Cancer Research and Treatment

Original Articles

Literature-Guided 6-Gene Signature for the Stratification of High-Risk Acute Myeloid Leukemia: Jong Keon Song, Dong Hyeok Lee, Hyery Kim, Sang-Hyun Hwang; Received November 20, 2024 Accepted January 22, 2025 Published online January 24, 2025; DOI: https://doi.org/10.4143/crt.2024.1114 [Accepted]

Abstract PDF: Purpose
Acute myeloid leukemia (AML) shows significant heterogeneity in therapeutic responses. We aimed to develop a gene signature for the stratification of high-risk pediatric AML using publicly available AML datasets, with a focus on literature-based prognostic gene sets. Materials and Methods We identified 300 genes from 12 well-validated studies on AML-related gene signatures. Clinical and gene expression data were obtained from three datasets: TCGA-LAML, TARGET-AML, and BeatAML. Least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was used to perform the initial gene selection and to construct a prognostic model using the TCGA database (n=132). The final gene signature was validated with two independent cohorts: BeatAML (n=411) and TARGET-AML (n=187).
Results
We identified a six-gene signature (ETFB, ARL6IP5, PTP4A3, CSK, HS3ST3B1, PLA2G4A), referred to as the literature-based signature 6 (LBS6), that was significantly associated with lower overall survival rates across the TCGA (HR=4.2, 95% CI: 2.59–6.81, p<0.0001), BeatAML (HR=1.52, 95% CI: 1.17–1.96, p=0.0013), and TARGET (HR=2.05, 95% CI: 1.36–3.08, p<0.001) datasets. The high-LBS6 score group exhibited significantly poorer five-year event-free survival compared to the low-LBS6 score group (HR=2.09, 95% CI: 1.38–3.15, p<0.001). After adjusting for key risk factors, including gene mutations (WT1, FLT3, and NPM1), protocol-based risk group, WBC count, and age, the LBS6 score was independently associated with worse survival rates in validation cohorts.
Conclusion
Our literature-driven approach identified a robust gene signature that stratifies AML patients into distinct risk groups. The LBS6 score shows promise in redefining initial risk stratification and identifying high-risk AML patients.

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Unraveling the Genetic Landscape of Langerhans Cell Histiocytosis in Korean Patients: Comprehensive Insights from Mutational Profiles and Clinical Correlations: Kyung-Nam Koh, Ha Ra Jun, Ji-Young Lee, Ji Young Kim, Su Hyun Yoon, Young Kwon Koh, Sung Han Kang, Hyery Kim, Ho Joon Im, Sung-Min Chun; Received August 14, 2024 Accepted December 22, 2024 Published online December 24, 2024; DOI: https://doi.org/10.4143/crt.2024.782 [Accepted]

Abstract PDF: Purpose
This study aimed to conduct a comprehensive genetic analysis of patients with Langerhans cell histiocytosis (LCH), focusing on the frequency of MAPK pathway mutations, detailed mutation profiles of MAPK pathway genes, and their correlation with clinical features and prognosis in Korean LCH patients.
Materials and Methods
We performed targeted next-generation sequencing, capable of capturing exons from 382 cancer-related genes, on genomic DNA extracted from formaldehyde-fixed and paraffin-embedded samples of 45 pathologically confirmed LCH patients.
Results
The majority of patients (91.1%) exhibited single-system disease, with bone being the most common location (84.4%). Initial treatments varied, and no patients died during a median follow-up of 6.8 years. Our genetic assays revealed that all patients had MAPK pathway alterations, including BRAF mutations in 51.2%, MAP2K1 mutations in 42.2%, RAF1 mutations in 4.4%, and a KRAS mutation in 2.2%. These mutations were mutually exclusive. Detailed mutation profiles indicated that among the BRAF mutations, there were 18 point mutations and 5 in-frame deletions, while most MAP2K1 mutations were in-frame deletions, with only one missense mutation. We detected previously unreported variations of point mutations in BRAF, MAP2K1, KRAS, and the first instance of a RAF1-KLC1 fusion in LCH. MAP2K1 mutations occurred more frequently in older patients, whereas BRAF V600 mutations were commonly associated with unifocal bone disease. Genetic mutations did not correlate with high-risk features or event-free survival.
Conclusion
This study identified mutually exclusive MAPK pathway mutations in every LCH patient through comprehensive genetic analysis, highlighting the importance of inclusive testing in understanding the disease's genetics.

