Identification of prognostic factors and risk-based post-remission therapy was proposed to improve the outcomes of acute myeloid leukemia (AML) and a mutation of FLT3 has been reported to be a risk factor, especially for pediatric patients. Recently, FLT3 expression level was implicated to have prognostic significance in adults, but little is known for childhood AML. To define the prognostic significance, transcript level of FLT3 was analyzed in 52 pediatric AML patients. The median copy number of FLT3 was 4.6×103 (40-5.9×107 copies)/1.0×106 GAPDH copy, and the relapse free survival of patients with high transcript level of FLT3 (>106 copy number) (0%) was significantly lower than that of the others (53.2%). High transcript level of FLT3 was associated with a markedly high risk of relapse. The development of new therapeutic scheme such as a frontline allogeneic stem cell transplantation or administration of FLT3 inhibitor is needed to improve outcomes.
FLT3; Transcript Level; Leukemia, Myeloid, Acute; Pediatric Age
Severe aplastic anemia (SAA) patients without an HLA-matched sibling donor need alternative treatment options. Umbilical cord blood transplantation (UCBT) has become an alternative means for treating various diseases, but it has not been proved to be a satisfactory method to treat SAA. Here, we report the case of a girl who underwent successful two-unit UCBT after engraftment failure with a single unit. Two-unit UCBT is proposed to have better engraftment potential and to offer a better chance of survival, according to some reports. Increased cell dose and graft-versus-graft reaction could contribute to these advantages. With this promising result, two-unit UCBT could be an alternative treatment option for patients with SAA without an HLA-matched donor.
Anemia, Aplastic; Cord Blood Stem Cell Transplantation; Two-unit
Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL), yet there is no established treatment for relapsed ALL. To improve the induction remission rate, we modified the dose of idarubicin in the original Children's Cancer Group (CCG)-1884 protocol, and retrospectively compared the results. Twenty-eight patients diagnosed with relapsed ALL received induction chemotherapy according to the CCG-1884 protocol. Complete remission (CR) rate in all patients after induction chemotherapy was 57%. The idarubicin 10 mg/m2/week group showed CR rate of 74%, compared with the 22% CR rate of the idarubicin 12.5 mg/m2/week group (p=0.010). Remission failure due to treatment-related mortality (TRM) was 44% and 5.2% in the idarubicin 12.5 mg/m2/week and 10 mg/m2/week groups, respectively (p=0.011). Overall survival (OS) and 4-yr event-free survival (EFS) were 12.8% and 10.3%, respectively. OS and 4-yr EFS were higher in the idarubicin 10 mg/m2/week group (19.3% and 15.6%) than in the 12.5 mg/m2/week group (0% and 0%). In conclusion, a modified dose of idarubicin from 12.5 mg/m2/week to 10 mg/m2/week resulted in an improved CR rate in the treatment of relapsed ALL, which was due to lower TRM. However, despite improved CR rate with modified dose of idarubicin, survival rates were unsatisfactory.
Idarubicin; Remission Induction; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease relapse after autologous peripheral blood stem cell transplantation (APBSCT) is the main cause of treatment failure in high-risk neuroblastoma (NBL). To reduce relapse, various efforts have been made such as CD34+ selection and double APBSCT. Here the authors reviewed the clinical features and outcomes of high-risk NBL patients and analyzed their survival. The medical records of 36 patients with stage III or IV NBL who underwent APBSCT at Seoul National University Children's Hospital between May 1996 and May 2004 were reviewed. Total 46 APBSCTs were performed in 36 patients. Disease free survival (DFS) and overall survival of all patients were 47.7% and 68.8%, respectively. The patients were allocated to three groups according to the APBSCT type. The DFS of CD34+ non-selected single APBSCT patients (N=13), CD34+ selected single APBSCT patients (N=14), and CD34+ selected double APBSCT patients (N=9) were 55.6%, 40.6%, and 50.0%, respectively, which were not significantly different. Thus the survival was not found to be affected by CD34+ selection or transplantation number. To improve long-term survival, various efforts should be made such as chemotherapy dose intensification, more effective tumor purging, and control of minimal residual disease via the use of differentiating and immune-modulating agents.
Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Autologous Transplantation
We verified the reliability and validity of the Korean version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form (KMMQL-AF) among Korean childhood cancer survivors. A total of 107 childhood cancer patients undergoing cancer treatment and 98 childhood cancer survivors who completed cancer treatment were recruited. To assess the internal structure of the KMMQL-AF, we performed multi-trait scaling analyses and exploratory factor analysis. Additionally, we compared each domains of the KMMQL-AF with those of the Karnofsky Performance Status Scale and the Revised Children's Manifest Anxiety Scale (RCMAS). Internal consistency of the KMMQL-AF was sufficient (Cronbach's alpha: 0.78-0.92). In multi-trait scaling analyses, the KMMQL-AF showed sufficient construct validity. The "physical functioning" domain showed moderate correlation with Karnofsky scores and the "psychological functioning" domain showed moderate-to-high correlation with the RCMAS. The KMMQL-AF discriminated between subgroups of different adolescent cancer survivors depending on treatment completion. The KMMQL-AF is a sufficiently reliable and valid instrument for measuring quality of life among Korean childhood cancer survivors.
Quality of Life; Questionnaires; Validation Studies; Child Psychology; Neoplasms; Survivors
Few literatures have elaborated on the clinical characteristics of children with thalassemia from low-prevalence areas. A retrospective analysis was conducted on children genetically confirmed with thalassemia at Seoul National University Children's Hospital in Korea. Nine children (1α thalassemia trait, 6β thalassemia minor, 2β thalassemia intermedia) were diagnosed with thalassemia at median age of 4.3 yr old with median hemoglobin of 9.7 g/dL. Seven (78%) children were incidentally found to be anemic and only 2 with β thalassemia intermedia had presenting symptoms. Five children (56%) were initially misdiagnosed with iron deficiency anemia. Despite the comorbidities due to α thalassemia mental retardation syndrome, the child with α thalassemia trait had mild hematologic profile. Children with β thalassemia intermedia had the worst phenotypes due to dominantly inherited mutations. None of the children was transfusion dependent and most of them had no complications associated with thalassemia. Only 1 child (11%) with codon 60 (T→A) mutation of the HBB gene needed red blood cell transfusions. He also had splenomegaly, cholelithiasis, and calvarial vault thickening. Pediatricians in Korea must acknowledge thalassemia as a possible diagnosis in children with microcytic hypochromic hemolytic anemia. High level of suspicion will allow timely diagnosis and managements.
α-Thalassemia; β-Thalassemia; Genotype; Phenotype; Child; Korea
Previous studies have shown that hematopoietic stem cell transplantation (HSCT) may result in growth impairment. The purpose of this study was to evaluate the growth during 5 yr after HSCT and to determine factors that influence final adult height (FAH). We retrospectively reviewed the medical records of acute myeloid leukemia (AML) patients who received HSCT. Among a total of 37 eligible patients, we selected 24 patients who began puberty at 5 yr after HSCT (Group 1) and 19 patients who reached FAH without relapse (Group 2). In Group 1, with younger age at HSCT, sex, steroid treatment, hypogonadism and hypothyroidism were not significantly associated with growth impairment 5 yr after HSCT. History of radiotherapy (RT) significantly impaired the 5 yr growth after HSCT. Chronic graft-versus-host disease (cGVHD) only temporarily impaired growth after HSCT. In Group 2, with younger age at HSCT, steroid treatment and hypogonadism did not significantly reduce FAH. History of RT significantly reduced FAH. Growth impairment after HSCT may occur in AML patients, but in patients without a history of RT, growth impairment seemed to be temporary and was mitigated by catch-up growth.
