Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data.

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.

Erratum: Correction of Affiliations in the Article "Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study".

This corrects the article on p. e393 in vol. 35, PMID: 33258329.

Antiphospholipid syndrome with mesenteric vein thrombosis and hepatic nodular regenerative hyperplasia in a child: A case report.

RATIONALE: Hepatic nodular regenerative hyperplasia (NRH), a nonspecific change in the liver parenchyma, is very rare in children. Hepatic microvascular changes may be the cause, as these vascular changes are uncommon in children. Antiphospholipid syndrome (APS), an autoimmune disease characterized by vascular thromboembolism, is extremely unusual in children. PATIENT CONCERNS: A 13-year-old girl who presented with abdominal pain and elevated liver enzymes was transferred to our hospital. Abdominal computed tomography and magnetic resonance imaging showed a massive mesenteric venous thrombus and a malignant mass with liver metastasis. DIAGNOSES: Her immunological profile was positive for antinuclear antibodies (ANA) at a titer of 1/160 (nucleolar pattern), anticardiolipin antibodies (aCL) immunoglobulin G, and anti-histone antibody. A liver biopsy revealed hepatic NRH. INTERVENTIONS: The patient was initially started on heparin upon hospitalization and switched to warfarin and a vitamin K antagonist and continued treatment with international normalized ratio monitoring. OUTCOMES: Her symptoms improved after 9 months of anticoagulation therapy. LESSONS: In the presence of hepatic NRH or vascular thrombosis in children, we recommend that APS be differentially diagnosed using lupus anticoagulant and aCL and appropriate management be implemented.

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

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 (P = 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.

Korean parents' perceptions of the challenges and needs on school re-entry during or after childhood and adolescent cancer: a multi-institutional survey by Korean Society of Pediatric Hematology and Oncology.

BACKGROUND: For children and adolescents with cancer, going back to school is a key milestone in returning to "normal life." PURPOSE: To identify the support vital for a successful transition, we evaluated the parents' needs and the challenges they face when their children return to school. METHODS: This multi-institutional study was conducted by the Korean Society of Pediatric Hematology and Oncology. The written survey comprised 24 questions and was completed by 210 parents without an interviewer. RESULTS: Most parents (165 of 206) reported that their children experienced difficulties with physical status (n=60), peer relationships (n=30), academic performance (n=27), emotional/behavioral issues (n=11), and relationships with teachers (n=4) on reentering school. Parents wanted to be kept informed about and remain involved in their children's school lives and reported good parent-teacher communication (88 of 209, 42.1%). Parents reported that 83.1% and 44.9% of teachers and peers, respectively, displayed an adequate understanding of their children's condition. Most parents (197 of 208) answered that a special program is necessary to facilitate return to school after cancer therapy that offers emotional support (n=85), facilitates social adaptation (n=61), and provides tutoring to accelerate catch up (n=56), and continued health care by hospital outreach and school personnel (n=50). CONCLUSION: In addition to scholastic aptitude-oriented programs, emotional and psychosocial support is necessary for a successful return to school. Pediatric oncologists should actively improve oncology practices to better integrate individualized school plans and educate peers and teachers to improve health literacy to aid them in understanding the needs of children with cancer.

Tandem high-dose chemotherapy with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin regimens for pediatric high-risk brain tumors.

BACKGROUND: High-dose chemotherapy (HDC) and autologous stem-cell transplantation (auto-SCT) are used to improve the survival of children with high-risk brain tumors who have a poor outcome with the standard treatment. This study aims to evaluate the outcome of HDC/auto-SCT with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin (TTC/MEC) regimens in pediatric brain tumors. METHODS: We retrospectively analyzed the data of 33 children (median age 6 years) who underwent HDC/auto-SCT (18 tandem and 15 single) with uniform conditioning regimens. RESULTS: Eleven patients aged < 3 years at diagnosis were eligible for HDC/auto-SCT to avoid or defer radiotherapy. In addition, nine patients with high-risk medulloblastoma (presence of metastasis and/or postoperative residual tumor ≥ 1.5 cm2), eight with other high-risk brain tumor (six CNS primitive neuroectodermal tumor, one CNS atypical teratoid/rhabdoid tumor, and one pineoblastoma), and five with relapsed brain tumors were enrolled. There were three toxic deaths, and two of which were due to pulmonary complications. The main reason for not performing tandem auto-SCT was due to toxicities and patient refusal. The event-free survival (EFS) and overall survival (OS) rates of all patients were 59.4% and 80.0% at a median follow-up with 49.1 months from the first HDC/auto-SCT, respectively. The EFS/OS rates of patients aged < 3 years at diagnosis, high-risk medulloblastoma, other high-risk brain tumor, and relapsed tumors were 50.0/81.8%, 87.5/85.7%, 66.7/88.9%, and 20.0/60.0%, respectively. CONCLUSIONS: Although tandem HDC/auto-SCT with TTC/MEC regimens showed promising survival rates, treatment modifications are warranted to reduce toxicities. The survival rates with relapsed brain tumors were unsatisfactory despite HDC/auto-SCT, and further study is needed.