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Pediatric cancer

Ten-Year Trends of Hematopoietic Stem Cell Transplantation in Korean Pediatric Cancer from the National Health Insurance Claims Data: Hyery Kim, Hwa Jung Kim, Youngjun Jo, Su Hyun Yoon, Young Kwon Koh, Sunghan Kang, Kyung-Nam Koh, Ho Joon Im; Cancer Res Treat. 2024;56(1):294-304. Published online September 7, 2023; DOI: https://doi.org/10.4143/crt.2023.598

Abstract PDF Supplementary Material PubReader ePub: Purpose
We aimed to determine the current application and survival trends of hematopoietic stem cell transplantation (HSCT) among Korean children and adolescents with cancer.
Materials and Methods
Data of patients aged < 20 years with KCD-10 (Korean Classifications of Diseases, 10th revision) C codes and specific designation codes were collected from the National Health Insurance Service database. Thirty claim codes for HSCT were included, and data from 2009 to 2019 were analyzed.
Results
The operational definition of pediatric cancer yielded an annual average of 2,000, with annual cases decreasing. In 2019, 221 HSCTs were performed, a decrease from the ten-year average of 276. Allografts outnumbered autografts with a ratio of 1.5:1. The source of allograft was bone marrow in 15% of patients in 2009; however, it substantially decreased to 3.3% in 2019. Furthermore, 70.5% of allogeneic HSCT used peripheral blood stem cell (PBSC) grafts, which increased to 89.3% by 2015. Cord blood utilization markedly decreased to 2.7% in 2018. The 5-year overall survival (OS) rate of all patients was 85.1%. Overall mortality decreased among patients who underwent recent HSCT, and they exhibited a higher 5-year OS rate.
Conclusion
In Korea, the number of pediatric patients with cancer is declining; however, the ratio of transplants to all patients remains constant. Patients who recently underwent transplantation showed better survival rates, possibly due to HSCT optimization. Korea showed a substantially greater PBSC utilization in pediatric HSCT. An in-depth examination encompassing donor relations and cause of death with a prospective registry is required in future studies.

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Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data: Kyung-Nam Koh, Jung Woo Han, Hyoung Soo Choi, Hyoung Jin Kang, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Kyung Taek Hong, Jung Yoon Choi, Sung Han Kang, Hyery Kim, Ho Joon Im, Seung Min Hahn, Chuhl Joo Lyu, Hee-Jo Baek, Hoon Kook, Kyung Mi Park, Eu Jeen Yang, Young Tak Lim, Seongkoo Kim, Jae Wook Lee, Nack-Gyun Chung, Bin Cho, Meerim Park, Hyeon Jin Park, Byung-Kiu Park, Jun Ah Lee, Jun Eun Park, Soon Ki Kim, Ji Yoon Kim, Hyo Sun Kim, Youngeun Ma, Kyung Duk Park, Sang Kyu Park, Eun Sil Park, Ye Jee Shim, Eun Sun Yoo, Kyung Ha Ryu, Jae Won Yoo, Yeon Jung Lim, Hoi Soo Yoon, Mee Jeong Lee, Jae Min Lee, In-Sang Jeon, Hye Lim Jung, Hee Won Chueh, Seunghyun Won, the Korean Pediatric Hematology and Oncology Group (KPHOG); Cancer Res Treat. 2023;55(1):279-290. Published online August 11, 2022; DOI: https://doi.org/10.4143/crt.2022.073

Abstract PDF Supplementary Material PubReader ePub

Purpose
Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea.
Materials and Methods
From January 2001 to December 2015, data of pediatric patients (0–18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed.
Results
Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001).
Conclusion
The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.

Citations

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Hope and challenges in the diagnosis and treatment of Wilms tumor: a single-center retrospective study in China
Kongkong Cui, Peng Hong, Jie Lin, Zaihong Hu, Zhiqiang Gao, XiaoMao Tian, Tao Lin, Qinlin Shi, Guanghui Wei
Frontiers in Pediatrics.2025;[Epub] CrossRef
Congenital Mesoblastic Nephroma Mimic Wilms Tumor on 18F-FDG PET/CT and PET/MR
Wenzhu Hu, Chunxia Qin, Fuqiang Shao, Mengting Li, Xiaoli Lan
Clinical Nuclear Medicine.2024; 49(4): 353. CrossRef
Progress towards Therapies for Solid Renal Tumors in Children
洁林
Advances in Clinical Medicine.2024; 14(06): 245. CrossRef

