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1.  Clinical Outcome of Relapsed or Refractory Burkitt Lymphoma and Mature B-Cell Lymphoblastic Leukemia in Children and Adolescents 
Purpose
Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients.
Materials and Methods
RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed.
Results
Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6±10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1±18.7%, vs. 16.7±10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05).
Conclusion
Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients.
doi:10.4143/crt.2013.047
PMCID: PMC4206068  PMID: 25043820
Burkitt lymphoma; Recurrence; Children
2.  Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Young Children with Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System 
Journal of Korean Medical Science  2012;27(2):135-140.
The feasibility and effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) were evaluated in children younger than 3 yr of age with atypical teratoid/rhabdoid tumors (ATRT). Tandem HDCT/autoSCT was administered following six cycles of induction chemotherapy. Radiotherapy (RT) was administered if the tumor relapsed or progressed, otherwise, it was administered after 3 yr of age. Tumors relapsed or progressed during induction chemotherapy in 5 of 9 patients enrolled; 3 of these 5 received tandem HDCT/autoSCT as a salvage treatment. One patient died from sepsis during induction chemotherapy. The remaining 3 patients proceeded to tandem HDCT/autoSCT; however, 2 of these patients showed tumor relapse/progression after tandem HDCT/autoSCT. All 7 relapses/progressions occurred at primary sites even in patients with leptomeningeal seeding. Toxicities during tandem HDCT/autoSCT were manageable. A total of 5 patients were alive with a median follow-up of 20 (range 16-70) months from diagnosis. Four of 5 patients who received RT after relapse/progression are alive. The probability of overall survival at 3 yr from diagnosis was 53.3% ± 17.3%. Our tandem HDCT/autoSCT is feasible; however, early administration of RT prior to tandem HDCT/autoSCT should be considered to improve the outcome after tandem HDCT/autoSCT.
doi:10.3346/jkms.2012.27.2.135
PMCID: PMC3271285  PMID: 22323859
Rhabdoid Tumor; Central Nervous System; Drug Therapy; Stem Cell Transplantation; Radiotherapy; Child
3.  A Novel Mutation in the GATA1 Gene Associated with Acute Megakaryoblastic Leukemia in a Korean Down Syndrome Patient 
Journal of Korean Medical Science  2008;23(6):1105-1108.
Although acquired mutations in the GATA1 gene have been reported for Down syndrome-related acute megakaryoblastic leukemia (DS-AMKL) in Caucasians, this is the first report of a Korean Down syndrome patient with AMKL carrying a novel mutation of the GATA1 gene. A 3-yr-old Korean girl with Down syndrome was admitted to our hospital complaining of pallor and fever. The findings of a peripheral blood smear and bone marrow study were compatible with the presence of AMKL. A chromosome study showed 48,XX,-7,+21c,+21,+r[3]/47,XX,+21c[17]. Following GATA1 gene mutation analysis, a novel mutation, c.145dupG (p.Ala49GlyfsX18), was identified in the N-terminal activation domain of the GATA1 gene. This mutation caused a premature termination at codon 67 and expression of an abnormal GATA-1 protein with a defective N-terminal activation domain, and the absence of full-length GATA-1 protein. This case demonstrates that a leukemogenic mechanism for DS-AMKL is contributed by a unique collaboration between overexpressed genes from trisomy 21 and an acquired GATA1 mutation previously seen in Caucasians and now in a Korean patient.
doi:10.3346/jkms.2008.23.6.1105
PMCID: PMC2610649  PMID: 19119459
Leukemia, Megakaryoblastic, Acute; Down Syndrome; GATA1 Transcription Factor; Korea
4.  Staphylococcal Endocarditis Presenting with a Renal Infarct in a Patient with Acute Lymphoblastic Leukemia 
We present here a patient with acute lymphoblastic leukemia (ALL) and who developed infective endocarditis during induction chemotherapy with prednisolone, L-asparaginase (Leunase®), vincristine and adriamycin. The patient did not have a history of a central venous catheter. Sharp flank pain and fever occurred on the 25th day of induction chemotherapy. In addition, a renal infarct and movable vegetations on the mitral valve were detected on the abdominal computed tomography (CT) and echocardiography. S. aureus was identified in the cultured blood. While the patient achieved remission, follow-up echocardiography revealed the vegetation had increased in size and an abscess pocket had developed despite the antibiotics and heparin therapy. Consequently, ten days after the diagnosis of infective endocarditis, a successful mitral valvuloplasty was performed without complications. The patient is currently on maintenance chemotherapy while in remission.
