Cancer Research and Treatment

Original Articles

Pediatric cancer

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

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
Cancers.2023; 15(14): 3637. CrossRef
Current Challenges of Asian National Children's Cancer Study Groups on Behalf of Asian Pediatric Hematology and Oncology Group
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
JCO Global Oncology.2023;[Epub] CrossRef
Childhood acute promyelocytic leukemia in a pediatric cancer referral center in Baghdad, Iraq. Improved results with ATRA extended consolidation
Anna Maria Testi, Mazin Faisal Al-Jadiry, Hasanein Habeeb Ghali, Samaher Abdulrazzaq Fadhil, Amir Fadhil Al-Darraji, Raghad Majid Al-Saeed, Ahmed Hatem Sabhan, Safaa A. Faraj Al-Badri, Wisan Majeed Abed, Najiha Ahmed Ameen, Ruaa Zaki Al-Tameemi, Arabiya I
Leukemia & Lymphoma.2022; 63(12): 2940. CrossRef
Death due to unsuspected acute myeloid leukaemia: an unusual forensic diagnosis
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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p15^Ink4b Loss of Expression by Promoter Hypermethylation Adds to Leukemogenesis and Confers a Poor Prognosis in Acute Promyelocytic Leukemia Patients: Shahid M. Baba, Niyaz A. Azad, Zafar A. Shah, Dil-Afroze , Arshad A. Pandith, Aleem Jan, Sheikh A. Aziz; Cancer Res Treat. 2017;49(3):790-797. Published online December 5, 2016; DOI: https://doi.org/10.4143/crt.2016.108

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Purpose
The p15^Ink4b gene exerts its influence as an inhibitor of cyclin-dependent kinases and is frequently associated with hematological malignancies. Inactivation of this gene through DNA methylation has been found to be the most prevalent epigenetic alteration reported, with a high frequency in all French-American-British subtypes of acute myeloid leukemias, including acute promyelocytic leukemia (APL). In this study,we investigated the prognostic significance of p15 gene promoter hypermethylation and its expression in APL patients of Kashmir(North India).
Materials and Methods
p15 gene promoter hypermethylation was conducted by methylation-specific polymerase chain reaction,while its subsequent expression analysiswas carried out by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR).
Results
Of the 37 patients, 16 (43.2%) were found to have methylated p15 genes. Of these 16 cases, seven (43.8%) were methylated partially and nine (56.2%) were found to have complete methylation. Moreover, nine of the 37 patients (24.3%) who presented with leukocytosis at their baseline had complete p15 gene methylation as well (p < 0.05). Semiquantitative RT-PCR showed a complete loss of p15 expression in nine patients with complete methylation coupled with leukocytosis (p=0.031), while seven patients with partial methylation showed decreased p15 expression. Six patients relapsed during the maintenance phase of treatment and were found to have a completely methylated p15 gene and no p15 mRNA.
Conclusion
Complete methylation and loss of p15 gene expression causes susceptibility to relapse and decreased survival in APL patients. Thus, p15 promoter hypermethylation is a prospective prognostic indicator and a reliable clinical aid in assessment of patients with APL.

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A study on DNA methylation status in promoter region of p15 gene in patients of acute myeloid leukemia and myelodysplastic syndrome
Sangeetha Sampath, Pratibha Misra, Sandeep Kumar Yadav, Sanjeevan Sharma, Venkatesan Somasundaram
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Gene regulations and delivery vectors for treatment of cancer
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Cristina Turcas, Vlad Moisoiu, Andrei Stefancu, Ancuta Jurj, Stefania D. Iancu, Patric Teodorescu, Sergiu Pasca, Anca Bojan, Adrian Trifa, Sabina Iluta, Alina-Andreea Zimta, Bobe Petrushev, Mihnea Zdrenghea, Horia Bumbea, Daniel Coriu, Delia Dima, Nicolae
Frontiers in Oncology.2020;[Epub] CrossRef
Clinical and prognostic effects ofCDKN2A,CDKN2BandCDH13promoter methylation in ovarian cancer: a study using meta-analysis and TCGA data
Liang Xia, Wenzhu Zhang, Li Gao
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Hye Young Shin, Mina Suh, Kui Son Choi, Sang-Hyun Hwang, Jae Kwan Jun, Dong Soo Han, You Kyoung Lee, Jae Hwan Oh, Chan Wha Lee, Do-Hoon Lee
BMC Cancer.2018;[Epub] CrossRef
Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes
Domenico Mattiucci, Giulia Maurizi, Pietro Leoni, Antonella Poloni
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Chen Yang, Xiaoxiao Gao, Jing Ye, Jianping Ding, Ya Liu, Hongyu Liu, Xiumei Li, Yunhai Zhang, Jie Zhou, Weiping Huang, Fugui Fang, Yinghui Ling
Reproduction in Domestic Animals.2018; 53(6): 1287. CrossRef