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Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: A Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group: Kyung Mi Park, Keon Hee Yoo, Seong Koo Kim, Jae Wook Lee, Nack-Gyun Chung, Hee Young Ju, Hong Hoe Koo, Chuhl Joo Lyu, Seung Min Han, Jung Woo Han, Jung Yoon Choi, Kyung Taek Hong, Hyoung Jin Kang, Hee Young Shin, Ho Joon Im, Kyung-Nam Koh, Hyery Kim, Hoon Kook, Hee Jo Baek, Bo Ram Kim, Eu Jeen Yang, Jae Young Lim, Eun Sil Park, Eun Jin Choi, Sang Kyu Park, Jae Min Lee, Ye Jee Shim, Ji Yoon Kim, Ji Kyoung Park, Seom Gim Kong, Young Bae Choi, Bin Cho, Young Tak Lim; Cancer Res Treat. 2022;54(1):269-276. Published online April 20, 2021; DOI: https://doi.org/10.4143/crt.2021.313

Abstract PDF PubReader ePub

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 children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×10⁹/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×10⁹/L than in those with initial WBC ≥ 10×10⁹/L (p=0.020).
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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Management of Acute Promyelocytic Leukemia at Extremes of Age
Sabine Kayser, Shannon E. Conneely
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Chi-kong Li, Purna Kurkure, Ramandeep Singh Arora, Bow Wen Chen, Kirill Kirgizov, Yasuhiro Okamoto, Panya Seksarn, Yongmin Tang, Keon Hee Yoo, Bharat Agarwal, Godfrey C.F. Chan, Rashmi Dalvi, Hiroki Hori, Muhammad Saghir Khan, Alice Yu, Akira Nakagawara
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Lila Krebs-Drouot, Georgia Karpathiou, Virginie Scolan, Carolyne Bidat-Callet, Baptiste Boyer, Michel Péoc’h
Forensic Science, Medicine and Pathology.2022; 19(1): 60. CrossRef
Successful Treatment of Isolated Central Nervous System Relapse with Intrathecal Chemotherapy in an Adolescent with Acute Promyelocytic Leukemia
Haerim Song, Eun Sang Yi
Clinical Pediatric Hematology-Oncology.2022; 29(2): 70. CrossRef

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Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea: Jung Yoon Choi, Che Ry Hong, Kyung Taek Hong, Hyoung Jin Kang, Seongkoo Kim, Jae Wook Lee, Pil Sang Jang, Nack-Gyun Chung, Bin Cho, Hyery Kim, Kyung-Nam Koh, Ho Joon Im, Jong Jin Seo, Seung Min Hahn, Jung Woo Han, Chuhl Joo Lyu, Eu Jeen Yang, Young Tak Lim, Keon Hee Yoo, Hong Hoe Koo, Hoon Kook, In Sang Jeon, Hana Cho, Hee Young Shin; Cancer Res Treat. 2021;53(4):1184-1194. Published online January 4, 2021; DOI: https://doi.org/10.4143/crt.2020.289

Abstract PDF Supplementary Material PubReader ePub

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 6 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 one (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 weeks). 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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Zan Liu, Zitong Zhao, Longlong Xie, Zhenghui Xiao, Ming Li, Yong Li, Ting Luo
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Christian Omar Ramos-Peñafiel, Carlos Martínez-Murillo, Daniela Pérez-Sámano, Camila Terreros-Palacios, Adán Germán Gallardo-Rodríguez, Irma Olarte-Carrillo, Adolfo Martínez-Tovar
Revista Médicas UIS.2024;[Epub] CrossRef
Clofarabine

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Patient-Level Meta-analysis of Clofarabine in Acute Lymphoblastic Leukemia
Sima Jeha, Hiroaki Goto, André Baruchel, Emmanuelle Boëlle-Le Corfec, Christine Geffriaud-Ricouard, Rob Pieters, Hee Young Shin
Advances in Therapy.2023; 40(12): 5447. CrossRef
Novel Treatments for Pediatric Relapsed or Refractory Acute B-Cell Lineage Lymphoblastic Leukemia: Precision Medicine Era
Shang Mengxuan, Zhou Fen, Jin Runming
Frontiers in Pediatrics.2022;[Epub] CrossRef