doi:10.4143/crt.2008.40.3.151
PMCID: PMC2697465  PMID: 19688123
Precursor cell lymphoblastic leukemia-lymphoma; Staphylococcus aureus; Vegetation; Coagulation
5.  Bone morphogenetic protein 4 (BMP4) promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling 
Fertility and sterility  2013;100(5):1468-1475.
Objective
To test whether bone morphogenetic protein 4 (BMP4) directly regulates differentiation of adult mouse ovary-derived oogonial stem cells (OSCs) in vitro.
Design
Animal study.
Setting
Research laboratory.
Animal(s)
Adult C57BL/6 female mice.
Intervention(s)
After purification from adult ovaries by fluorescence-activated cell sorting (FACS), OSCs were cultured without or with BMP4 in the absence or presence of the BMP4 antagonist, Noggin.
Main outcome measure(s)
Rates of in vitro-derived (IVD) oocyte formation and changes in gene expression were assessed.
Result(s)
Cultured OSCs expressed BMP receptor (BMPR) 1A (BMPR1A), BMPR1B and BMPR2, suggesting that BMP signaling can directly affect OSC function. In agreement with this, BMP4 significantly increased the number of IVD-oocytes formed by cultured OSCs in a dose-dependent manner, and this response was inhibited in a dose-dependent fashion by co-treatment with Noggin. Exposure of OSCs to BMP4 was associated with rapid phosphorylation of BMPR-regulated Smad1/5/8 protein, and this response was followed by increased expression of the meiosis initiation factors, stimulated by retinoic acid gene 8 (Stra8), muscle-segment homeobox 1 (Msx1) and Msx2. In keeping with the IVD-oocyte formation data, the ability of BMP4 to activate Smad1/5/8 signaling and meiotic gene expression in OSCs was abolished by co-treatment with Noggin.
Conclusion(s)
Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD-oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes.
doi:10.1016/j.fertnstert.2013.07.1978
PMCID: PMC4266321  PMID: 23993924
BMP4; oogenesis; oocyte; germ cells; stem cells
6.  Denys-Drash syndrome, septated vagina and low level of anti-Mullerian hormone in male neonate 
There is a wide variety of genital abnormalities observed in patients with Denys-Drash syndrome (DDS). WT1 is thought to influence the genes related to genital development and mutations in this gene have been associated with DDS. DDS should be considered in the differential diagnosis of newborns with genital anomalies. In contrast to other conditions with 46,XY disorders of sex development, individuals with DDS often have duplicated genital organs (a double vagina, cervix or uterus). A double uterus has not yet been reported with 1390G>A (Arg464 Asn) mutation. However, duplicated genitals have been reported with other genetic mutations in patients with DDS. The duplicated genitals in DDS may be associated with low anti-Mullerian hormone (AMH) secretion. Measurement of the AMH levels may add to our understanding of variations in genital development and their abnormalities in disorders such as DDS. In conclusion, this is first case of low level of AMH and double uterus in 1390G>A (Arg464 Asn) mutations of DDS male.
doi:10.6065/apem.2014.19.2.100
PMCID: PMC4114052  PMID: 25077094
Wilms tumor gene; Denys Drash Syndrome; Anti-Mullerian hormone
7.  The Role for Runt Related Transcription Factor 2 (RUNX2) as a Transcriptional Repressor in Luteinizing Granulosa Cells 
Molecular and cellular endocrinology  2012;362(0):10.1016/j.mce.2012.06.005.
