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1.  Effect of Ex Vivo Culture Conditions on Immunosuppression by Human Mesenchymal Stem Cells 
BioMed Research International  2013;2013:154919.
A microarray analysis was performed to investigate whether ex vivo culture conditions affect the characteristics of MSCs. Gene expression profiles were mainly influenced by the level of cell confluence rather than initial seeding density. The analysis showed that 276 genes were upregulated and 230 genes downregulated in MSCs harvested at ~90% versus ~50% confluence (P < 0.05, FC > 2). The genes that were highly expressed in MSCs largely corresponded to chemotaxis, inflammation, and immune responses, indicating direct or indirect involvement in immunomodulatory functions. Specifically, PTGES and ULBP1 were up-regulated in MSCs harvested at high density. Treatment of MSCs with PTGES or ULBP1 siRNA reversed their inhibition of T-cell proliferation in vitro. The culture conditions such as cell confluence at harvest seem to be important for gene expression profile of MSCs; therefore, the results of this study may provide useful guidelines for the harvest of MSCs that can appropriately suppress the immune response.
doi:10.1155/2013/154919
PMCID: PMC3687591  PMID: 23862134
2.  Human bone marrow-derived mesenchymal stem cell gene expression patterns vary with culture conditions 
Blood research  2013;48(2):107-114.
Background
Because of the heterogeneity of human mesenchymal stem cells (MSCs), methods for cell expansion in culture and the effects on gene expression are critical factors that need to be standardized for preparing MSCs. We investigated gene expression patterns of MSCs with different seeding densities and culture times.
Methods
Bone marrow-derived MSCs were plated at densities from 200 cells/cm2 to 5,000 cells/cm2, and the gene expression patterns were evaluated over time using a reverse-transcription polymerase chain reaction assay.
Results
The mRNA levels of factors that play a critical role in cell migration and tissue regeneration, such as podocalyxin-like protein (PODXL), α4-integrin, α6-integrin, and leukemia inhibitory factor (LIF), were higher in MSCs plated at 200 cells/cm2 than in MSCs plated at 5,000 cells/cm2. The mRNA levels of these factors gradually increased for 10 days and then decreased by day 15 in culture. MSCs seeded at 200 cells/cm2 that were cultured for 10 days expressed high levels of Oct-4 and Nanog. Indoleamine 2,3-dioxygenase, cyclooxygenase-1, and hepatocyte growth factor expression were upregulated in the presence of the proinflammatory cytokine interferon-γ in these cells.
Conclusion
We found differences in the gene expression patterns of MSCs under different culture conditions. MSCs from 10-day cultures seeded at a low density were efficiently expanded, expressed PODXL, α6-integrin, α4-integrin, and LIF, and maintained properties like stemness and immunomodulation. Therefore, ex vivo expansion of MSCs maintained for an adequate culture time after plating at low cell density can provide an effective regenerative medicinal strategy for cell therapies using MSCs.
doi:10.5045/br.2013.48.2.107
PMCID: PMC3698395  PMID: 23826579
Mesenchymal stem cell; Gene expression pattern; Seeding density; Culture time; Cell therapy
3.  Hematopoietic stem cell transplantation in children with acute leukemia: similar outcomes in recipients of umbilical cord blood versus marrow or peripheral blood stem cells from related or unrelated donors 
Korean Journal of Pediatrics  2012;55(3):93-99.
Purpose
This study compared outcomes in children with acute leukemia who underwent transplantations with umbilical cord blood (UCB), bone marrow, or peripheral blood stem cells from a human leukocyte antigen (HLA)-matched related donor (MRD) or an unrelated donor (URD).
Methods
This retrospective study included consecutive acute leukemia patients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) at Samsung Medical Center between 2005 and 2010. Patients received stem cells from MRD (n=33), URD (n=46), or UCB (n=41).
Results
Neutrophil and platelet recovery were significantly longer after HSCT with UCB than with MRD or URD (P<0.01 for both). In multivariate analysis using the MRD group as a reference, the URD group had a significantly higher risk of grade III to IV acute graft-versus-host disease (GVHD; relative risk [RR], 15.2; 95% confidence interval [CI], 1.2 to 186.2; P=0.03) and extensive chronic GVHD (RR, 6.9; 95% CI, 1.9 to 25.2; P<0.01). For all 3 donor types, 5-year event-free survival (EFS) and overall survival were similar. Extensive chronic GVHD was associated with fewer relapses (RR, 0.1; 95% CI, 0.04 to 0.6; P<0.01). Multivariate analysis showed that lower EFS was associated with advanced disease at transplantation (RR, 3.2; 95% CI, 1.3 to 7.8; P<0.01) and total body irradiation (RR, 2.1; 95% CI, 1.0 to 4.3; P=0.04).