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Central nervous system

Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years: Meerim Park, Jung Woo Han, Seung Min Hahn, Jun Ah Lee, Joo-Young Kim, Sang Hoon Shin, Dong-Seok Kim, Hong In Yoon, Kyung Taek Hong, Jung Yoon Choi, Hyoung Jin Kang, Hee Young Shin, Ji Hoon Phi, Seung-Ki Kim, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Do Hoon Lim, Hyung Jin Shin, Hyery Kim, Kyung-Nam Koh, Ho Joon Im, Seung Do Ahn, Young-Shin Ra, Hee-Jo Baek, Hoon Kook, Tae-Young Jung, Hyoung Soo Choi, Chae-Yong Kim, Hyeon Jin Park, Chuhl Joo Lyu; Cancer Res Treat. 2021;53(2):378-388. Published online October 28, 2020; DOI: https://doi.org/10.4143/crt.2020.756

Abstract PDF PubReader ePub

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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Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors
Marjolein M.G. Kes, Francisco Morales-Rodriguez, Esther A. Zaal, Terezinha de Souza, Natalie Proost, Marieke van de Ven, Marry M. van den Heuvel-Eibrink, Jeroen W.A. Jansen, Celia R. Berkers, Jarno Drost
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High-throughput screening of FDA-approved drugs identifies colchicine as a potential therapeutic agent for atypical teratoid/rhabdoid tumors (AT/RTs)
Phongthon Kanjanasirirat, Kedchin Jearawuttanakul, Sawinee Seemakhan, Suparerk Borwornpinyo, Patompon Wongtrakoongate, Suradej Hongeng, Sitthivut Charoensutthivarakul
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Supratentorial ATRT in a young Infant: Expanding the diagnostic spectrum beyond medulloblastoma
Ali Msheik, Mohamad Aoun, Youssef Fares
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Radiation Therapy Plays an Important Role in the Treatment of Atypical Teratoid/Rhabdoid Tumors: Analysis of the EU-RHAB Cohorts and Their Precursors
Sabine Frisch, Hanna Libuschewski, Sarah Peters, Joachim Gerß, Katja von Hoff, Rolf-Dieter Kortmann, Karolina Nemes, Stefan Rutkowski, Martin Hasselblatt, Torsten Pietsch, Michael C. Frühwald, Beate Timmermann
International Journal of Radiation Oncology*Biology*Physics.2024; 119(4): 1147. CrossRef
An adult with recurrent atypical teratoid rhabdoid tumor of the spine
Antoinette J Charles, Vanessa L Smith, C Rory Goodwin, Margaret O Johnson
CNS Oncology.2024;[Epub] CrossRef
Dynamic Survival Risk Prognostic Model and Genomic Landscape for Atypical Teratoid/Rhabdoid Tumors: A Population-Based, Real-World Study
Sihao Chen, Yi He, Jiao Liu, Ruixin Wu, Menglei Wang, Aishun Jin
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ESTRO-SIOPE guideline: Clinical management of radiotherapy in atypical teratoid/rhabdoid tumors (AT/RTs)
Beate Timmermann, Claire Alapetite, Karin Dieckmann, Rolf-Dieter Kortmann, Yasmin Lassen-Ramshad, John H. Maduro, Monica Ramos Albiac, Umberto Ricardi, Damien C. Weber
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Development and epigenetic regulation of Atypical teratoid/rhabdoid tumors in the context of cell-of-origin and halted cell differentiation
Laura Huhtala, Goktug Karabiyik, Kirsi J Rautajoki
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Comparative treatment results of children with atypical teratoid/rhabdoid tumor of the central nervous system in the younger age group
L. V. Olkhova, O. G. Zheludkova, L. S. Zubarovskaya, A. S. Levashov, A. Yu. Smirnova, Yu. V. Dinikina, Yu. V. Kushel, A. G. Melikyan, S. K. Gorelyshev, M. V. Ryzhova, Yu. Yu. Trunin, A. G. Gevorgyan, O. B. Polushkina, V. E. Popov, L. P. Privalova, N. B. Y
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Yen-Lin Liu, Min-Lan Tsai, Chang-I Chen, Noi Yar, Ching-Wen Tsai, Hsin-Lun Lee, Chia-Chun Kuo, Wan-Ling Ho, Kevin Li-Chun Hsieh, Sung-Hui Tseng, James S. Miser, Chia-Yau Chang, Hsi Chang, Wen-Chang Huang, Tai-Tong Wong, Alexander T. H. Wu, Yu-Chun Yen
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Cinzia Baiano, Rosa Della Monica, Raduan Ahmed Franca, Maria Laura Del Basso De Caro, Luigi Maria Cavallo, Lorenzo Chiariotti, Tamara Ius, Emmanuel Jouanneau, Teresa Somma
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Vismaya S. Bachu, Pavan Shah, Adrian E. Jimenez, Adham M. Khalafallah, Jignesh Tailor, Debraj Mukherjee, Alan R. Cohen
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Chang Zhang, Hao Li
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The results of multicenter treatment of atypical teratoid/rhabdoid tumors of the central nervous system in children under 3 years
L. V. Olkhova, O. G. Zheludkova, L. S. Zubarovskaya, A. Yu. Smirnova, Yu. V. Dinikina, Yu. V. Kushel, A. G. Melikyan, S. K. Gorelyshev, M. V. Ryzhova, Yu. Yu. Trunin, E. I. Shults, A. G. Gevorgyan, S. V. Gorbatykh, A. N. Kislyakov, V. E. Popov, L. P. Priv
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Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients: Hyery Kim, Hyoung Jin Kang, Kyung Duk Park, Kyung-Nam Koh, Ho Joon Im, Jong Jin Seo, Jae Wook Lee, Nack-Gyun Chung, Bin Cho, Hack Ki Kim, Jae Min Lee, Jeong Ok Hah, Jun Ah Lee, Young Ho Lee, Sang Kyu Park, Hee Jo Baek, Hoon Kook, Ji Yoon Kim, Heung Sik Kim, Hwang Min Kim, Hee Won Chueh, Meerim Park, Hoi Soo Yoon, Mee Jeong Lee, Hyoung Soo Choi, Hyo Seop Ahn, Yoshifumi Kawano, Ji Won Park, Seokyung Hahn, Hee Young Shin; Cancer Res Treat. 2019;51(1):357-367. Published online May 14, 2018; DOI: https://doi.org/10.4143/crt.2017.457

