoon Kook"

95 Publications

Open-Label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Pediatric Patients with Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 Jul 24. Epub 2021 Jul 24.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Electronic address:

Steroid-refractory chronic graft-versus-host disease (cGVHD) is associated with high morbidity. To date, there is no standard therapy for patients who fail to respond to steroids. In this nonrandomized, open-label, single-arm, multicenter prospective phase II study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF) to treat sclerotic/fibrotic type cGVHD. The primary endpoint was the overall response rate (ORR) to imatinib mesylate plus MMF in 1 year, and the secondary endpoints included safety, quality of life, discontinuation of steroids, and overall survival (OS) rate. A total of 13 patients were enrolled, with a median age of 10.4 years (range, 5.0 to 20.1 years). All patients received a myeloablative conditioning regimen. Specifically, 6 of these patients had previously experienced acute GVHD. The most frequently affected organs were the eyes, lungs, skin, and liver. There were 2 premature deaths. One patient died of pulmonary infection and progression of cGVHD, and the other patient died from neuroblastoma progression and septic shock. The ORR was 76.9% (10 of 13 patients), and the median steroid dose was decreased from 1.0 mg/kg/day to 0.21 mg/kg/day. One-year OS was 84.6% (n = 13), and common adverse events included elevated liver enzyme and serum creatinine levels and fever. Although our sample size was limited, treatment of cGVHD with imatinib mesylate plus MMF shows promising results with acceptable toxicity.
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http://dx.doi.org/10.1016/j.jtct.2021.07.019DOI Listing
July 2021

Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: a Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group.

Cancer Res Treat 2021 Apr 20. Epub 2021 Apr 20.

Department of Pediatrics, Kosin University of Medicine, Busan, Korea.

Purpose: Acute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea.

Materials And Methods: Seventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively.

Results: Of 801 acute myeloid leukemia(AML) children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3-18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had WBC count greater than 10x109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid (ATRA) and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 (86.8%) patients achieved complete remission (CR) after induction chemotherapy. The causes of death were 3 intracranial hemorrhage (ICH), 1 cerebral infarction, and 1 sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival rate (EFS) and overall survival rates (OS) were 82.1 ± 4.4%, 89.7 ± 5.1% respectively. The 4-yr OS was significantly higher in patients with initial WBC <10x109/L than in those with initial WBC ≥10x109/L (p=0.02).

Conclusion: This study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.
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http://dx.doi.org/10.4143/crt.2021.313DOI Listing
April 2021

Successful Management of Massive Congenital Hepatic Hemangioma and Systemic Hypertension With Sirolimus.

J Pediatr Hematol Oncol 2021 May 5. Epub 2021 May 5.

Department of Pediatrics, Chonnam National University Children's Hospital Department of Pediatrics, Chonnam National University Medical School Department of Radiology, Chonnam National University Hospital, Gwangju Department of Pediatrics Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun, Korea.

Congenital hepatic hemangioma (CHH) is a common benign vascular tumor of the liver, seen in infancy. The clinical manifestations vary from incidental findings to life-threatening complications. The authors present here a case of an infant with massive CHH who developed systemic hypertension because of compression of the right renal artery by the CHH and did not respond to other lines of treatment. After sirolimus therapy, the CHH size decreased and antihypertensive drugs were no longer necessary. In a critical situation, if the embolization and/or steroids do not seem to control the situation, then adding sirolimus may be considered as secondary therapy with good additive effects.
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http://dx.doi.org/10.1097/MPH.0000000000002146DOI Listing
May 2021

Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea.

Cancer Res Treat 2021 Jan 4. Epub 2021 Jan 4.

Department of Pediatrics, Seoul National University Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Effectiveness and safety of clofarabine (one of the treatment mainstays in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [ALL]) was assessed in Korean pediatric patients with ALL to facilitate conditional coverage with evidence development.

Materials And Methods: In this multicenter, prospective, observational study, patients receiving clofarabine as mono/combination therapy were followed-up every 4-6 weeks for 6-months or until hematopoietic stem cell transplantation (HSCT). Response rates, survival outcomes, and adverse events were assessed.