Hematopoietic Stem Cell Transplantation; Growth; Radiotherapy; Total Body Irradiation; Acute Myeloid Leukemia
This study was performed to characterize respiratory viral infections in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Study samples included 402 respiratory specimens obtained from 358 clinical episodes that occurred in the 116 children of the 175 consecutive HSCT cohort at Seoul National University Children's Hospital, Korea from 2007 to 2010. Multiplex reverse-transcription polymerase chain reactions were performed for rhinovirus, respiratory syncytial virus (RSV), parainfluenza viruses (PIVs), adenovirus, human coronavirus (hCoV), influenza viruses and human metapneumovirus. Viruses were identified in 89 clinical episodes that occurred in 58 patients. Among the 89 clinical episodes, frequently detected viruses were rhinovirus in 25 (28.1%), RSV in 23 (25.8%), PIV-3 in 16 (18.0%), adenovirus in 12 (13.5%), and hCoV in 10 (11.2%). Lower respiratory tract infections were diagnosed in 34 (38.2%). Neutropenia was present in 24 (27.0%) episodes and lymphopenia was in 31 (34.8%) episodes. Sixty-three percent of the clinical episodes were hospital-acquired. Three patients died of respiratory failure caused by respiratory viral infections. Respiratory viral infections in pediatric patients who have undergone HSCT are common and are frequently acquired during hospitalization. Continuous monitoring is required to determine the role of respiratory viruses in immunocompromised children and the importance of preventive strategies.
Hematopoietic Stem Cell Transplantation; Respiratory Virus; Respiratory Infections
Primary CNS lymphoma (PCNSL) is a very uncommon disease in children, and usually treated by chemotherapy, combined with focal or craniospinal radiotherapy (RT). However, adverse effects of RT are a concern. We evaluated the outcomes of childhood PCNSL, treated with systemic and intrathecal chemotherapy, but without RT. For fifteen years, six patients among 175 of non-Hodgkin lymphoma were diagnosed as PCNSL in Seoul National University Children's Hospital and we analyzed their medical records retrospectively. Their male:female ratio was 5:1, and median age was 10.1 yr. The primary sites were the sellar area in three patients, parietal area in one, cerebellum in one, and multiple areas in one. Their pathologic diagnoses were diffuse large B-cell lymphoma in three patients, Burkitt lymphoma in two, and undifferentiated B-cell lymphoma in one. Five were treated with the LMB96 treatment protocol, and one was treated with the CCG-106B protocol. None had RT as a first-line treatment. One patient had a local relapse and received RT and salvage chemotherapy, without success. No patient had treatment-related mortality. Their estimated 5-yr event-free and overall survival rates were both 83.3%. In conclusion, PCNSL is a rare disease in childhood, but successfully treated by chemotherapy without RT.
Primary CNS Lymphoma; Children; Irradiation
Diamond Blackfan anemia (DBA), characterized by impaired red cell production, is a rare condition that is usually symptomatic in early infancy. The purpose of this study was to assess nationwide experiences of DBA encountered over a period of 20 years.
The medical records of 56 patients diagnosed with DBA were retrospectively reviewed from November 1984 to July 2010. Fifteen institutions, including 13 university hospitals, participated in this study.
The male-to-female ratio of patients with DBA was 1.67:1. The median age of diagnosis was 4 months, and 74.1% were diagnosed before 1 year of age. From 2000 to 2009, annual incidence was 6.6 cases per million. Excluding growth retardation, 38.2% showed congenital defects: thumb deformities, ptosis, coarctation of aorta, ventricular septal defect, strabismus, etc. The mean hemoglobin concentration was 5.1±1.9 g/dL, mean corpuscular volume was 93.4±11.6 fL, and mean number of reticulocytes was 19,700/mm3. The mean cellularity of bone marrow was 75%, with myeloid:erythroid ratio of 20.4:1. After remission, 48.9% of patients did not need further steroids. Five patients with DBA who received hematopoietic transplantation have survived. Cancer developed in 2 cases (3.6%).