Abstract PDF Supplementary Material PubReader ePub

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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Veronika Keresteš, Jan Kubeš, Lenka Applová, Petra Kollárová, Olga Lenčová-Popelová, Iuliia Melnikova, Galina Karabanovich, Mushtaq M Khazeem, Hana Bavlovič-Piskáčková, Petra Štěrbová-Kovaříková, Caroline A Austin, Jaroslav Roh, Martin Štěrba, Tomáš Šimůn
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Circ-0006332 stimulates cardiomyocyte pyroptosis via the miR-143/TLR2 axis to promote doxorubicin-induced cardiac damage
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Pediatric Cardio-Oncology: Screening, Risk Stratification, and Prevention of Cardiotoxicity Associated with Anthracyclines
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Parya Rahimi, Behsheed Barootkoob, Ahmed ElHashash, Arun Nair
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Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group
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Cardiotoxicity After Anthracycline Chemotherapy for Childhood Cancer in a Multiethnic Asian Population
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APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia: Hyery Kim, Heewon Seo, Yoomi Park, Byung-Joo Min, Myung-Eui Seo, Kyung Duk Park, Hee Young Shin, Ju Han Kim, Hyoung Jin Kang; Cancer Res Treat. 2018;50(3):823-834. Published online September 4, 2017; DOI: https://doi.org/10.4143/crt.2017.351

Abstract PDF Supplementary Material PubReader ePub

Purpose
Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients.
Materials and Methods
Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients.
Results
Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01).
Conclusion
We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.