Transcription factors induced by the LH surge play a vital role in reprogramming the gene expression in periovulatory follicles. The present study investigated the role of RUNX2 transcription factor in regulating the expression of Runx1, Ptgs2, and Tnfaip6 using cultured granulosa cells isolated from PMSG-primed immature rats. hCG or forskolin+PMA induced the transient increase in Runx1, Ptgs2, and Tnfaip6 expression, while the expression of Runx2 continued to increase until 48 h. The knockdown of the agonist-stimulated Runx2 expression increased Runx1, Ptgs2, and Tnfaip6 expression and PGE2 levels in luteinizing granulosa cells. Conversely, the over-expression of RUNX2 inhibited the expression of these genes and PGE2 levels. The mutation of RUNX binding motifs in the Runx1 promoter enhanced transcriptional activity of the Runx1 promoter. The knockdown and overexpression of Runx2 increased and decreased Runx1 promoter activity, respectively. ChlP assays revealed the binding of RUNX2 in the Runx1 and Ptgs2 promoters. Together, these novel findings provide support for the role of RUNX2 in down-regulation of Runx1, Ptgs2, and Tnfaip6 during the late ovulatory period to support proper ovulation and/or luteinization.
doi:10.1016/j.mce.2012.06.005
PMCID: PMC3864655  PMID: 22713854
Runx2; Runx1; Ptgs2; Tnfaip6; Granulosa cells; LH; Ovary
8.  Gastric Autoantigenic Proteins in Helicobacter Pylori Infection 
Yonsei Medical Journal  2013;54(6):1342-1352.
Purpose
This study tried to identify novel gastric autoimmune antigens that might be involved in aggravating the atrophic gastritis among patients with Helicobacter pylori infection using two-dimensional immunoblotting analysis.
Materials and Methods
Proteins from gastric mucosal antrectomy specimens and AGS cells (gastric adenocarcinoma cell lines derived from a Caucasian patient who had received no prior therapy) were 2-dimensionally immunoblotted separately with a pool of 300 sera from H. pylroi-infected patients at Gyeongsang National University Hospital.
Results
Thirty-eight autoantigenic proteins including alcohol dehydrogenase [NADP+], alpha enolase, gastrokine-1, gastric triacylglycerol lipase, heat shock 70 kDa protein 1, and peroxiredoxin-2 were identified in the gastric mucosal tissue. Fourteen autoantigenic proteins including programmed cell death 6-interacting protein, serum albumin and T-complex protein 1 subunit gamma were identified in the AGS cells. Albumin, alpha-enolase, annexin A3, cytoplasmic actin 1, heat shock cognate 71 kDa protein and leukocyte elastase inhibitor were commonly observed autoantigenic proteins in both gastric mucosal tissue and AGS cells. Alpha-enolase, glutathione S-transferase P, heat shock cognate 71 kDa protein, heat shock 70 kDa protein 1, human mitochondrial adenosine triphosphate synthase (ATP) subunit beta, mitochondrial 60 kDa heat shock protein, peroxiredoxin-2, 78 kDa glucose-regulated protein precursor, tyrosine-protein phosphatase non-receptor type 11 and Tryptophan-Aspartic acid (WD) repeat-containing protein 1 showed 60% or higher amino acid positivity.
Conclusion
These newly identified gastric autoimmune antigens might be useful in the control and prevention of gastroduodenal disorders, and might be valuable in breaking the vicious circle that exists in gastroduodenal disorders if their pathophysiological roles could be understood in the progress of chronic atrophic gastritis, gastroduodenal ulcers, intestinal metaplasia, and gastric carcinogenesis.
doi:10.3349/ymj.2013.54.6.1342
PMCID: PMC3809852  PMID: 24142637
Helicobacter pylori; gastric atrophy; autoantigen; 2D immunoblotting
9.  Hereditary hemolytic anemia in Korea from 2007 to 2011: A study by the Korean Hereditary Hemolytic Anemia Working Party of the Korean Society of Hematology 
Blood research  2013;48(3):211-216.
Background
The number of patients diagnosed with hereditary hemolytic anemia (HHA) has increased since the advent of novel diagnostic techniques that accurately identify this disorder. Here, we report data from a survey on the prevalence and characteristics of patients diagnosed with HHA in Korea from 2007 to 2011.
Methods
Information on patients diagnosed with HHA in Korea and their clinical and laboratory results were collected using a survey questionnaire. Globin gene and red blood cell (RBC) enzyme analyses were performed. In addition, we analyzed data collected by pediatricians.