Upfront chemotherapy followed by response adaptive radiotherapy for intracranial germinoma: Prospective multicenter cohort study.

PURPOSE: To assess the efficacy of upfront chemotherapy followed by response-adapted reduced-dose/reduced-volume radiotherapy (RT) for intracranial germinoma. MATERIALS AND METHODS: Ninety-one patients from five institutions were registered in the KSPNO G051/G081 Protocol. Germinomas were classified as solitary or multiple/disseminated diseases, and upfront chemotherapy was administered. For all patients with multiple or disseminated disease, and patients with partial response after chemotherapy, 19.5-24 Gy of craniospinal irradiation plus 10.8-19.8 Gy of tumor bed boost were planned. For patients with complete response (CR), reduced-dose RT (30.6 Gy) was planned, along with a reduced field for solitary lesions. RESULTS: The median patient age was 14 (range, 3-30) years. Sixty-five patients (71.4%) had a solitary lesion. The median follow-up duration was 67.9 (range, 6.6-119.3) months. Recurrence was not observed in 32 patients in the protocol compliant group. Four patients (4.4%) in the protocol non-compliant group experienced relapse after CR and one patient died of the disease. The 5-year and 7-year overall survival rates were 98.8% and 98.8%, while the corresponding event-free survival rates were 96.6% and 93.8%, respectively. All three patients with basal ganglia germinomas who were treated with local RT experienced recurrence outside the RT field. Among the 23 patients with pineal or suprasellar lesions who received whole-ventricle RT, there was no recurrence. CONCLUSIONS: Currently used upfront chemotherapy followed by reduced-dose, reduced-volume RT appears acceptable, when whole-ventricle RT for pineal or suprasellar tumors and, at minimum, whole-brain RT for basal ganglia/thalamus lesions are applied.

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

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.

Thromboembolism in children with cancer: a retrospective multicenter study in Korea.

Thromboembolism (TE) is a major cause of morbidity and mortality in adult cancer patients; however, there is a lack of sufficient knowledge on TE in pediatric cancer patients. We aimed to determine the epidemiology of TE in Korean children with cancer. Between January 2000 and July 2015, we retrospectively analyzed pediatric patients newly diagnosed with cancer at six tertiary hospitals in Korea. Of 3611 children with cancer, 33 (0.91%) had TE. A higher number of patients with acute lymphoblastic leukemia (n = 13), brain tumors (n = 6), lymphoma (n = 4), and bone/soft tissue sarcomas (n = 5) tended to develop TE. The male/female ratio was 17/16, and the median age at TE diagnosis was 10 years and 2 months. TE was detected a median of 2 months after cancer diagnosis. Symptoms including pain and swelling were present in 18 of the 33 patients. In terms of location, three intracerebral, 23 upper venous, six lower venous and one combined upper and lower venous system TEs were observed. Additional risk factors for TE included central venous catheter (CVC) use in 12 patients, steroid and/or L-asparaginase use in nine, and CVC and steroid and/or L-asparaginase use in seven. The TE incidence rate was quite low among Korean children with cancer, but higher than in the general pediatric population and among children hospitalized for diseases other than cancer. Further investigation of a larger pool of patients is warranted to determine the most effective strategies to prevent and treat TE in Korean children with cancer.

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

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.

Successful Treatment of Pediatric Epstein-Barr Virus-positive Aggressive Natural Killer-Cell Leukemia.

Epstein-Barr virus (EBV)-positive aggressive natural killer-cell leukemia (ANKL) is a rare malignancy of mature natural killer cells, with a very poor survival rate. Patients have a rapidly declining clinical course and a poor prognosis, with a median survival of only a few months. Herein, we describe a 16-year-old boy who was diagnosed with EBV-positive ANKL and successfully treated using combination chemotherapy and a subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT). The patient is disease free 4 years and 9 months after alloHSCT. Thus, combination chemotherapy followed by alloHSCT seems to be a promising therapeutic option for EBV-positive ANKL.