The incidence of DBA is similar to data already published, but our study had a male predilection. Although all patients responded to initial treatment with steroids, about half needed further steroids after remission. It is necessary to collect further data, including information regarding management pathways, from nationwide DBA registries, along with data on molecular analyses.
Diamond Blackfan anemia; Anemia; Congenital defects
Chronic graft versus host disease (GVHD) is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT), but simultaneous small bowel obstruction is rare. Here, we report a child with acute myeloid leukemia who received an allogeneic HSCT from an unrelated matched donor. After HSCT, the patient developed severe chronic GVHD involving the small intestine, leading to obstruction of the terminal ileum. Small bowel resection was performed, and the symptoms improved without severe complications. Bowel obstruction should be considered as a possible complication of chronic GVHD; surgery may be a valuable corrective measure.
Acute myeloid leukemia; Hematopoietic stem cell transplantation; Graft versus host disease; Intestinal obstruction
It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether the reported intercellular mitochondrial transfer could be replicated in different types of cells or under different experimental conditions, and tried to elucidate possible mechanism. Using biochemical selection methods, we found exponentially growing cells in restrictive media (uridine− and bromodeoxyuridine [BrdU]+) during the coculture of MSCs (uridine-independent and BrdU-sensitive) and 143B-derived cells with severe mitochondrial dysfunction induced by either long-term ethidium bromide treatment or short-term rhodamine 6G (R6G) treatment (uridine-dependent but BrdU-resistant). The exponentially growing cells had nuclear DNA fingerprint patterns identical to 143B, and a sequence of mitochondrial DNA (mtDNA) identical to the MSCs. Since R6G causes rapid and irreversible damage to mitochondria without the removal of mtDNA, the mitochondrial function appears to be restored through a direct transfer of mitochondria rather than mtDNA alone. Conditioned media, which were prepared by treating mtDNA-less 143B ρ0 cells under uridine-free condition, induced increased chemotaxis in MSC, which was also supported by transcriptome analysis. Cytochalasin B, an inhibitor of chemotaxis and cytoskeletal assembly, blocked mitochondrial transfer phenomenon in the above condition. However, we could not find any evidence of mitochondrial transfer to the cells harboring human pathogenic mtDNA mutations (A3243G mutation or 4,977 bp deletion). Thus, the mitochondrial transfer is limited to the condition of a near total absence of mitochondrial function. Elucidation of the mechanism of mitochondrial transfer will help us create a potential cell therapy-based mitochondrial restoration or mitochondrial gene therapy for human diseases caused by mitochondrial dysfunction.
Tumor seeding is a strong negative prognostic factor for patients with medulloblastoma. Because Chang's M staging is based primarily on CT and myelographic findings and might be contradictory to the direction of normal cerebrospinal fluid (CSF) flow, seeding patterns and appropriate staging of medulloblastoma need to be revisited in patients diagnosed in the MRI era. We retrospectively reviewed the clinical and radiological data of 86 patients with a diagnosis of medulloblastoma who were treated in the MRI era. The presence of seeding in each subarachnoid space compartment and the patterns of seeding were analyzed in correlation with patient survival data. Thirty-four patients had gross seeding on perioperative MRI. Thirty-two patients had seeding in the spinal compartment. Sixteen and 12 patients had seeding in the infratentorial and supratentorial compartments, respectively. There was an apparent hierarchy of seeding (ie, from seeding in the spinal compartment up to the supratentorial compartment). Patients with seeding in the spinal compartment had longer progression-free survival (P = .038) and a tendency toward better overall survival (P = .053) compared with patients with seeding in intracranial compartments. We modified Chang's M staging based on the CSF flow and termed this approach “CSF M staging.” CSF M staging for medulloblastoma, in which intracranial seeding occupies a higher rank than spinal seeding, was a better predictor of patient prognosis. This modified staging method may be applied to metastatic staging of brain tumors located in the fourth ventricle.
cerebrospinal fluid, medulloblastoma; prognosis; seeding; staging
We compared the outcomes of patients with Burkitt lymphoma and French-American-British (FAB) L3 acute lymphoblastic leukemia treated using Lymphoma Malignancy B (LMB) or other treatment protocols.