Results: Sixty patients (2-26 years old; 65% B-cell ALL, received prior ≥2 regimen, 68.3% refractory to previous regimen) were enrolled and treated with at least one dose of clofarabine; of whom 26 (43.3%) completed six months of follow-up after the last dose of clofarabine. Fifty-eight patients (96.7%) received clofarabine combination therapy. Overall remission rate (complete remission [CR] or CR without platelet recovery [CRp]) was 45.0% (27/60; 95% confidence interval [CI] 32.4 to 57.6) and the overall response rate (CR, CRp, or partial remission [PR]) was 46.7% (28/60; 95% CI, 34.0 to 59.3), with 11 (18.3%), 16 (26.7%), and 1 (1.7%) patients achieving CR, CRp, and PR, respectively. The median time to remission was 5.1 weeks (95% CI: 4.7 to 6.1). Median duration of remission was 16.6 weeks (range: 2.0 to 167.6). Sixteen patients (26.7%) proceeded to HSCT. There were 24 deaths; 14 due to treatment-emergent adverse events.

Conclusion: Remission with clofarabine was observed in approximately half of the study patients who had overall expected safety profile; however, there was no favorable long-term survival outcome in this study.
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http://dx.doi.org/10.4143/crt.2020.289DOI Listing
January 2021

Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study.

J Korean Med Sci 2020 Nov 30;35(46):e393. Epub 2020 Nov 30.

Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.

Background: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea.

Methods: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016.

Results: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively ( = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively.

Conclusion: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL.
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http://dx.doi.org/10.3346/jkms.2020.35.e393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707923PMC
November 2020

The First Korean Family with Hemoglobin-M Milwaukee-2 Leading to Hereditary Methemoglobinemia.

Yonsei Med J 2020 Dec;61(12):1064-1067

Department of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun, Korea.

Hemoglobin M (HbM) is a group of abnormal hemoglobin variants that form methemoglobin, which leads to cyanosis and hemolytic anemia. HbM-Milwaukee-2 is a rare variant caused by the point mutation CAC>TAC on codon 93 of the hemoglobin subunit beta () gene, resulting in the replacement of histidine by tyrosine. We here report the first Korean family with HbM-Milwaukee-2, whose diagnosis was confirmed by gene sequencing. A high index of suspicion for this rare Hb variant is necessary in a patient presenting with cyanosis since childhood, along with methemoglobinemia and a family history of cyanosis.
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http://dx.doi.org/10.3349/ymj.2020.61.12.1064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700874PMC
December 2020

MEF2D-BCL9 B-Lymphoblastic Leukemia Blast Morphology Does Not Always Mimic Mature B-Cell Leukemia.

J Pediatr Hematol Oncol 2021 04;43(3):112-113

Department of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun.

MEF2D (myocyte enhancer factor 2D)-rearranged acute lymphoblastic leukemia (ALL) has recently been documented by transcriptome sequencing in B-cell precursor ALL. It is associated with older age of onset (median: 14 y), and characterized by very early relapse and poorer outcomes than other B-cell precursor ALL groups. According to report by Suzuki and colleagues, all 4 cases of MEF2D-BCL9-fusion ALL among 59 children with relapsed or primary refractory ALL had leukemic blasts morphologically mimicking mature B-cell leukemia cells. However, we display morphologically different blast populations in 2 patients with MEF2D-BCL9-rearranged ALL. Mature B-cell leukemia-like morphology would aid the detection of MEF2D-BCL9 fusion, but not all cases might have typical morphology.
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http://dx.doi.org/10.1097/MPH.0000000000002009DOI Listing
April 2021

Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.

Cancer Res Treat 2021 Apr 28;53(2):378-388. Epub 2020 Oct 28.

Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Purpose: Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.

Materials And Methods: A search of medical records from seven centers was performed between January 2005 and December 2016.

Results: Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).

Conclusion: Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
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http://dx.doi.org/10.4143/crt.2020.756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053862PMC
April 2021

Benign spindle cell tumor surrounding the bronchovascular structures in a 14-year-old male with neurofibromatosis type I.

