Jung Yoon Choi

Effect of FOXP3 polymorphism on the clinical outcomes after allogeneic hematopoietic stem cell transplantation in pediatric acute leukemia patients.

Forkhead BOX P3 (FOXP3) polymorphisms have recently been investigated as candidate risk factors in several tumors and autoimmune diseases. This study aims to evaluate the potential influence of FOXP3 rs3761548 polymorphism in the donor on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 171 patients were enrolled for this study and genotyped using direct sequencing. Patients with rs3761548 CC genotype had higher incidence of hepatic veno-occlusive disease (HVOD) and cytomegalovirus (CMV) infection than that of the individuals with AA or AC genotype (P=0.011, P=0.023). Treatment-related mortality (TRM) rate of patients with AA or AC genotype was lower than that of the patients with CC genotype (P=0.044) resulting in a difference in overall survival (OS). However, there was no difference in graft-versus-host disease (GVHD) relapse or blood stream infection (BSI), depending on the genotype at rs3761548 locus. In multivariate analysis, CC genotype showed as a risk factor in the development of HVOD and CMV infection, with low OS. In conclusion, this is the first report on FOXP3 rs3761548 SNP in allo-HSCT and we suggest that this SNP be considered a candidate marker for predicting the development of HVOD and CMV infection after allo-HSCT.

A Significant Influence of Metronidazole on Busulfan Pharmacokinetics: A Case Report of Therapeutic Drug Monitoring.

Busulfan is a cytotoxic agent used in preconditioning for hematopoietic stem cell transplantation. Therapeutic drug monitoring of busulfan is necessary owing to its narrow therapeutic range. Patients undergoing preconditioning are susceptible to infection and might require coadministration of antibiotics. We present a case study of a 3-year-old girl with precursor T-cell acute lymphoblastic leukemia who received intravenous busulfan before hematopoietic stem cell transplantation. Metronidazole was coadministered before the third dose of busulfan because of Clostridium difficile infection. The daily pharmacokinetic analysis revealed that the clearance reduced to 57% of that before the coadministration. Although the underlying mechanism is unclear, a significant pharmacokinetic interaction was observed between busulfan and metronidazole, underscoring the importance of therapeutic drug monitoring.

Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant

&NA; STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post‐hematopoietic stem cell transplantation (post‐HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post‐HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno‐occlusive disease, acute graft‐vs‐host disease, chronic graft‐vs‐host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P = 0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P = 0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post‐transplant outcomes. HighlightsAssociation of rs7574865 polymorphism in donors with outcomes after HSCTPresence of TT genotype increases susceptibility to CMV infection.Possible association of rs7574865 with a weaker immune response in recipients

Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once‐daily intravenous busulfan dosing nomogram

Busulfan, a bifunctional alkylating agent, has been used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to derive a novel once‐daily intravenous (IV) busulfan dosing nomogram for pediatric patients undergoing HSCT using a population pharmacokinetic (PK) model. A population PK analysis was performed using 2183 busulfan concentrations in 137 pediatric patients (age: 0.6‐22.2 years), who received IV busulfan once‐daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once‐daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration‐time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once‐daily regimen without therapeutic drug monitoring (TDM). A one‐compartment open linear PK model incorporating patients body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration–time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in >60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept <25% during the entire treatment period. A novel once‐daily busulfan dosing nomogram for pediatric patients undergoing HSCT is useful for clinicians, particularly in a setting where TDM service is not readily available or to optimize the dose on day 1.

Very late relapse of bilateral retinoblastoma.

Retinoblastoma usually recurs within the first few years after treatment completion. We report a rare case of very late relapse in a 6-month-old girl who was diagnosed with bilateral retinoblastoma. The patient achieved first remission after treatment with neoadjuvant chemotherapy, enucleation of the right eye, local laser therapy of the left eye, and adjuvant chemotherapy. Extraocular relapse with multiple metastases occurred 13 years and 8 months after treatment. The patient is currently in second complete remission after receiving high-dose chemotherapy and autologous stem cell transplantation. In conclusion, long-term follow-up is needed for early detection of recurrent retinoblastoma.

Radiologic evaluation of pulmonary injury following carmustine- and cyclophosphamide-based preparative regimen for autologous peripheral blood stem cell transplantation in children

BackgroundToxicity of carmustine and cyclophosphamide can cause pulmonary injury after hematopoietic stem cell transplantation.ObjectiveTo evaluate the radiologic findings of pulmonary injuries following carmustine- and cyclophosphamide-based preparative regimens in children.Materials and methodsFrom 2010 to 2014, 35 children received carmustine- and cyclophosphamide-based preparative regimens. Fourteen of 35 children presented with symptoms and radiologic abnormalities. Eight of 14 children had no evidence of infection, cardiogenic edema, or other explainable causes. We retrospectively analyzed their chest radiographs and CT scans for ground-glass opacity, consolidation, septal thickening and pleural effusion.ResultsMajor chest radiographic findings were bilateral diffuse ground-glass opacity (n=8) and septal thickening (n=7). CT findings were multifocal patchy (n=4) or inhomogeneously diffuse (n=4) ground-glass opacity, multifocal consolidations (n=7) and septal thickening (n=7). All of these lesions at CT were bilateral, but showed lower lobe predominance in 88, 100, and 63%, respectively. There was no central/peripheral or anterior/posterior predilection. Six children had small pleural effusions, which were bilateral in five children.ConclusionBilateral ground-glass opacity with or without consolidation, septal thickening and pleural effusion were common radiologic findings in pulmonary injury following carmustine- and cyclophosphamide-based preparative regimens.

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. Conclusions 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.

WHIM Syndrome With a Novel CXCR4 Variant in a Korean Child

Dong Woo Shin, M.D., Si Nae Park, M.S., Sung-Min Kim, B.S., Kyongok Im, M.T., Jung-Ah Kim, M.D., Kyung Taek Hong, M.D. , Jung Yoon Choi, M.D. , Che Ry Hong, M.D. , Kyung Duk Park, M.D. , Hee Young Shin, M.D. , Hyoung Jin Kang, M.D. , Hyun Kyung Kim, M.D., and Dong Soon Lee, M.D. Department of Laboratory Medicine, Seoul National University College of Medicine; Cancer Research Institute, Seoul National University College of Medicine; Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea

Therapy-related Acute Myeloid Leukemia After the Treatment of Primary Solid Cancer in Children: A Single-center Experience

Therapy-related acute myeloid leukemia (t-AML) has a dismal prognosis and is one of the most frequent second malignant neoplasms which could be encountered by pediatric oncologists. Between October 2000 and September 2016, 16 patients who had primary solid tumors were diagnosed with t-AML at the Seoul National University Children’s Hospital. The median patient age at the time of diagnosis of their primary solid tumors was 9.6 years (range, 0.1 to 15.4 y), and that of t-AML was 14.0 years (range, 4.7 to 23.9 y). The median latency period from the end of the primary tumor treatment to the initial diagnosis of t-AML was 29 months (range, 6 to 130 mo). Twelve patients achieved complete remission. Of them, only 7 patients underwent hematopoietic stem cell transplantation (HSCT). The 3-year overall survival (OS) rates and event-free survival rates were 33.7±12.2% and 26.9±11.5% respectively. The patients who underwent HSCT showed favorable 5-year OS rates (57.1±18.7%), whereas the 5-year OS rates of those who did not undergo HSCT was 0%. This study demonstrates that an achievement of complete remission and a subsequent HSCT can be the optimal solution for the treatment of t-AML, and this strategy showed acceptable outcomes.