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Src Family Kinase Inhibitor PP2 Has Different Effects on All-Trans-Retinoic Acid or Arsenic Trioxide-Induced Differentiation of an Acute Promyelocytic Leukemia Cell Line: Suk-Gu Yoon, Hee-Jeong Cheong, Sook-Ja Kim, Kyoung Ha Kim, Sang-Cheol Lee, Namsu Lee, Hee Sook Park, Jong-Ho Won; Cancer Res Treat. 2013;45(2):126-133. Published online June 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.2.126

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PURPOSE
Leukemic promyelocytes have the unique ability to undergo differentiation after exposure to retinoic acid and both differentiation and apoptosis after exposure to arsenic trioxide (ATO). Recent studies have shown that inhibition of Src family kinases (SFKs) resulted in enhancement of retinoic acid-induced myeloid differentiation.
MATERIALS AND METHODS
In this study, we investigated the question of whether the SFK inhibitor PP2 enhanced the differentiation of NB4 cells when combined with ATO as well as when combined with all-trans-retinoic acid (ATRA). In addition, we attempted to determine the difference in retinoic acid-induced gene expression between cells treated with PP2 in combination with ATRA and in combination with ATO.
RESULTS
SFK inhibitor PP2 induced significant enhancement of ATRA- or ATO-induced differentiation of NB4 cells. A significantly stronger synergistic effect was observed when PP2 was combined with ATRA than when combined with ATO. Flow cytometric analysis demonstrated a significant increase in CD11b-positive granulocytes up to 60.73% and 31.58%, respectively. These results were confirmed by nitroblue tetrazolium staining. These effects were not related to apoptosis. Results of Annexin-V-fluorescein staining revealed that PP2 combined with ATRA or PP2 combined with ATO did not induce apoptosis in NB4 cells. Retinoic acid-induced gene expression was different in both groups. Intercellular adhesion molecule-1 expression showed a significant increase in cells treated with PP2 in combination with ATRA, whereas cathepsin D expression showed a significant increase in cells treated with PP2 in combination with ATO.
CONCLUSION
Our data showed that SFK inhibitor PP2 enhanced acute promyelocytic leukemia cell differentiation when combined with either ATRA or ATO with difference in activation of retinoic acid-induced genes.

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An overview of arsenic trioxide-involved combined treatment algorithms for leukemia: basic concepts and clinical implications
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Liya Feng, Sha Zhu, Jian Ma, Yali Hong, Meixia Wan, Qian Qiu, Hongjing Li, Juan Li
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Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide
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Leukemia Research.2014; 38(8): 977. CrossRef

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Autologous or Allogeneic Bone Marrow Transplantation Compared with Consolidation Chemotherapy in Acute promyelocytic Leukemia: Chang Ki Min, Woo Sung Min, Hee Je Kim, Hyun Suk Eom, Jong Wook Lee, Kyungja Han, Ihl Bhong Choi, Chun Choo Kim, Won IL Kim, Dong Jip Kim; J Korean Cancer Assoc. 1999;31(2):331-338.

Abstract PDF: PURPOSE
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myelogenous leukemia characterized by the morphology of blast cells (M3 in FAB classification), the t (15;17) translocation, and a coagulopathy combining disseminated intravascular coagulation and fibrinolysis. It has been considered to have better response to combination chemo- therapy of an anthracycline and cytosine arabinoside and a higher cure rate than other subtypes because of recent approach of differentiating leukemic blasts by all-transretinoic acid (ATRA). The role of stem cell transplantation in APL has to be determined in comparison with that of consolidation chemotherapy.
MATERIALS AND METHODS
We compared the leukemia-free survival and overall survival between APL patients receiving the consolidation chemotherapy and those undergoing the allogeneic or autologous stem cell transplantation following the high-dose anticancer therapy. Of the 65 patients achieving the first complete remission from 1992 to 1997, 33 patients were treated with 3 courses of consolidation chemotherapies and 32 with the stem cell transplantation.
RESULTS
With a median follow-up of 22 months (8-60), the actuarial leukemia-free survival at 3 years was significantly higher in transplantation group than in chematherapy group (73.8% versus 33.5%; P=0.0087), and the probability of leukemic relapse was considerably lower in transplantation group than in chemotherapy group (6.3% versus 57.5%; P=0.001). The treatment-related mortalities of the groups were 0% in chemotherapy group and 14.3% in transplantation group. The main cause of deaths was relapse in the consolidation chemotherapy group.
CONCLUSION
These data demonstrate that the stem cell transplantation results in better leukemia-free survival than the consolidation chemotherapy for patients with APL in the first complete remission because of lower risk of relapse.

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