Pediatr Pulmonol 2020 06 28;55(6):1305-1307. Epub 2020 Apr 28.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, South Korea.

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http://dx.doi.org/10.1002/ppul.24769DOI Listing
June 2020

Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children.

J Korean Med Sci 2020 Feb 24;35(7):e46. Epub 2020 Feb 24.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

Background: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).

Methods: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.

Results: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) ( = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; = 0.001) and GFFS (85.7% vs. 35.7%; = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.

Conclusion: This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.
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http://dx.doi.org/10.3346/jkms.2020.35.e46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036341PMC
February 2020

Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia.

Br J Haematol 2019 10 17;187(2):227-237. Epub 2019 Jun 17.

Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%-91%) vs. 91% (95% CI, 82%-96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.
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http://dx.doi.org/10.1111/bjh.16055DOI Listing
October 2019

Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: matching with osmotic fragility test and presence of spherocyte.

Orphanet J Rare Dis 2019 05 23;14(1):114. Epub 2019 May 23.

Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Republic of Korea.

Background: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS.

Methods: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform.

Results: Among 59 patients with HS, 50 (84.7%) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7%). Positive rate of osmotic fragility test was 86.8% among patients harboring HS-related gene mutations.

Conclusions: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.
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http://dx.doi.org/10.1186/s13023-019-1070-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533652PMC
May 2019

Biphenotypic acute leukemia or acute leukemia of ambiguous lineage in childhood: clinical characteristics and outcome.

Blood Res 2019 Mar 21;54(1):63-73. Epub 2019 Mar 21.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

Background: Acute leukemia (AL), not clearly assigned to myeloid, B-lymphoid, or T-lymphoid lineage, is classified as either biphenotypic acute leukemia (BAL) based on the European Group for Immunological Classification of Leukemias (EGIL) or acute leukemia of ambiguous lineage (ALAL) encompassing acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemia (MPAL) based on the World Health Organization (WHO) criteria.

Methods: Medical records of children newly diagnosed with BAL or ALAL, based on the EGIL or the 2008/2016 WHO criteria, respectively, admitted at Chonnam National University Hospital in 2001-2017 were retrospectively reviewed.

Results: Twelve (3.2%) of 377 AL patients satisfied the BAL or ALAL definitions based on the EGIL or the WHO criteria, respectively. Among 12 patients including 11 with BAL and another with undefined case based on the EGIL criteria, 7 (1.9%) had ALAL based on more stringent 2016 WHO criteria (AUL, 2; MPAL, 5). One patient had MPAL with t(9;22)(q34;q11.2), +, and two had gene abnormality. ALL-directed regimen was associated with better complete remission rate compared with AML-directed regimen (100.0% vs. 16.7%; =0.015). The 5-year overall survival (OS) and event-free survival (EFS) were 51.1±15.8% and 51.9±15.7%, respectively. AUL was associated with poor OS and EFS compared with MPAL (0.0% vs. 75.0±21.7%; =0.008).

Conclusion: Due to the rarity of the cases, future multicenter, prospective studies incorporating large number of cases are urgently warranted to identify the clinical, biologic, and molecular markers for the prediction of prognosis and determine the best tailored therapy for each patient.
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http://dx.doi.org/10.5045/br.2019.54.1.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439300PMC
March 2019

Validation of treatment outcomes according to revised severity criteria from European Society for Blood and Marrow Transplantation (EBMT) for sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD).

Bone Marrow Transplant 2019 08 26;54(8):1361-1368. Epub 2019 Feb 26.