Conclusion
Survival after UCB transplantation was similar to survival after MRD and URD transplantation. For patients lacking an HLA matched donor, the use of UCB is a suitable alternative.
doi:10.3345/kjp.2012.55.3.93
PMCID: PMC3315625  PMID: 22474464
Umbilical cord blood; Hematopoietic stem cell transplantation; Stem cell donor
4.  Philadelphia chromosome-positive acute lymphoblastic leukemia in childhood 
Korean Journal of Pediatrics  2011;54(3):106-110.
In pediatric patients with acute lymphoblastic leukemia (ALL), the Philadelphia chromosome translocation is uncommon, with a frequency of less than 5%. However, it is classified as a high or very high risk, and only 20-30% of Philadelphia chromosome-positive (Ph+) children with ALL are cured with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation from a closely matched donor cures 60% of patients in first complete remission. Recent data suggest that chemotherapy plus tyrosine kinase inhibitors (TKIs) may be the initial treatment of choice for Ph+ ALL in children. However, longer observation is required to determine whether long-term outcome with intensive imatinib and chemotherapy is indeed equivalent to that with allogeneic related or alternative donor hematopoietic stem cell transplantation (HSCT). Reports on the use of second-generation TKIs in children with Ph+ ALL are limited. A few case reports have indicated the feasibility and clinical benefit of using dasatinib as salvage therapy enabling HSCT. However, more extensive data from clinical trials are needed to determine whether the administration of second-generation TKIs in children is comparable to that in adults. Because Ph+ ALL is rare in children, the question of whether HSCT could be a dispensable part of their therapy may not be answered for some time. An international multicenter study is needed to answer the question of whether imatinib plus chemotherapy could replace sibling allogeneic HSCT in children with Ph+ ALL.
doi:10.3345/kjp.2011.54.3.106
PMCID: PMC3120995  PMID: 21738539
Philadelphia chromosome; Acute lymphoblastic leukemia; Tyrosine kinase inhibitor; Child
5.  Responses and adverse effects of carboplatin-based chemotherapy for pediatric intracranial germ cell tumors 
Korean Journal of Pediatrics  2011;54(3):128-132.
Purpose
Cisplatin-based chemotherapy has been commonly used for the treatment of intracranial germ cell tumors (IC-GCTs). However, this treatment exhibits some adverse effects such as renal problems and hearing difficulty. Carboplatin-based chemotherapy was administered to pediatric patients with IC-GCTs from August 2004 at the Samsung Medical Center. In this study, we assessed the responses and adverse effects of carboplatin-based chemotherapy in pediatric IC-GCTs patients according to the risk group, and compared the results with those of the previous cisplatin-based chemotherapy.
Methods
We examined 35 patients (27 men and 8 women) diagnosed with IC-GCTs between August 2004 and April 2008 and received risk-adapted carboplatin-based chemotherapy at the Samsung Medical Center. Patients were divided into either low-risk (LR) or high-risk (HR) groups and a retrospective analysis was performed using information from the medical records.
Results
Although hematological complications were common, hearing difficulties or grade 3 or 4 creatinine level elevation were not observed in patients who underwent carboplatin-based chemotherapy. The frequency of febrile neutropenia did not differ between the risk groups. The overall survival was 100% and event-free survival (EFS) was 95.7%. The EFS rate was 100% in the LR group and 90% in the HR group, respectively.
Conclusion
Despite their common occurrence in high-risk patients, no lethal hematological complications were associated with carboplatin-based treatment. The current carboplatin-based chemotherapy protocol is safe and effective for the treatment of pediatric patients with IC-GCTs.
doi:10.3345/kjp.2011.54.3.128
PMCID: PMC3120999  PMID: 21738543
Intracranial germ cell tumor; Carboplatin; Adverse effects
6.  Overexpression of X-linked Inhibitor of Apoptosis Protein (XIAP) is an Independent Unfavorable Prognostic Factor in Childhood de Novo Acute Myeloid Leukemia 
Journal of Korean Medical Science  2009;24(4):605-613.