Favorable Outcome of Post-Transplantation Cyclophosphamide Haploidentical Peripheral Blood Stem Cell Transplantation with Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring in Pediatric Patients.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PTCy) was performed previously in adults using a nonmyeloablative conditioning regimen and bone marrow as a graft source. In an effort to reduce relapse rates, myeloablative conditioning regimens with higher intensities are now used. We used an intensive daily pharmacokinetic monitoring method for busulfan dosing in children for effective myeloablation and to reduce toxicity. Here, we report the retrospective results of 34 patients (median age 11.1 years) who underwent haplo-HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen and peripheral blood as a stem cell source. The donor-type neutrophil engraftment rate was 97.1%, and the cumulative incidence rates of grade II to IV and grade III to IV acute and extensive chronic graft-versus-host disease were 38.2%, 5.9%, and 9.1%, respectively. The overall survival and event-free survival rates, and treatment-related mortality were 85.0%, 79.4%, and 2.9%, respectively. Based on the subgroup analysis of patients with malignancies (n = 23), the relapse incidence rate was 21.7%. Haplo-HSCT using PTCy with targeted busulfan-based myeloablative conditioning and peripheral blood as a stem cell source was a safe and promising therapeutic option for children.

Thyroid dysfunction in patients with childhood-onset medulloblastoma or primitive neuroectodermal tumor.

PURPOSE: We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). METHODS: The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children's Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR). RESULTS: During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9-4.6 years). Younger age (<5 years) at radiation exposure (P=0.014 vs. ≥9 years) and HDCT (P=0.042) were significantly predictive for hypothyroidism based on log-rank test. However, sex, type of tumor, and dose of craniospinal irradiation (less vs. more than 23.4 Gy) were not significant predictors. Cox proportional hazard model showed that both younger age (<5 years) at radiation exposure (hazard ratio [HR], 3.1; vs. ≥9 years; P=0.004) and HDCT (HR, 2.4; P=0.010) were significant predictors of hypothyroidism. CONCLUSION: Three-quarters of patients with pediatric medulloblastoma or PNET showed thyroid dysfunction, and over half had permanent thyroid dysfunction. Thus, frequent monitoring of thyroid function is mandatory in all patients treated for medulloblastoma or PNET, especially, in very young patients and/or high-risk patients recommended for HDCT/ASCR.

School performance of childhood cancer survivors in Korea: A multi-institutional study on behalf of the Korean Society of Pediatric Hematology and Oncology.

OBJECTIVE: To investigate school performance of childhood cancer survivors focusing on the child's functioning, including peer relationships, school attendance, and academic achievement. METHODS: We studied 241 children from 15 institutions in Korea between 2015 and 2016. The self-reported paper-and-pencil questionnaires were used. RESULTS: Approximately 22% of the survivors suffered from lack of friends. Bullying was reported by 30% of survivors. Survivors who returned to primary school reported a higher incidence of bullying compared with survivors who returned to middle or high school (P = 0.03). The percentage of children who missed classes more than 4 days in a month was higher in survivors with brain tumors than those with other tumors (P = 0.04). Approximately 41% of children reported learning difficulty. After returning to school, 53% of the patients reported that they had lower overall mark averages than they had before. Patients who returned to high school showed the highest rate of repeating a grade and the lowest rate of achieving high academic marks. The school marks in the Korean (P = 0.03), English (P = 0.04), and physical education (P = 0.04) were worse for the children with brain tumors than for the children with other tumors. CONCLUSION: We found that 20% to 25% of survivors experienced peer-related difficulties upon returning to school. Patients who return to school, especially high school, should be provided more educational support to overcome low academic achievement. Particular concern is needed to the patients with brain tumors, who are at risk for significant academic and social difficulties and therefore may require more intensive support in school.

Pediatric Spinal Epidural Lymphoma Presenting with Compressive Myelopathy: A Distinct Pattern of Disease Presentation.

OBJECTIVE: Spinal epidural lymphoma with compressive myelopathy is a rarely found condition. The aims of this study are to describe the clinical features and to analyze its treatment outcome and prognostic factors. METHODS: We searched for all pediatric patients with newly diagnosed spinal epidural lymphoma from 1999 to 2014 in our institution. We evaluated the clinical features, including neurologic status, time interval to treatment, treatment modality, and outcomes. RESULTS: Twelve of 302 pediatric patients with lymphoma (4.0%) presented with compressive myelopathy, and they were all found to have spinal epidural lymphoma. In 11 patients, epidural space was the only site of lymphoma involvement. The median age was 9 years (range, 5-15 years). Common initial symptoms were back pain and low extremity weakness. Surgery was performed on 9 patients, biopsy on 2 patients, and radiation therapy on 1 patient. In 9 patients who received surgery, 6 patients with preoperative motor power grade ≥II attained improvement in weakness. Three patients with preoperative motor power grade

Experiences of peer exclusion and victimization, cognitive functioning, and depression among adolescent cancer survivors in South Korea.