Thirty-eight patients diagnosed between July 1996 and December 2007 were treated using LMB 96, and 22 patients diagnosed between January 1991 and May 1998 (defined as the early period) were treated using the D-COMP or CCG-106B protocols. We retrospectively reviewed their medical records and analyzed cumulative survival according to the treatment period by using Kaplan-Meier analysis.
There were no intergroup differences in the distribution of age, disease stage, or risk group. The median follow-up period of the 33 live patients in the LMB group was 72 months (range, 36-170 months). Overall survival (OS) and event-free survival (EFS) of patients treated using LMB 96 were 86.8%±5.5% and 81.6%±6.3%, respectively, whereas OS and EFS of patients treated in the early period were 72.7%±9.6% and 68.2%±9.9%, respectively. In the LMB 96 group, OS of cases showing non-complete response (N=8) was 62.5%±17.1%, and OS of relapsed or primary refractory cases (N=6) was 33.3%±19.3%. Central nervous system (CNS) disease, high lactate dehydrogenase levels at diagnosis, and treatment response were significant prognostic factors.
Survival outcome has drastically improved over the last 2 decades with short-term, dose-intensive chemotherapy. However, CNS involvement or poor response to chemotherapy was worse prognostic factors; therefore, future studies addressing this therapeutic challenge are warranted.
Burkitt lymphoma; L3 lymphocytic leukemia; Treatment outcome; Prognosis
The impact of HLA matching on outcomes of unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) varies in different racial or ethnic groups. Since little is known about the impact of such matching on URD HSCT in Korean children, we analyzed this issue.
We analyzed the outcomes of 142 patients who underwent URD HSCT at 4 Korean medical centers. All patient donor pairs were fully typed for HLA-A, -B, -C, and -DR alleles.
At a median follow-up of 22 months, 3-year survival rates for patients with 8, 7, and ≤6 matched alleles were 88.4%, 70.7%, and 53.6%, respectively. A single mismatch (Mm) at HLA-B or -C was associated with lower survival compared with that associated with 8 matched alleles. No significant differences were observed between single-allele and single-antigen Mms with respect to survival rate or acute graft-versus-host disease (aGVHD) incidence rates. HLA disparity had a greater impact on the survival of patients with high-risk malignancy than of those with low-risk malignancy. Among pairs with a single Mm, only locus A showed a significant association and higher risk of grade III-IV aGVHD compared to those in patients with 8 matched alleles.
Disparity in HLA class I, regardless of antigen or allele Mm, adversely affected both survival and grade III-IV aGVHD development. An increased number of HLA Mms was associated with a higher risk of post-transplantation complications. Further investigations using larger cohorts are required to confirm the effects of HLA mismatching on URD HSCT patient outcomes.
URD HSCT; HLA; Korean children
To evaluate the visual outcomes of retinoblastoma in the posterior pole (RBPP) treated with chemotherapy plus local treatments and to address the prognostic factors that influence such outcomes.
The medical records of patients with RBPP diagnosed at the Department of Pediatric Ophthalmology, Seoul National University Children's Hospital between August 1987 and September 2007 were reviewed retrospectively. Only those patients treated via primary chemotherapy plus local treatments were included. The presence of foveal involvement and tumors in the posterior pole before and after treatment, the type of regression pattern and the best corrected visual acuity (BCVA) of each patient were evaluated.
A total of 13 eyes in 12 patients were included. The mean final BCVA for treated RBPP was 20/210 (range, hand motion to 20/16). However, eight eyes (61.5%) had an acuity of 20/200 or better and seven eyes (53.8%) had an acuity of 20/50 or better. The mean final BCVA was significantly better in cases with negative foveal involvement; however, four eyes (37.5%) with positive foveal involvement had an acuity of 20/200 or better. Tumors area in the posterior pole and the type of regression pattern were not significantly related to final BCVA.