The overexpression of X-linked inhibitor of apoptosis protein (XIAP), a member of IAP family protein, is intuitively expected to be associated with unfavorable clinical features in malignancies; however, there have been only a very limited number of studies reporting the clinical relevance of XIAP expression. This study was performed to investigate the prognostic relevance of XIAP expression in childhood acute myeloid leukemia (AML). In 53 children with de novo AML, the level of XIAP expression was determined by using quantitative reverse transcriptase-polymerase chain reaction and was analyzed with respect to the clinical characteristics at diagnosis and treatment outcomes. As a result, the XIAP expression was found to be higher in patients with extramedullary disease than in those without (P=0.014). In addition, XIAP overexpression (≥median expression) was associated with an unfavorable day 7 response to induction chemotherapy and also associated with a worse 3-yr relapsefree survival rate (52.7±20.9% vs. 85.9±14.8%, P=0.014). Multivariate analyses revealed that XIAP overexpression was an independent unfavorable prognostic factor for relapse-free survival (hazard ratio, 6.16; 95% confidence interval, 1.48-25.74; P=0.013). Collectively, XIAP overexpression may be used as an unfavorable prognostic marker in childhood AML.
doi:10.3346/jkms.2009.24.4.605
PMCID: PMC2719207  PMID: 19654940
X-Linked Inhibitor of Apoptosis Protein; Apoptosis; Inhibitor of Apoptosis Protein; Leukemia, Myeloid, Acute
7.  Cotransplanted Bone Marrow Derived Mesenchymal Stem Cells (MSC) Enhanced Engraftment of Hematopoietic Stem Cells in a MSC-dose Dependent Manner in NOD/SCID Mice 
Journal of Korean Medical Science  2006;21(6):1000-1004.
Transplantation of marrow-derived mesenchymal stem cells (MSCs), expanded by culture in addition to whole bone marrow, has been shown to enhance engraftment of human hematopoietic stem cells (HSCs). Our hypothesis was that there might be an optimum ratio range that could enhance engraftment. We examined the percent donor chimerism according to the ratio of HSCs to MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We tested a series of ratios of co-transplanted CD34+-selected bone marrow cells, and marrow-derived MSCs into sublethally irradiated NOD/SCID mice. In all experiments, 1×105 bone marrow derived human CD34+ cells were administered to each mouse and human MSCs from different donors were infused concomitantly. We repeated the procedure three times and evaluated engraftment with flow cytometry four weeks after each transplantation. Serial ratios of HSCs to MSCs were 1:0, 1:1, 1:2 and 1:4, in the first experiment, 1:0, 1:1, 1:2, 1:4 and 1:8 in the second and 1:0, 1:1, 1:4, 1:8 and 1:16 in the third. Cotransplantation of HSCs and MSCs enhanced engraftment as the dose of MSCs increased. Our results suggest that the optimal ratio of HSCs and MSCs for cotransplantation might be in the range of 1:8-1:16; whereas, an excessive dose of MSCs might decrease engraftment efficiency.
doi:10.3346/jkms.2006.21.6.1000
PMCID: PMC2721918  PMID: 17179676
Hematopoietic Stem Cells; Mesenchymal Stem Cells; Transplantation; Mice, SCID; Engraftment
8.  Reduced-dose craniospinal radiotherapy followed by tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk medulloblastoma 
Neuro-Oncology  2012;15(3):352-359.
Background
We assessed the feasibility and effectiveness of reduced-dose craniospinal (CS) radiotherapy (RT) followed by tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in reducing late adverse effects without jeopardizing survival among children with high-risk medulloblastoma (MB).
Methods
From October 2005 through September 2010, twenty consecutive children aged >3 years with high-risk MB (presence of metastasis and/or postoperative residual tumor >1.5 cm2) were assigned to receive 2 cycles of pre-RT chemotherapy, CSRT (23.4 or 30.6 Gy) combined with local RT to the primary site (total 54.0 Gy), and 4 cycles of post-RT chemotherapy followed by tandem HDCT/autoSCT. Carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens were used for the first and second HDCT, respectively.