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Parallel Toxicities: A Comparative Analysis of Chemotherapy-Induced Neutropenia and Alopecia
Simonetta I. Gaumond, Karen J. Lee, Peyton V. Warp, Isabella Kamholtz, Emilee M. Dreifus, Joaquin J. Jimenez
Cancers.2025; 17(7): 1163. CrossRef
Role of Drug Transporters in Elucidating Inter-Individual Variability in Pediatric Chemotherapy-Related Toxicities and Response
Ashwin Kamath, Suresh Kumar Srinivasamurthy, Mukta N. Chowta, Sheetal D. Ullal, Youssef Daali, Uppugunduri S. Chakradhara Rao
Pharmaceuticals.2022; 15(8): 990. CrossRef
The Effect of NUDT15, TPMT, APEX1, and ITPA Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia
Jae Min Lee, Ye Jee Shim, Do-Hoon Kim, Nani Jung, Jung-Sook Ha
Children.2021; 8(3): 224. CrossRef
Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT
Hyery Kim, Seungwon You, Yoomi Park, Jung Yoon Choi, Youngeun Ma, Kyung Tak Hong, Kyung-Nam Koh, Sunmin Yun, Kye Hwa Lee, Hee Young Shin, Suehyun Lee, Keon Hee Yoo, Ho Joon Im, Hyoung Jin Kang, Ju Han Kim
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NUDT15 polymorphism in healthy children with Bai nationality in Yunnan of China
Gangling Pu, Yali Wang, Shaoqin Duan, Jingpei Chen, Chunhui Yang, Tingting Cui, Chunlian Fang, Yan Zhou, Han Zhang, Xin Tian
Pediatrics International.2021; 63(7): 790. CrossRef
A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives
Gabriela Betlej, Ewelina Bator, Antoni Pyrkosz, Aleksandra Kwiatkowska
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Homozygote CRIM1 variant is associated with thiopurine-induced neutropenia in leukemic patients with both wildtype NUDT15 and TPMT
Yoomi Park, Hyery Kim, Heewon Seo, Jung Yoon Choi, Youngeun Ma, Sunmin Yun, Byung-Joo Min, Myung-Eui Seo, Keon Hee Yoo, Hyoung Jin Kang, Ho Joon Im, Ju Han Kim
Journal of Translational Medicine.2020;[Epub] CrossRef
Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology
Emma C. Bernsen, Melanie M. Hagleitner, Theodorus W. Kouwenberg, Lidwien M. Hanff
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Long-term treatment outcomes of children and adolescents with lymphoblastic lymphoma treated with various regimens: a single-center analysis
Ho Jung Choi, Juhee Shin, Sunghan Kang, Jin Kyung Suh, Hyery Kim, Kyung-Nam Koh, Ho Joon Im
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NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia
Eun Sang Yi, Young Bae Choi, Rihwa Choi, Na Hee Lee, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Soo-Youn Lee, Hong Hoe Koo
Cancer Research and Treatment.2018; 50(3): 872. CrossRef

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Extra-cranial Malignant Rhabdoid Tumor in Children: A Single Institute Experience: Che Ry Hong, Hyoung Jin Kang, Hee Young Ju, Ji Won Lee, Hyery Kim, Sung-Hye Park, Il Han Kim, Kyung Duk Park, Hee Young Shin; Cancer Res Treat. 2015;47(4):889-896. Published online January 2, 2015; DOI: https://doi.org/10.4143/crt.2013.176

Abstract PDF PubReader ePub

Purpose
Malignant rhabdoid tumor (MRT) is a rare and highly aggressive tumor that affects young children. Due to its extreme rarity, most of the available data are based on retrospective case series. To add to the current knowledge of this disease, we reviewed the patients treated for extra-cranial MRT in our institute. Materials and Methods A retrospective medical record review was conducted on children treated for pathologically confirmed extra-cranial MRT at Seoul National University Children’s Hospital between January 2003 and May 2013. Results Eleven patients (7 boys, 4 girls) were diagnosed with extra-cranial MRT at a median age of 9 months old. INI1 staining was important in the pathological confirmation. Six patients (55%) had renal MRT and five (45%) had soft tissue MRT. Five patients (45%) had metastases at diagnosis. All patients underwent chemotherapy, eight patients (73%) underwent surgery, six patients (55%) received therapeutic radiotherapy, and four patients (36%) underwent high dose chemotherapy with autologous stem cell rescue (HDCT/ASCR) with melphalan, etoposide, and carboplatin. Five patients (45%) died of disease following progression (n=3) or relapse (n=2), however, there was no treatment related mortality. The overall survival of the cohort was 53.0% and the event-free survival was 54.5% with a median follow-up duration of 17.8 months (range, 2.3 to 112.3 months). Conclusion Extra-cranial MRT is still a highly aggressive tumor in young children. However, the improved survival of our cohort is promising and HDCT/ASCR with melphalan, etoposide, and carboplatin may be a promising treatment option.