Results
In total, 195 cases of HHA were identified. Etiologies identified for HHA were RBC membranopathies, hemoglobinopathies, and RBC enzymopathies, which accounted for 127 (64%), 39 (19.9%), and 26 (13.3%) cases, respectively. Of the 39 patients with hemoglobinopathies, 26 were confirmed by globin gene analysis, including 20 patients with β-thalassemia minor, 5 patients with α-thalassemia minor, and 1 patient with unstable hemoglobin disease.
Conclusion
The number of patients diagnosed with hemoglobinopathies and RBC enzymopathies has increased considerably since the previous survey on HHA in Korea, dated from 1997 to 2006. This is likely the result of improved diagnostic techniques. Nevertheless, there is still a need for more sensitive diagnostic tests utilizing flow cytometry and for better standardization of test results to improve the accuracy of diagnosis of RBC membranopathies in Korea. Additionally, more accurate assays for the identification of RBC enzymopathies are warranted.
doi:10.5045/br.2013.48.3.211
PMCID: PMC3786282  PMID: 24086942
Congenital hemolytic anemia; Hereditary spherocytosis; Thalassemia; Congenital nonspherocytic anemia
10.  Kawasaki disease in infants 
Korean Journal of Pediatrics  2013;56(9):377-382.
Kawasaki disease (KD) is an acute febrile illness that is the predominant cause of pediatric acquired heart disease in infants and young children. Because the diagnosis of KD depends on clinical manifestations, incomplete cases are difficult to diagnose, especially in infants younger than 1 year. Incomplete clinical manifestations in infants are related with the development of KD-associated coronary artery abnormalities. Because the diagnosis of infantile KD is difficult and complications are numerous, early suspicion and evaluation are necessary.
doi:10.3345/kjp.2013.56.9.377
PMCID: PMC3819680  PMID: 24223598
Kawasaki disease; Diagnosis; Infant
11.  Orthostatic symptoms does not always manifest during tilt-table test in pediatric postural orthostatic tachycardia syndrome patients 
Korean Journal of Pediatrics  2013;56(1):32-36.
Purpose
Chronic day-to-day symptoms of orthostatic intolerance are the most notable features of postural orthostatic tachycardia syndrome (POTS). However, we have encountered patients with such symptoms and excessive tachycardia but with no symptoms during the tilt-table test (TTT). We aimed to investigate whether POTS patients with chronic orthostatic intolerance always present orthostatic symptoms during the TTT and analyze the factors underlying symptom manifestation during this test.
Methods
We retrospectively examined patients who presented with POTS at the Gyeongsang National University Hospital between 2008 and 2011. Diagnosis of POTS was based on chronic day-to-day orthostatic intolerance symptoms as well as excessive tachycardia during the TTT. The patients were divided two groups depending on the presentation of orthostatic symptoms during the TTT. Clinical data and the results of the TTT were compared between these groups.
Results
In 22 patients, 7 patients (31.8%) did not present orthostatic symptoms during the test. Diastolic blood pressure (BP) was significantly lower in the symptom-positive group. The head-up tilt resulted in a significant increase in diastolic BP in the symptom-negative group (P=0.04), while systolic BP had a tendency to decrease in the symptom-positive group (P=0.06).
Conclusion
Significant patients with POTS did not present orthostatic symptoms during the TTT despite having chronic daily symptoms. This finding may be important for establishing definitive diagnostic criteria for pediatric POTS. Development of symptoms during TTT might be related to low diastolic BP and abnormal compensatory responses to orthostasis.
doi:10.3345/kjp.2013.56.1.32
PMCID: PMC3564028  PMID: 23390443
Postural orthostatic tachycardia syndrome; Tilt-table test; Diastolic blood pressure
12.  Signal change in hippocampus and current source of spikes in Panayiotopoulos syndrome 
Korean Journal of Pediatrics  2012;55(2):63-67.