Over one half of the studied RBPP patients had working vision. Although the eyes had RBPP with positive foveal involvement, about one-third of the patients had working vision. Vision preservation should be considered when deciding on RBPP treatment.
Fovea; Macula; Posterior pole; Prognosis; Retinoblastoma
To evaluate whether candidate genes in innate immunity are associated with childhood leukemia, we conducted an association study with the 1,536 SNPs in 203 genes related to innate immunity.
Incident childhood leukemia cases (n=136) aged from 0 to 18 were recruited from three teaching hospitals in Seoul between 2003 and 2006. Non-cancer controls (n=140) were frequency-matched to cases by age and gender. The information on the characteristics of children and their parents were collected by trained interviewers using structured questionnaire. Candidate genes were selected based on SNP databases (CGAP and SNP500 database), and genotype assay was performed using GoldenGate (Illumina) oligonucleotide pool assay (OPA). False discovery rate (FDR), permutation test, and haplotype analyses were used to identify the SNP with significant association with childhood leukemia. Childhood leukemia risk was estimated as ORs and 95% CIs adjusted for age, gender and birth weight.
Fourteen SNPs in 13 genes (LMAN1, TLR4, STAT4, CCR9, MBP, ZP1, C8B, XDH, C7, C1QG, FGF2, LOC390183, and STAT6) were significantly associated with childhood leukemia risk (FDR p-values <0.05). In particular, LMAN1 rs1127220, TLR4 rs11536897, STAT4 rs13020076, CCR9 rs1471962, and MBP rs10514234 were significant in 5,000 permutation tests (Permutation p-value <0.05). The most significant association with childhood leukemia risk was for the LMAN1 rs1127220 that is in the protein-coding region, this finding was also supported by haplotype analysis.
A number of innate immunity related genes are associated with childhood leukemia, suggesting possible links between the innate immunity system and development of the childhood leukemia.
Childhood Leukemia; Innate Immunity; Single Nucleotide Polymorphism
This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8±83.4 mg/m2 in the dexrazoxane group and 266.1±75.0 mg/m2 in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.
Dexrazoxane; Doxorubicin; Cardiotoxicity; Child; Solid Tumors
Leukemic cells originate from hypoxic bone marrow, which protects them from anti-cancer drugs. Although many factors that cause drug resistance in leukemic cells have been studied, the effect of hypoxia on drug-induced apoptosis is still poorly understood.
In this study, we examined the effect of hypoxia on anti-leukemic drug resistance in leukemic cell lines treated with cobalt chloride (CoCl2), a hypoxia-mimetic agent. Cellular proliferation was evaluated using the methyl thiazolyl tetrazolium (MTT) assay. Flow cytometry analysis and western blots were performed to investigate apoptosis-related proteins.
Unlike its previously known apoptotic effect, the expression of HIF-1α increased the survival rate of human promyelocytic leukemia HL-60 cells when these cells were exposed to anti-leukemic drugs; these effects were mediated by heat-shock protein HSP70 and the pro-apoptotic protein Bax.
These findings may provide new insights for understanding the mechanisms underlying hypoxia and for designing new therapeutic strategies for acute myeloid leukemia.
Hypoxia; Arsenic trioxide; HIF-1α; Cobalt chloride; Bax; HSP70
To evaluate the efficacy of primary chemotherapy combined with local therapy in the treatment of retinoblastomas not treatable with a single therapeutic method.
We performed a retrospective chart review of 227 patients diagnosed with retinoblastoma. Sixty-five eyes in 52 patients had tumors not treatable with a single therapeutic method and received primary chemotherapy combined with local therapy as needed.
Tumor control and eye salvage was achieved in 34 of the 65 eyes; the probability of ocular survival was 46.56% using the Kaplan-Meier method. Forty-three of the 65 eyes were group D or E tumors, in which tumor control and eye salvage was achieved in 16 eyes. Twenty eyes were treated with chemotherapy only, while 28 eyes received one additional modality of local therapy, and 17 eyes received two modalities of local therapy. Of the eyes treated with chemotherapy only, tumor control was achieved in 5 eyes.