Department of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Traditional severity criteria of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were determined retrospectively but found inappropriate for therapeutic decisions. Data of 203 patients with SOS/VOD were collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised severity criteria recently proposed from European Society for Blood and Marrow Transplantation (EBMT). According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised EBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. The 100-day overall survival (OS) of mild, moderate, severe and very severe groups was 83.3, 84.3, 94.6, and 58.6%, respectively. Very severe SOS/VOD showed a significantly lower OS than the others (58.6 vs. 89.3%, p < 0.0001). The 100-day transplantation-related mortality was 25.2% in the entire cohort; 8.3% in mild, 8.0% in moderate, 2.7% in severe, and 36.7% in very severe SOS/VOD (p < 0.0001). The very severe grade newly classified by the revised EBMT criteria accounted for the majority of SOS/VOD associated with worse 100-day OS. Therefore, intervention should be applied at the latest for moderate to severe SOS/VOD before deterioration.
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http://dx.doi.org/10.1038/s41409-019-0492-6DOI Listing
August 2019

Author Correction: Regulatory role of G9a and LSD1 in the Transcription of Olfactory Receptors during Leukaemia Cell Differentiation.

Sci Rep 2018 Nov 19;8(1):17075. Epub 2018 Nov 19.

Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul, 156-756, Republic of Korea.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-35591-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242810PMC
November 2018

Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients.

Cancer Res Treat 2019 Jan 14;51(1):357-367. Epub 2018 May 14.

Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients.

Materials And Methods: Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected.

Results: Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis.

Conclusion: Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.
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http://dx.doi.org/10.4143/crt.2017.457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333985PMC
January 2019

Treatment Decisions of World Health Organization Grade II and III Ependymomas in Molecular Era.

J Korean Neurosurg Soc 2018 May 1;61(3):312-318. Epub 2018 May 1.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

Surgery and radiotherapy are mainstays of treatment for ependymomas (EPNs). Recent molecular subgrouping could be superior to histopathological grading for predicting the prognosis of patients with EPNs. Gross total resection is an effective treatment approach regardless of its locations or pathologic grades. Adjuvant therapeutic strategies could be decided based on molecular subgrouping with risk-stratification. Information of histologic-molecular biology is now providing clues to therapeutic insights.
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http://dx.doi.org/10.3340/jkns.2018.0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957310PMC
May 2018

Improvement of treatment outcome over 2 decades in children with acute myeloid leukemia.

Blood Res 2018 Mar 27;53(1):25-34. Epub 2018 Mar 27.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

Background: The prognosis of pediatric acute myeloid leukemia (AML) has recently improved. This study aimed to describe the epidemiology, changes in treatment strategies, and improvement of outcomes in Gwangju-Chonnam children with AML over 2 decades.

Methods: Medical records of 116 children with newly diagnosed AML were retrospectively reviewed for demographic characteristics, prognostic groups including cytogenetic risks, treatment protocols, and survival rates over the periods between 1996 and 2005 (Period I, N=53), and 2006 and 2015 (Period II, N=38).

Results: The annual incidence of AML has decreased with reduced pediatric population. The 5-year Kaplan-Meier (K-M) estimated overall survival (OS) and event-free survival (EFS) rates in 110 AML patients were 53.2±5.1% and 43.8±5.1%, respectively. The 5-year OS rate significantly improved during period II (70.3±7.0%) as compared to that during period I (40.0±6.8%) ( =0.001). The 5-year OS was not significantly different among cytogenetic risk groups ( =0.11). Fifty-eight patients underwent hematopoietic stem cell transplantation (HSCT). The K-M 5-year estimated survival for transplanted patients was 53.7±7.0%, while that for chemotherapy-only patients was 30.1±9.1% ( =0.014). Among the prognostic factors, treatment modality was the only independent factor. The chemotherapy-only group had a relative risk of 2.06 for death compared with the transplantation group (=0.015).

Conclusion: The survival of Korean children with AML has improved to a level comparable with that of developed countries over 2 decades, owing to a change in induction strategy, better supportive care with economic growth, refinement of HSCT techniques including a better selection of patients based on prognostic groups, and stem cell donor selection.
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http://dx.doi.org/10.5045/br.2018.53.1.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898990PMC
March 2018

Management of immune thrombocytopenia: Korean experts recommendation in 2017.

Blood Res 2017 Dec 26;52(4):254-263. Epub 2017 Dec 26.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun, Korea.