Results
Of 20 patients with high-risk MB, 17 had metastatic disease and 3 had a postoperative residual tumor >1.5 cm2 without metastasis. The tumor relapsed/progressed in 4 patients, and 2 patients died of toxicities during the second HDCT/autoSCT. Therefore, 14 patients remained event-free at a median follow-up of 46 months (range, 23−82) from diagnosis. The probability of 5-year event-free survival was 70.0% ± 10.3% for all patients and 70.6% ± 11.1% for patients with metastases. Late adverse effects evaluated at a median of 36 months (range, 12−68) after tandem HDCT/autoSCT were acceptable.
Conclusions
In children with high-risk MB, CSRT dose might be reduced when accompanied by tandem HDCT/autoSCT without jeopardizing survival. However, longer follow-up is needed to evaluate whether the benefits of reduced-dose CSRT outweigh the long-term risks of tandem HDCT/autoSCT.
doi:10.1093/neuonc/nos304
PMCID: PMC3578484  PMID: 23258845
autologous stem cell transplantation; high-dose chemotherapy; late effect; medulloblastoma; radiotherapy
10.  Gene Expression Profiles of Human Adipose Tissue-Derived Mesenchymal Stem Cells Are Modified by Cell Culture Density 
PLoS ONE  2014;9(1):e83363.
Previous studies conducted cell expansion ex vivo using low initial plating densities for optimal expansion and subsequent differentiation of mesenchymal stem cells (MSCs). However, MSC populations are heterogeneous and culture conditions can affect the characteristics of MSCs. In this study, differences in gene expression profiles of adipose tissue (AT)-derived MSCs were examined after harvesting cells cultured at different densities. AT-MSCs from three different donors were plated at a density of 200 or 5,000 cells/cm2. After 7 days in culture, detailed gene expression profiles were investigated using a DNA chip microarray, and subsequently validated using a reverse transcription polymerase chain reaction (RT-PCR) analysis. Gene expression profiles were influenced primarily by the level of cell confluence at harvest. In MSCs harvested at ∼90% confluence, 177 genes were up-regulated and 102 genes down-regulated relative to cells harvested at ∼50% confluence (P<0.05, FC>2). Proliferation-related genes were highly expressed in MSCs harvested at low density, while genes that were highly expressed in MSCs harvested at high density (∼90% confluent) were linked to immunity and defense, cell communication, signal transduction and cell motility. Several cytokine, chemokine and growth factor genes involved in immunosuppression, migration, and reconstitution of damaged tissues were up-regulated in MSCs harvested at high density compared with MSCs harvested at low density. These results imply that cell density at harvest is a critical factor for modulating the specific gene-expression patterns of heterogeneous MSCs.
doi:10.1371/journal.pone.0083363
PMCID: PMC3882209  PMID: 24400072
11.  Optimal Time to Start Peripheral Blood Stem Cell Collection in Children with High-Risk Solid Tumors 
Journal of Korean Medical Science  2013;29(1):110-116.
In order to clarify the optimal timing for peripheral blood stem cell (PBSC) collection, PBSC collection records of 323 children who were scheduled to undergo autologous stem cell transplantation from two study periods differing in the timing of PBSC collection were analyzed. In the early study period (March 1998 to August 2007, n=198), PBSC collection was initiated when the peripheral WBC count exceeded 1,000/µL during recovery from chemotherapy. Findings in this study period indicated that initiation of PBSC collection at a higher WBC count might result in a greater CD34+ cell yield. Therefore, during the late study period (September 2007 to December 2012, n=125), PBSC collection was initiated when the WBC count exceeded 4,000/µL. Results in the late study period validated our conclusion from the early study period. Collection of a higher number of CD34+ cells was associated with a faster hematologic recovery after transplant in the late study period. Initiation of PBSC collection at WBC count > 4,000/µL was an independent factor for a greater CD34+ cell yield. In conclusion, PBSC collection at a higher WBC count is associated with a greater CD34+ cell yield, and consequently a faster hematologic recovery after transplant.
doi:10.3346/jkms.2014.29.1.110
PMCID: PMC3890460  PMID: 24431914
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; Peripheral Blood Stem Cell Collection
12.  Breast Metastasis from Rhabdomyosarcoma of the Anus in an Adolescent Female 
Journal of Breast Cancer  2013;16(3):345-348.