Adolescents who reenter school after treatment for cancer may face certain challenges, such as social exclusion by their peers and difficulties in cognitive functioning, due to the cancer treatment and its psychosocial sequelae. Such challenges may have an impact on their mental health. This cross-sectional study examined the impact of peer exclusion-victimization and cognitive functioning on depression among adolescent survivors of childhood cancer. A total of 175 adolescent survivors of childhood cancer between the ages of 13 and 19 years completed a self-reported questionnaire. Their mean age was 15.33 years (SD = 1.65), the mean time since diagnosis was 7.97 years (SD = 3.91), and 49.7% experienced at least 1 kind of peer exclusion in school. Multiple regression analysis was conducted to examine the effects of survivors' experiences related to peer exclusion-victimization and cognitive functioning on depression, controlling for demographic (age and gender) and cancer-related (cancer type, time since diagnosis, recurrence) characteristics. The model with peer exclusion-victimization and cognitive functioning as predictors accounted for 27.9% of the variance in depression. More experiences in peer exclusion-victimization (ß = .200, p = .024) and lower cognitive functioning (ß = -.465, p < .001) were associated with greater levels of depression. Understanding the impact of survivors' experiences of peer exclusion-victimization and cognitive functioning on their mental health will help professionals to provide appropriate counseling services to moderate peer exclusion-victimization as well as resources for academic performance for those cancer survivors at risk for depression. (PsycINFO Database Record

Foundation of pediatric cancer treatment in Lao People's Democratic Republic at the Lao-Korea National Children's Hospital.

AIM: The Lao-Korea National Children's Hospital initiated and developed a pediatric cancer treatment program for the first time in September 2012, through education by the Lee Jong-Wook project, establishment of infrastructure by the Korea International Cooperation Agency, and cooperation of medical staff. MATERIAL AND METHODS: we describe the experience of initiating and building this program by retrospectively reviewing the data from pediatric patients with cancer diagnosed at the Lao-Korea National Children's Hospital between September 2012 and December 2016. RESULTS: A total of 78 patients diagnosed with acute lymphoblastic leukemia (ALL) (n = 44), acute myeloid leukemia (AML) (n = 12), chronic myeloid leukemia (n = 7), lymphoma (n = 6), retinoblastoma (n = 5), Wilms tumor (n = 3), and germ cell tumor (n = 1) were included. Of the 44 patients with ALL, 40 received induction chemotherapy, and 4 refused chemotherapy. Of these 40 patients, 29 (73.6%) achieved complete remission (CR) and 9 (22.5%) died during chemotherapy. Of the 29 patients with CR, 4 completed the chemotherapy, 19 were still on chemotherapy, 4 relapsed, and 2 were deceased. Treatment was unsuccessful for all 12 patients with AML. CONCLUSION: We successfully initiated the pediatric cancer care program but faced challenges associated with high mortality because of insufficient resources. We should continue our efforts to find more abandoned patients, detect cancer earlier, and reduce the overall associated mortality.

ALK Protein Expression Is Related to Neuroblastoma Aggressiveness But Is Not Independent Prognostic Factor.

PURPOSE: In this study, anaplastic lymphoma kinase (ALK) mutation and amplification, ALK protein expression, loss of the nuclear alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein, and telomerase reverse transcriptase (TERT) protein expressionwere studied to investigate potential correlations between these molecular characteristics and clinical features or outcomes in neuroblastoma. MATERIALS AND METHODS: Seventy-two patients were enrolled in this study. Polymerase chain reaction amplification and direct sequencing were used for mutation analysis. ALK and MYCN amplifications were detected by fluorescence in situ hybridization. Protein expressionwas evaluated by immunohistochemical (IHC) staining. RESULTS: ALK mutation was found in only two patients (4.1%); ALK amplification was not detected. ALK positivity, loss of nuclear ATRX protein, TERT positivity by IHC were detected in 40 (55.6%), nine (13.0%), and 42 (59.2%) patients, respectively. The incidence of ALK expression increased in accordance with increasing tumor stage (p=0.001) and risk group (p < 0.001). The relapse rate was significantly higher in ALK+ patients compared to that of other patients (47.5% vs. 11.3%, p=0.007). However, there was no significant difference in relapse rate when the survival analysis was confined to the high-risk patients. CONCLUSION: Although ALK mutation was rare and no amplification was observed, ALK protein expression was found in a significant number of patients and was correlated with advanced stage and high-risk neuroblastoma. ALK protein expression could be considered as a marker related to the aggressive neuroblastoma, but it was not the independent prognostic factor for the outcome.

APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia.

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.