Management options for patients with immune thrombocytopenia (ITP) have evolved substantially over the past decades. The American Society of Hematology published a treatment guideline for clinicians referring to the management of ITP in 2011. This evidence-based practice guideline for ITP enables the appropriate treatment of a larger proportion of patients and the maintenance of normal platelet counts. Korean authority operates a unified mandatory national health insurance system. Even though we have a uniform standard guideline enforced by insurance reimbursement, there are several unsolved issues in real practice in ITP treatment. To optimize the management of Korean ITP patients, the Korean Society of Hematology Aplastic Anemia Working Party (KSHAAWP) reviewed the consensus and the Korean data on the clinical practices of ITP therapy. Here, we report a Korean expert recommendation guide for the management of ITP.
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http://dx.doi.org/10.5045/br.2017.52.4.254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762735PMC
December 2017

Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype.

Medicine (Baltimore) 2017 Jul;96(29):e7387

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine Asan Institute for Life Sciences Medical Genetics Center, Asan Medical Center Children's Hospital, Seoul Department of Pediatrics, Pusan National University Children's Hospital Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan Department of Pediatrics, Seoul National University Children's Hospital, Seoul Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon Department of Pediatrics, College of Medicine, Soonchunhyang University, Bucheon Hospital, Bucheon Department of Pediatrics, College of Medicine, Soonchunhyang University, Seoul Hospital, Seoul Department of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun Department of Pediatrics, Chungnam National University Hospital, Daejeon Department of Cardiology, Bucheon Sejong Hospital, Bucheon Department of Cardiology, Kyung Hee University Hospital Department of Cardiology, Yonsei University Severance Hospital Department of Nephrology, Chung-Ang University Hospital Department of Cardiology, Eulji University Hospital, Seoul Department of Nephrology, Kyungpook National University Hospital, Daegu Division of Nephrology, Department of Internal Medicine, Dankook University Hospital, Dankook University, College of Medicine, Cheonan Department of Cardiology, Inje University Busan Paik Hospital, Busan, Republic of Korea.

Fabry disease is a rare X-linked lysosomal storage disorder caused by an α-galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey.This study included 94 patients from 46 independent pedigrees: 38 adult males, 46 symptomatic females, and 10 pediatric males. Each diagnosis was based on an enzyme assay and GLA gene mutation analysis.The mean age at presentation was 24 years (range, 5-65 years); however, the diagnoses were delayed by 21 ± 19 years after the onset of symptoms. Those patients with late-onset Fabry disease were diagnosed by family screening or milder symptoms at a later age. Forty different mutations were identified: 20 missense (50%), 10 nonsense (25%), 8 frameshift (20%), and 2 splice site (5%) mutations. Five of them were novel. IVS4+919G>A (c.936+919 G>A) was not detected among the 6505 alleles via newborn screening using dried blood spots. Enzyme replacement therapy (ERT) was performed in all the males and pediatric patients, whereas 75% of the symptomatic females underwent ERT for 4.2 ± 3.6 years.This study described the demographic data, wide clinical spectrum of phenotypes, and GLA mutation spectrum of Fabry disease in Korea. Most of the patients had classical Fabry disease, with a 4 times higher incidence than that of late-onset Fabry disease, indicating an underdiagnosis of mild, late-onset Fabry disease.
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http://dx.doi.org/10.1097/MD.0000000000007387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521888PMC
July 2017

Regulatory role of G9a and LSD1 in the Transcription of Olfactory Receptors during Leukaemia Cell Differentiation.

Sci Rep 2017 04 7;7:46182. Epub 2017 Apr 7.

Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756, Republic of Korea.

Recent studies have reported the ectopic expression of olfactory receptors (ORs) in non-olfactory tissues, however, their physiological roles were not well elucidated. ORs are expressed in and function in different types of cancers. Here, we identified that the H3K9me2 levels of several OR promoters decreased during differentiation in the HL-60, human myeloid leukaemia cell line, by all-trans-retinoic acid (ATRA). We found that the differential OR promoters H3K9me2 levels were regulated by G9a and LSD1, resulting in the decrease of ORs transcription during HL-60 differentiation. G9a and LSD1 could regulate the expression of ORs in several non-olfactory cells via the methylation and demethylation of H3K9me2. In addition, we demonstrated that knockdown of OR significantly reduced cell proliferation. Therefore, the epigenetic regulation of ORs transcription is critical for carcinogenesis.
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http://dx.doi.org/10.1038/srep46182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384044PMC
April 2017

Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey.