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A Review of Wilms Tumor
Valeria Smith, Andrew Wahba, Murali Chintagumpala, Priya Mahajan
Pediatrics in Review.2025; 46(4): 206. CrossRef
Extracranial malignant rhabdoid tumors in children: high mortality even with the help of an aggressive clinical approach
Siqi Xie, Yuanyuan Fang, Yingying Yang, Lan Liu, Jianxi Bai, Sheng Lin, Bing Zhang, Yifan Fang
European Journal of Pediatrics.2023; 183(2): 557. CrossRef
Infantile Extracranial Rhabdoid Tumor of the Scalp
Sura Al Rawabdeh, Deifallah Alsharari, Hayat Khasawneh, Ola M. Al Waqfi, Qamar Yaser Malabeh, Hiathem Abu Alhaija, Raed Mohammad Aljubour, Hamzeh M. Alkhawaldeh, Pablo Fernandez Pe as
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Pharmacokinetics of high-dose carboplatin in children undergoing high-dose chemotherapy and autologous stem cell transplantation with BSA-based dosing
Che Ry Hong, Hyoung Jin Kang, Seol Ju Moon, Jaeseong Oh, Kyung Taek Hong, Jung Yoon Choi, Kyung-Sang Yu, Hee Young Shin
Bone Marrow Transplantation.2020; 55(1): 137. CrossRef
Successful Treatment of Extra‐Renal Noncerebral Rhabdoid Tumors with VIDE
Naoko Yasui, Akihiko Yoshida, Eisuke Kobayashi, Fumihiko Nakatani, Hiroshi Kawamoto
Pediatric Blood & Cancer.2016; 63(2): 352. CrossRef

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Clinical Outcome of Relapsed or Refractory Burkitt Lymphoma and Mature B-Cell Lymphoblastic Leukemia in Children and Adolescents: Hyery Kim, Eun Sil Park, Soo Hyun Lee, Hong Hoe Koo, Hyo Sun Kim, Chuhl Joo Lyu, So Eun Jun, Young Tak Lim, Hee Jo Baek, Hoon Kook, Ji Won Lee, Hyoung Jin Kang, Kyung Duk Park, Hee Young Shin, Hyeo Seop Ahn; Cancer Res Treat. 2014;46(4):358-365. Published online July 21, 2014; DOI: https://doi.org/10.4143/crt.2013.047

Abstract PDF PubReader ePub

Purpose
Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients.
Materials and Methods
RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed.
Results
Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6±10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1±18.7%, vs. 16.7±10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05).
Conclusion
Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients.

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Clinical Characteristics and Treatment Results of Pediatric Osteosarcoma: The Role of High Dose Chemotherapy with Autologous Stem Cell Transplantation: Ji Won Lee, Hyery Kim, Hyoung Jin Kang, Han-Soo Kim, Sung-Hye Park, In-One Kim, Hyo Seop Ahn, Hee Young Shin; Cancer Res Treat. 2008;40(4):172-177. Published online December 31, 2008; DOI: https://doi.org/10.4143/crt.2008.40.4.172

Abstract PDF PubReader ePub

Purpose

In this study, we investigated the clinical characteristics and treatment results of osteosarcoma during the past 7 years, and evaluated the role of high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT).

Materials and Methods

We retrospectively analyzed the clinical data of patients who were diagnosed as osteosarcoma at our center from January, 2000 to December, 2007.

Results

The 5-year overall survival and event-free survival of the patients were 72.6% and 55.9%, respectively. Seventeen (41.5%) patients showed disease progression during treatment or relapse after the end of treatment. The patients who had metastasis at diagnosis or who had a lower grade of necrosis after neoadjuvant chemotherapy showed decreased overall and event-free survival. Four patients received ASCT after HDCT, and 3 of them are alive without disease.

Conclusions

The patients who relapsed or had refractory osteosarcoma or who had metastasis at diagnosis or a lower grade of necrosis after neoadjuvant chemotherapy showed poor prognosis. HDCT with ASCT could be an alternative treatment option for these patients.

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Clinical Results of Chemotherapy based Treatment in Retinoblastoma Patients: A Single Center Experience: Hyery Kim, Ji Won Lee, Hyoung Jin Kang, Hyeon Jin Park, Yoon Yi Kim, Hee Young Shin, Young Suk Yu, Il Han Kim, Hyo Seop Ahn; Cancer Res Treat. 2008;40(4):164-171. Published online December 31, 2008; DOI: https://doi.org/10.4143/crt.2008.40.4.164

Abstract PDF PubReader ePub

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.

Citations

Citations to this article as recorded by

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