Rhabdomyosarcoma (RMS) of the breast is rare and there is scant information about the clinical behavior and treatment strategies. We report an adolescent female patient with metastatic RMS of the breast from the anus. An 18-year-old female patient was referred to our clinic due to palpable mass in the left breast. At age seven, she was diagnosed with acute lymphoblastic leukemia and treated with chemoradiation therapy. After 10 years of complete remission state, she presented with anal mass which was diagnosed as RMS and she received chemoradiation therapy. After 1 year of complete remission state, she noticed a palpable mass in her left breast. The breast mass was diagnosed as metastatic RMS based on core needle biopsy specimen. The RMS in breast was excised for the decreasing tumor burden despite of another metastatic lesion. Although rarely reported, metastasis of RMS should be considered as a cause of breast mass. Tissue biopsy is recommended when clinically suspected lesion is detected.
doi:10.4048/jbc.2013.16.3.345
PMCID: PMC3800733  PMID: 24155766
Adolescent; Anus; Breast; Neoplasm metastasis; Rhabdomyosarcoma
13.  EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood 
Korean Journal of Pathology  2013;47(2):137-147.
Background
Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality.
Methods
Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed.
Results
STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis.
Conclusions
EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.
doi:10.4132/KoreanJPathol.2013.47.2.137
PMCID: PMC3647126  PMID: 23667373
Epstein-Barr virus infections; Lymphoma, T-cell; Killer cells, natural; Lymphoproliferative disorders; Clonality
14.  Therapy-Related Myeloid Neoplasms in 39 Korean Patients: A Single Institution Experience 
Annals of Laboratory Medicine  2013;33(2):97-104.
Background
Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea.
Methods
The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients.
Results
Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months).
Conclusions
In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.
doi:10.3343/alm.2013.33.2.97
PMCID: PMC3589647  PMID: 23483787
Therapy-related neoplasms; Myelodysplastic syndrome; Acute myeloid leukemia; Cytogenetics; Korea
15.  Blood Research: a new journey of passion with harmony beyond Asia onto the world 
Blood research  2013;48(1):3-4.
doi:10.5045/br.2013.48.1.3
PMCID: PMC3625004  PMID: 23589785
16.  A proposal for improvement in the utilization rate of banked cord blood 
Blood research  2013;48(1):5-7.
doi:10.5045/br.2013.48.1.5
PMCID: PMC3625003  PMID: 23589786
17.  Hematologic Recovery after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Children with High-Risk Solid Tumors 
Journal of Korean Medical Science  2013;28(2):220-226.
Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34+ cells transplanted during the first and second HDCT/autoSCT were 4.3 × 106/kg (range 0.6-220.2) and 4.1 × 106/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34+ cells was lower, especially if it was < 2 × 106/kg. A lower CD34+ cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34+ cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.
doi:10.3346/jkms.2013.28.2.220
PMCID: PMC3565133  PMID: 23400387
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; CD34+ Cells; Hematologic Recovery; Iron Overload
18.  MYC Rearrangement Involving a Novel Non-immunoglobulin Chromosomal Locus in Precursor B-cell Acute Lymphoblastic Leukemia 
Annals of Laboratory Medicine  2012;32(4):289-293.
MYC rearrangement, a characteristic cytogenetic abnormality of Burkitt lymphoma and several subsets of other mature B-cell neoplasms, typically involves an immunoglobulin gene partner. Herein, we describe a case of precursor B-cell lymphoblastic leukemia harboring a MYC rearrangement with a novel non-immunoglobulin partner locus. The patient was a 4-yr-old Korean boy with ALL of the precursor B-cell immunophenotype. At the time of the second relapse, cytogenetic analyses revealed t(4;8)(q31.1;q24.1) as a clonal evolution. The MYC rearrangement was confirmed by FISH analysis. He died 3 months after the second relapse without achieving complete remission. To our knowledge, this is the first report of a case of MYC rearrangement with a non-immunoglobulin partner in precursor B-cell lymphoblastic leukemia.