A 4-year-old girl with Panayiotopoulos syndrome presented with a history of 4 prolonged autonomic seizures. The clinical features of her seizures included, in order of occurrence, blank staring, pallor, vomiting, hemi-clonic movement on the right side, and unresponsiveness. A brain magnetic resonance imaging (MRI) showed a slightly high T2 signal in the left hippocampus. Interictal electoencephalogram revealed spikes in the occipital area of the left hemisphere. We analyzed the current-source distribution of the spikes to examine the relationship between the current source and the high T2 signal. The current source of the occipital spikes was not only distributed in the occipital area of both cerebral hemispheres, but also extended to the posterior temporal area of the left hemisphere. These findings suggest that the left temporal lobe may be one of the hyperexcitable areas and form part of the epileptogenic area in this patient. We hypothesized that the high T2 signal in the left hippocampus of our patient may not have been an incidental lesion, but instead may be related to the underlying electroclinical diagnosis of Panayiotopoulos syndrome, and particularly seizure. This notion is important because an abnormal T2 signal in the hippocampus may represent an acute stage of hippocampal injury, although there is no previous report of hippocampal pathology in Panayiotopoulos syndrome. Therefore, long-term observation and serial follow-up MRIs may be needed to confirm the clinical significance of the T2 signal change in the hippocampus of this patient.
doi:10.3345/kjp.2012.55.2.63
PMCID: PMC3286765  PMID: 22375152
Electroencephalography; Hippocampus; Childhood benign focal epilepsy
13.  Treatment outcomes in children with Burkitt lymphoma and L3 acute lymphoblastic leukemia treated using the lymphoma malignancy B protocol at a single institution 
The Korean Journal of Hematology  2011;46(2):96-102.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.5045/kjh.2011.46.2.96
PMCID: PMC3128907  PMID: 21747881
Burkitt lymphoma; L3 lymphocytic leukemia; Treatment outcome; Prognosis
14.  Novel influenza A (H1N1) 2009 infection in the pediatric patients with hematologic and oncologic diseases in the Yeungnam region 
Korean Journal of Pediatrics  2011;54(3):117-122.
Purpose
Natural history and consequences of the novel 2009 influenza A H1N1 (2009 H1N1) infection in immunocompromised pediatric patients are not yet fully understood. In this study, we investigated the clinical features and outcomes of the 2009 H1N1 infection in pediatric patients with hematological and oncological diseases.
Methods
We retrospectively reviewed the medical records of 528 patients who had hematological and oncological diseases and who were treated at 7 referral centers located in the Yeungnam region. Among the 528 patients, 27 with definite diagnosis of 2009 H1N1 infection were the subjects of this study. All patients were divided into the following 3 groups: patients who were receiving chemotherapy (group 1), patients who were immunosuppressed due to a non-malignant hematological disease (group 2), and patients who were off chemotherapy and had undergone their last chemotherapy course within 2 years from the influenza A pandemic (group 3).
Results
All 28 episodes of 2009 H1N1 infection were treated with the antiviral agent oseltamivir (Tamiflu®), and 20 episodes were treated after hospitalization. Group 1 patients had higher frequencies of lower respiratory tract infection and longer durations of fever and hospitalization as compared to those in group 2. Ultimately, all episodes resolved completely with no complications.
Conclusion
These results suggest that early antiviral therapy did not influence the morbidity or mortality of pediatric patients with hematological and oncological diseases in the Yeungnam region of Korea after the 2009 H1N1 infection. However, no definite conclusions can be drawn because of the small sample size.
doi:10.3345/kjp.2011.54.3.117
PMCID: PMC3120997  PMID: 21738541
Influenza A Virus; H1N1 Subtype; Immunocompromised Patients; Hematologic Diseases; Oseltamivir; Child
15.  Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors 
Journal of Korean Medical Science  2010;25(9):1336-1342.
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.
doi:10.3346/jkms.2010.25.9.1336
PMCID: PMC2923785  PMID: 20808678
Dexrazoxane; Doxorubicin; Cardiotoxicity; Child; Solid Tumors
16.  STI571 SENSITIZES BREAST CANCER CELLS TO 5-FLUOROURACIL, CISPLATIN AND CAMPTOTHECIN IN A CELL TYPE-SPECIFIC MANNER 
Biochemical pharmacology  2009;78(3):249-260.