J Korean Med Sci 2016 Aug 18;31(8):1254-61. Epub 2016 May 18.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea .

This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t-MNs and CNS tumors.
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http://dx.doi.org/10.3346/jkms.2016.31.8.1254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951555PMC
August 2016

Higher Gemcitabine Dose Was Associated With Better Outcome of Osteosarcoma Patients Receiving Gemcitabine-Docetaxel Chemotherapy.

Pediatr Blood Cancer 2016 09 16;63(9):1552-6. Epub 2016 May 16.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea.

Background: Efficacy of gemcitabine and docetaxel (GEM + DOC) chemotherapy in patients with recurrent or refractory osteosarcoma was evaluated.

Methods: Data of 53 patients from 9 institutions, who received GEM (675 or 900 mg/m(2) on days 1 and 8) and DOC (100 mg/m(2) on day 8), were retrospectively reviewed.

Results: GEM + DOC was administered as adjuvant (n = 25) or palliative chemotherapy (n = 28). Patients received a median 3 courses (range, 1-10 courses). Objective response rate (CR + PR, where CR is complete response and PR is partial response) and disease control rate (CR+ PR + SD, where SD is stable disease) were 14.3% and 28.6%, respectively. Disease control rate was higher in patients receiving 900 mg/m(2) GEM than in patients receiving 675 mg/m(2) (50.0% vs. 12.5%, P = 0.03). Higher GEM dose was associated with better survival, both in adjuvant (1-year overall survival, 90.9 ± 8.7% vs. 38.5 ± 13.5%, P = 0.002) and palliative settings (50.0 ± 14.4% vs. 31.3 ± 11.6%, P = 0.04).

Conclusions: Further studies are necessary to investigate the efficacy of more aggressive and higher doses of GEM + DOC chemotherapy in osteosarcoma.
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http://dx.doi.org/10.1002/pbc.26058DOI Listing
September 2016

Acquired aplastic anemia in Korean children: treatment guidelines from the Bone Marrow Failure Committee of the Korean Society of Pediatric Hematology Oncology.

Int J Hematol 2016 Apr 19;103(4):380-6. Epub 2016 Feb 19.

Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

The treatment of choice for aplastic anemia (AA) in children has been HLA-matched family donor (MFD) hematopoietic stem cell transplantation (HSCT). For those lacking MFD, immunosuppressive therapy (IST) consisting of horse antithymocyte globulin (ATG) and cyclosporine has been successful. The choices of second and third line treatments are more complex and debatable, especially in the situation of unavailability of horse ATG. IST with rabbit ATG seems to be less effective. Recently, improved survival of non-MFD HSCTs has been documented. The outcome of matched or mismatched unrelated donor, umbilical cord blood, or haploidentical family donor transplantations will be discussed in AA children after IST failure. Experimental approaches of upfront HSCT using non-MFDs will be briefly touched. In this review, a treatment guideline for children with AA from the Korean Society of Pediatric Hematology Oncology will be presented along with a brief review of literature on current clinical practices in Korea.
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http://dx.doi.org/10.1007/s12185-016-1956-8DOI Listing
April 2016

Alveolar rhabdomyosarcoma with massive disseminated intravascular coagulopathy treated with systemic chemotherapy.