doi:10.3343/alm.2012.32.4.289
PMCID: PMC3384811  PMID: 22779071
Precursor B-cell acute lymphoblastic leukemia; MYC gene rearrangement; Non-immunoglobulin partner
19.  Etoposide sensitizes neuroblastoma cells expressing caspase 8 to TRAIL 
TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is a promising agent for clinical use since it kills a wide range of tumour cells without affecting normal cells. We provide evidence that pretreatment with etoposide significantly enhanced TRAIL-mediated apoptosis via up-regulation of DR5 (death receptor 5 or TRAIL-R2) expression in the caspase 8 expressing neuroblastoma cell line, SK-N-MC. In addition, sequential treatment with etoposide and TRAIL increased caspases 8, 9 and 3 activation, Mcl-1 cleavage and Bid truncation, which suggests that the ability of etoposide and TRAIL to induce apoptosis is mediated through activation of an intrinsic signalling pathway. Although TRAIL-R2 expression increased in IMR-32 cells in response to etoposide treatment, cell death was not increased by concurrent treatment with TRAIL compared with etoposide alone, because the cells lacked caspase 8 expression. Restoration of caspase 8 expression by exposure to IFNγ (interferon γ) sensitizes IMR-32 cells to TRAIL. Moreover, pretreatment with etoposide increased TRAIL-induced apoptosis in caspase 8 restored IMR-32 cells through activation of a caspase cascade that included caspases 8, 9 and 3. These results indicate that the etoposide-mediated sensitization of neuroblastoma cells to TRAIL is associated with an increase in TRAIL-R2 expression and requires caspase 8 expression. These observations support the potential use of a combination of etoposide and TRAIL in future clinical trials.
doi:10.1042/CBR20110008
PMCID: PMC3475444  PMID: 23124518
caspase 8; death receptor; etoposide; inferferon γ; mitochondrial cascade; TRAIL; AzaC, 5-aza-2′ deoxycytidine; BCA, bicinchoninic acid; DD, death domain; DcR, decoy receptor; DR5, death receptor 5; FADD, Fas-associated death domain; FBS, fetal bovine serum; IFNγ, interferon γ; NF-κB, nuclear factor κB; PARP, poly(ADP-ribose) polymerase; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand
20.  Clinical and hematologic manifestations in patients with Diamond Blackfan anemia in Korea 
The Korean Journal of Hematology  2012;47(2):131-135.
Background
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.
Methods
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.
Results
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%).
Conclusion
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.
doi:10.5045/kjh.2012.47.2.131
PMCID: PMC3389062  PMID: 22783360
Diamond Blackfan anemia; Anemia; Congenital defects
21.  Successful and safe treatment of hemangioma with oral propranolol in a single institution 
Korean Journal of Pediatrics  2012;55(5):164-170.
Purpose
Dramatic improvement of hemangioma to propranolol has been recently reported; however, details on dose and duration of treatment, potential risks, and monitoring have not been determined. The objective of this study is to describe and analyze the use of propranolol as a first-line treatment or as a single therapy in management of complicated hemangioma.
Methods
A retrospective chart review of eight patients diagnosed with hemangioma and treated with propranolol in Kangbuk Samsung Hospital from February 2010 to April 2011 was performed.
Results
Eight patients with hemangioma with functional impairment, cosmetic disfigurement, or rapid growth were treated with propranolol. Five patients had solitary facial hemangioma. The mean age of symptoms at onset was 5 weeks. The median age for starting propranolol treatment was 5.5 months. Propranolol at 2 mg/kg/day was finally administered in divided doses with a gradual increase. Significant regression was observed in seven patients, and shrinkage in size, softening in consistency, and decrease in redness were evident within 4 weeks. Among them, six patients were still taking propranolol, and one patient had stopped after 12 months. Other one patient did not show significant improvement with satisfactory result after 3 months of propranolol use. Treatment with propranolol was well tolerated and had few side effects. No rebound growth was observed in any of the patients.
Conclusion
We observed that use of propranolol was very effective in treatment of hemangioma without obvious adverse effects or relapse.
doi:10.3345/kjp.2012.55.5.164
PMCID: PMC3362730  PMID: 22670151
Hemangioma; Propranolol; Treatment
22.  Iron Overload during Follow-up after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma 
Journal of Korean Medical Science  2012;27(4):363-369.
Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.
doi:10.3346/jkms.2012.27.4.363
PMCID: PMC3314847  PMID: 22468098
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; Iron Overload; Deferasirox; Iron Chelation Treatment; Neuroblastoma
23.  The metabolic syndrome and body composition in childhood cancer survivors 
Korean Journal of Pediatrics  2011;54(6):253-259.
Purpose
Long-term survivors of childhood cancer appear to have an increased risk for the metabolic syndrome, subsequent type 2 diabetes and cardiovascular disease in adulthood compared to healthy children. The purpose of this study was to investigate the frequency of the metabolic syndrome and associated factors in childhood cancer survivors at a single center in Korea.