Previously, we demonstrated that Abl kinases are highly active in invasive breast cancer cell lines, and contribute to survival in response to nutrient deprivation, invasion and proliferation. To determine whether an Abl kinase inhibitor, STI571 (Gleevec; imatinib mesylate) sensitizes breast cancer cells to chemotherapeutic agents, we treated three breast cancer cell lines (BT-549, MDA-MB-231, and MDA-MB-468) that have active Abl kinases, with STI571 in combination with several conventional chemotherapeutic drugs frequently used to treat breast cancer, and assessed the effect on cell viability, proliferation, and apoptosis. We found that STI571 had synergistic effects with cisplatin in BT-549 and to some extent in MDA-MB-468 cells, STI571 synergized with camptothecin using an alternate dosing regimen in MDA-MB-231 cells, and STI571 synergistically sensitized MDA-MB-468 cells to paclitaxel and to high doses of 5-fluorouracil. Significantly, STI571 increased the ability of cisplatin to inhibit constitutive activation of PI3K/Akt, synergized with camptothecin to increase the stability of IκB in MDA-MB-231 cells, and in MDA-MB-468 cells, camptothecin and 5-fluorouracil inhibited STI571-dependent activation of STAT3. In other cell line/drug combinations, STI571 had additive or antagonistic effects, indicating that the ability of STI571 to sensitize breast cancer cells to chemotherapeutic agents is cell type-dependent. Significantly, unlike cisplatin, paclitaxel, and camptothecin, mechloroethamine was strongly antagonistic to STI571, and the effect was not cell line-dependent. Taken together, these data indicate that the cellular milieu governs the response of breast cancer cells to STI571/chemotherapeutic combination regimens, which suggests that treatment with these combinations requires individualization.
doi:10.1016/j.bcp.2009.04.007
PMCID: PMC2735471  PMID: 19427998
STI571; cisplatin; camptothecin; 5-fluorouracil; breast cancer
17.  Successful treatment by exchange transfusion of a young infant with sodium nitroprusside poisoning 
Korean Journal of Pediatrics  2010;53(8):805-808.
Although sodium nitroprusside (SNP) is often used in pediatric intensive care units, cyanide toxicity can occur after SNP treatment. To treat SNP-induced cyanide poisoning, antidotes such as amyl nitrite, sodium nitrite, sodium thiosulfate, and hydroxycobalamin should be administered immediately after diagnosis. Here, we report the first case of a very young infant whose SNP-induced cyanide poisoning was successfully treated by exchange transfusion. The success of this alternative method may be related to the fact that exchange transfusion not only removes the cyanide from the blood but also activates detoxification systems by supplying sulfur-rich plasma. Moreover, exchange transfusion replaces cyanide-contaminated erythrocytes with fresh erythrocytes, thereby improving the blood's oxygen carrying capacity more rapidly than antidote therapy. Therefore, we believe that exchange transfusion might be an effective therapeutic modality for critical cases of cyanide poisoning.
doi:10.3345/kjp.2010.53.8.805
PMCID: PMC3004497  PMID: 21189979
Nitroprusside; Exchange transfusion; Cyanides; Poisoning; Detoxification; Infant
18.  Clinical and radiologic evaluation of cytomegalovirus-induced thrombocytopenia in infants between 1 and 6 months of age 
Background
Up to 90% of neonates with congenital or perinatal cytomegalovirus (CMV) infection are asymptomatic, and little is known about CMV-associated thrombocytopenia after the neonatal period. We investigated the clinical findings of a series of infants diagnosed with CMV infection and thrombocytopenia.
Methods
From July 2005 to July 2008, infants aged younger than 6 months with thrombocytopenia were screened for CMV infection, using CMV IgM. Those who were positive for CMV IgM were then tested for CMV IgG via polymerase chain reaction (PCR) for CMV and CMV pp65 Ag and urine culture. Brain magnetic resonance imaging (MRI) and otologic and ophthalmologic evaluations were also performed.
Results
Twenty-one patients aged between 1 and 6 months (11 boys and 10 girls) were admitted and tested for CMV infection. Six patients (28.6%) were positive for CMV IgM; these were also positive for CMV IgG, CMV PCR, and urine culture, and 4 were also positive for CMV pp65 Ag. The median platelet count at admission was 6,500/µL (range, 2,000-105,000/µL). One patient (16.7%) was diagnosed with Evans syndrome and had calcifications on brain MRI. One patient had unilateral sensorineural hearing loss.