Primary chemotherapy combined with local therapy can be effective and safe in the treatment of retinoblastomas otherwise untreatable with other therapeutic methods, such as group D and E retinoblastomas. More vigorous treatment with more local therapeutic methods combined may yield even better results.
Chemotherapy; Eye preservation; Retinoblastoma
In this study, we investigated the effects of reduced-dose craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in children with a newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET).
Between March 2005 and April 2007, patients older than 3 years with a newly diagnosed high-risk MB or sPNET were enrolled. The patients received two cycles of pre-RT chemotherapy consisting of cisplatin, etoposide, vincristine, and cyclophosphamide (cycle A), and carboplatin, etoposide, vincristine, and ifosphamide (cycle B), followed by CSRT with 23.4 Gy and local RT with 30.6 Gy. After four cycles of post-RT chemotherapy (cycles A, B, A, and B), tandem double HDCT with ASCR was performed.
A total of 13 patients (MB=11, sPNET=2) were enrolled. Of these, one patient progressed, one patient died of septic shock after the second cycle of B, and one patient relapsed after the third cycle of B. The 3-year event-free survival (EFS) rate of the patients intended for HDCT was 76.9%, whereas the 3-year EFS rate of the patients who received HDCT was 100%. No treatment-related mortality occurred during HDCT.
Although the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by HDCT and ASCR warrant further exploration in a larger study population.
Radiotherapy; High-dose chemotherapy; Autologous stem cell transplantation; Medulloblastoma; Supratentorial primitive neuroectodermal tumor; Children
The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival±95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2±12.4% vs. 31.3±11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients.
Neuroblastoma; High-dose Chemotherapy; Transplantation, Autologous
We investigated the outcome of idarubicin plus N4-behenoyl-1-β-D-arabinofuranosyl cytosine (BHAC)-based chemotherapy (BHAC group, n=149) compared to idarubicin plus cytarabine-based chemotherapy (cytarabine group, n=191) for childhood acute myeloid leukemia (AML). Between January 1996 and December 2005, 340 children with AML from 5 university hospitals in Korea received the BHAC-based or cytarabine-based chemotherapy, with or without hematopoietic stem cell transplantation. After induction therapy, 264 (77.6%) of 340 children achieved a complete remission (CR) and 43 (12%) achieved a partial remission (PR). The CR rate in the BHAC group was higher than in the cytarabine group (85.2% vs. 71.7%, P=0.004). However, the overall response rate (CR+PR) was not different between the two groups (93.3% vs. 87.9%, P=0.139). The 5-yr estimates of overall survival (OS) of children in the two groups were similar (54.9% for the BHAC group vs. 52.4% for the cytarabine group, P=0.281). Although the results were analyzed according to the treatment type and cytogenetic risk, the OS showed no significant difference between the BHAC group and the cytarabine group. In the present study, the clinical outcomes of the BHAC-based chemotherapy, consisting of BHAC, idarubicin, and 6-TG, are comparable to that of the cytarabine-based chemotherapy for childhood AML.
Leukemia, Myeloid, Acute; Enocitabine; Childhood
We conducted a case–control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (–17961T>C, –9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8, 95% CI = 1.1–2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2–3.4). An increasing trend in risk was observed for pack-years smoked after birth (Ptrend = 0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (Ptrend = 0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5–5.3) and the presence of at least one smoker in the home (2.3, 1.2–4.4), and the test for interaction was significant (Pinteraction = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04–1.24) and smoking before the pregnancy of the child (1.12, 1.04–1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.
Childhood leukemia; Paternal smoking; CYP1A1; Interaction; Haplotype
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.
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.
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.
Retinoblastoma; Chemotherapy; Radiotherapy; Enucleation; Survival rate; Eyeball-saving