Methods
We performed a retrospective review of medical records of 98 childhood cancer survivors who were diagnosed and completed anticancer treatment at Samsung Medical Center, Seoul, Korea between Jan. 1996 and Dec. 2007. Parameters of metabolic syndrome were evaluated between Jan. 2008 and Dec. 2009. Clinical and biochemical findings including body fat percentage were analyzed.
Results
A total of 19 (19.4%) patients had the metabolic syndrome. The median body fat percentage was 31.5%. The body mass index and waist circumference were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.00, respectively). Sixty-one (62.2%) patients had at least one abnormal lipid value. The triglyceride showed significant positive correlation with the body fat percentage (r=0.26, P=0.03). The high density lipoprotein cholesterol showed significant negative correlation with the percent body fat (r=-0.26, P=0.03).
Conclusion
Childhood cancer survivors should have thorough metabolic evaluation including measurement of body fat percentage even if they are not obese. A better understanding of the determinants of the metabolic syndrome during adolescence might provide preventive interventions for improving health outcomes in adulthood.
doi:10.3345/kjp.2011.54.6.253
PMCID: PMC3174361  PMID: 21949520
Cancer survivor; Metabolic syndrome; Body composition; Fat percentage
24.  Desmoplastic small round cell tumor of the stomach mimicking a gastric cancer in a child 
Journal of the Korean Surgical Society  2011;80(Suppl 1):S80-S84.
Intra-abdominal desmoplastic small round cell tumor (DSRCT) is a highly malignant tumor of uncertain histogenesis. Here we report a case of DSRCT involving the stomach, initially misdiagnosed as gastric cancer. A 12-year-old boy presented with upper abdominal pain developed 1 month prior. On gastroscopy, a 7-cm mass was noted involving the esophago-gastric junction to the fundus, and positron emission tomography showed multiple hot uptakes suggesting distant metastasis. Gastroscopic biopsy showed poorly differentiated malignant cells. We diagnosed as stage IV gastric cancer and treated with 6 cycles of chemotherapy. Laparotomy revealed a huge gastric mass along with peritoneal disseminations. Palliative proximal gastrectomy was performed. Pathological examination revealed transmural involvement of DSRCT, and t(11;22)(p12;q12) was demonstrated on fluorescence in situ hybridization test. The chemotherapeutic regimen was changed and the patient underwent 8 additional cycles of post-operative chemotherapy. The patient is now alive and the residual tumor shows no significant changes after chemotherapy.
doi:10.4174/jkss.2011.80.Suppl1.S80
PMCID: PMC3205364  PMID: 22066092
Stomach; Desmoplastic small round cell tumor; Children
25.  Efficacy of Itraconazole Prophylaxis for Autologous Stem Cell Transplantation in Children with High-Risk Solid Tumors: A Prospective Double-Blind Randomized Study 
Yonsei Medical Journal  2011;52(2):293-300.
Purpose
The risk of invasive fungal infection is greater for allogeneic hematopoietic stem cell transplantation (HSCT) than for autologous transplantation. Therefore, many transplantation centers use antifungal prophylaxis for allogeneic HSCT, however, there exists no standard guidelines or consensus regarding autologous HSCT.
Materials and Methods
A prospective double-blind randomized study was conducted in autologous HSCT recipients who were divided into prophylaxis and empirical treatment groups, and we investigated the efficacy of itraconazole prophylaxis in pediatric autologous HSCT.
Results
Total 87 autologous HSCT episodes in 55 children with high-risk solid tumors were studied. No invasive fungal infections occurred in either group. However, patients in the prophylaxis group had a significantly shorter duration of fever (p < 0.05) and received antibacterial treatment of shorter duration (p < 0.05) with fewer numbers of antibiotics (p < 0.05 for the use of second line antibiotics) than those in the empirical group. No significant additional adverse events were found with itraconazole prophylaxis.
Conclusion
Although beneficial effects such as a shorter duration of fever and reduced need for antibiotic use were observed in the prophylaxis group, the results were not sufficient to draw a definite recommendation about the routine use of antifungal prophylaxis in pediatric autologous HSCT recipients with high-risk solid tumors (Trial registration: NCT00336531).
doi:10.3349/ymj.2011.52.2.293
PMCID: PMC3051209  PMID: 21319349
Itraconazole; autologous transplantation; antifungal prophylaxis; solid tumor

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