Conclusion
Thrombocytopenia can be the main clinical manifestation of otherwise asymptomatic CMV infection after the neonatal period, and close follow-up of neurodevelopmental sequelae is needed.
doi:10.5045/kjh.2010.45.1.29
PMCID: PMC2983005  PMID: 21120160
Thrombocytopenia; Cytomegalovirus; Infant
19.  Kawasaki Disease Presenting as Parotitis in a 3-Month-Old Infant 
Korean Circulation Journal  2009;39(11):502-504.
A male infant aged 3 months and 1 week had persistently high fever with parotitis that was unresponsive to antibiotics. Mumps was identified by serologic study, but he was finally diagnosed by clinical features as having Kawasaki disease and echocardiographic findings on the 9th day of fever. Parotitis, which is unresponsive to antibiotics, should be considered Kawasaki disease even though typical symptoms are not present.
doi:10.4070/kcj.2009.39.11.502
PMCID: PMC2790127  PMID: 19997548
Kawasaki disease; Mumps; Parotitis
20.  Improved Survival in Patients with Recurrent Wilms Tumor: the Experience of the Seoul National University Children's Hospital 
Journal of Korean Medical Science  2006;21(3):436-440.
The survival in cases with relapsed Wilms tumor is dismal. Recently, however the introduction of new therapeutic agents and experimental strategies has improved the survival. We analysed the survival of patients with relapsed Wilms tumor according to the treatment period. During the early period 1983-1993, patients who had received two drugs were treated with doxorubicin and the others were treated with cisplatin and etoposide, whereas during the late period 1994-2004, patients were treated with combinations of cyclophosphamide/etoposide and carboplatin/etoposide. During the early period, 8 of 57 experienced relapse, and 8 of 41 relapsed during the late period. Only 2 patients treated during the early period survived in complete response (CR), whereas during the late period, 5 patients remained alive in CR, and 3 of those received high-dose chemotherapy (HDC) with autologous peripheral stem cell rescue (SCR). The estimated 5 yr event-free survival rate was 37.5% in the entire study group, 50% for patients in the late period, and 25% for patients in the early period (p=0.38). The survival in patients with relapsed Wilms tumor dramatically improved during the late period and HDC with SCR was one of the effective salvage strategies.
doi:10.3346/jkms.2006.21.3.436
PMCID: PMC2729947  PMID: 16778385
Wilms Tumor; Nephroblastoma; Recurrence; Salvage Therapy; Stem Cells
21.  Carboxypeptidase-G2 Rescue in a Patient with High Dose Methotrexate-induced Nephrotoxicity 
A 13 year-old girl with osteosarcoma and pulmonary tumor recurrence developed acute renal failure following high dose methotrexate (12 g/m2) therapy, she had previously tolerated high dose methotrexate and her renal and hepatic functions were normal. Briefly, 48 hours after beginning methotrexate infusion her methotrexate concentration and creatinine level were 1338.8 µM/L and 5.8 mg/dl, respectively. Grade IV oral mucositis and neutropenia with fever developed at 144 hours after MTX infusion. Hydration and alkalinization were continued and leucovorin rescue was intensified based on the plasma MTX concentrations. Plasma exchange was performed twice and hemodialysis 3 times without problems, but methotraxate and creatinine levels remained high, 91.9 µM/L, and 2.5 mg/dl, respectively. After 3 courses of hemodialysis carboxypeptidase-G2 (CPDG2) was administered at 50 U/kg, intravenously over 5 minutes. After 15 minutes of CPDG2 (Voraxaze™) infusion, her plasma MTX concentration was 0.91 µM/L and no rebound elevation or side effects developed. Thirteen days post-MTX infusion her renal function had normalized. We report here our experience of a dramatic methotrexate level reduction caused by CPDG2 administration.
doi:10.4143/crt.2005.37.2.133
PMCID: PMC2785403  PMID: 19956493
High dose methotrexate; Acute renal failure; Leucovorin; Carboxypeptidase-G2

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