Korean J Pediatr 2015 Dec 22;58(12):505-8. Epub 2015 Dec 22.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

It is uncommon for pediatric patients with rhabdomyosarcoma to present with clinical and/or laboratory features of disseminated intravascular coagulation (DIC). We report a case of metastatic alveolar rhabdomyosarcoma with severe bleeding because of DIC in a 13-year-old boy. He experienced persistent oozing at the site of a previous operation, gross hematuria, and massive epistaxis. Two weeks after initiating combination chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide, the patients' laboratory indications of DIC began to resolve. During this period, the patient received massive blood transfusion of a total of 311 units (26 units of red blood cells, 26 units of fresh frozen plasma, 74 units of platelet concentrates, 17 units of single donor platelets, and 168 units of cryoprecipitate), antithrombin-III and a synthetic protease inhibitor. Despite chemotherapy and radiation therapy, he died 1 year later because of disease progression. In children with metastatic rhabdomyosarcoma and massive DIC, prompt chemotherapy and aggressive supportive care is important to decrease malignancy-triggered procoagulant activities.
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http://dx.doi.org/10.3345/kjp.2015.58.12.505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705332PMC
December 2015

Clinicopathological Implications of Mitochondrial Genome Alterations in Pediatric Acute Myeloid Leukemia.

Ann Lab Med 2016 Mar;36(2):101-10

Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Korea.

Background: To the best of our knowledge, the association between pediatric AML and mitochondrial aberrations has not been studied. We investigated various mitochondrial aberrations in pediatric AML and evaluated their impact on clinical outcomes.

Methods: Sequencing, mitochondrial DNA (mtDNA) copy number determination, mtDNA 4,977-bp large deletion assessments, and gene scan analyses were performed on the bone marrow mononuclear cells of 55 pediatric AML patients and on the peripheral blood mononuclear cells of 55 normal controls. Changes in the mitochondrial mass, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) levels were also examined.

Results: mtDNA copy numbers were about two-fold higher in pediatric AML cells than in controls (P<0.0001). Furthermore, a close relationship was found between mtDNA copy number tertiles and the risk of pediatric AML. Intracellular ROS levels, mitochondrial mass, and mitochondrial membrane potentials were all elevated in pediatric AML. The frequency of the mtDNA 4,977-bp large deletion was significantly higher (P<0.01) in pediatric AML cells, and pediatric AML patients harboring high amount of mtDNA 4,977-bp deletions showed shorter overall survival and event-free survival rates, albeit without statistical significance.

Conclusions: The present findings demonstrate an association between mitochondrial genome alterations and the risk of pediatric AML.
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http://dx.doi.org/10.3343/alm.2016.36.2.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713842PMC
March 2016

Graves disease following rabbit antithymocyte globulin treatment of severe aplastic anemia in a Korean child.

Korean J Pediatr 2015 Jul 22;58(7):267-9. Epub 2015 Jul 22.

Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea.

Antithymocyte globulin (ATG) is used as an immunosuppressive treatment (IST) to deplete clonal suppressor T cells in patients with severe aplastic anemia (SAA). The depletion of suppressor T cells by ATG may affect the activation of B cells, which results in an increased risk for autoimmune conditions. A 12-year-old boy was diagnosed with idiopathic SAA. As he did not have an human leukocyte antigen-matched sibling, he was treated with rabbit ATG (3.5 mg/kg/day for 5 days) and cyclosporine. Five months later, he became transfusion independent. However, 23 months after IST, he complained of mild hand tremors, sweating, weight loss, palpitations, and goiter. Results of thyroid function tests revealed hyperthyroidism (free thyroxine, 3.42 ng/dL; thyroid stimulating hormone [TSH], <0.01 nIU/mL; triiodothyronine, 3.99 ng/mL). Results of tests for autoantibodies were positive for the antimicrosome antibody and TSH-binding inhibitory immunoglobulin, but negative for the antithyroglobulin antibody and antinuclear antibody. He was treated with methimazole, and his symptoms improved. The patient has been disease free for 39 months after IST and 9 months after methimazole treatment. This case report suggests that although rare, rabbit ATG may have implications in the pathogenesis of autoimmune hyperthyroidism. Our findings suggest that thyroid function tests should be incorporated in the routine follow-up of SAA patients treated with ATG.
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http://dx.doi.org/10.3345/kjp.2015.58.7.267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543187PMC
July 2015
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