Kyu-Chang Wang

Seoul National University, Sŏul, Seoul, South Korea

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Publications (221)612.2 Total impact

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    ABSTRACT: OBJECTIVE In a minority of patients with neurofibromatosis Type 1 (NF-1), cerebral vasculopathy reminiscent of moyamoya disease develops. This phenomenon is called moyamoya syndrome (MMS), but there are no known risk factors for the prediction of MMS in NF-1 patients. Polymorphism of the RNF213 gene has exhibited strong associations with familial and sporadic moyamoya disease and other cerebral vasculopathies. The aim of this study is to find whether the RNF213 c.14576G>A variant is associated with MMS development in the NF-1 population or not. METHODS The MMS group included 16 NF-1 patients with documented MMS. The control group consisted of 97 NF-1 patients without MMS. Genomic DNA samples were obtained from the saliva or blood of both groups, and the presence of the RNF213 c.14576G>A variant was assessed by Sanger sequencing. RESULTS In the MMS group, 3 patients had the RNF213 c.14576G>A variant (18.7%), whereas no patients with this genetic variation were observed in the control group (0%). There was a meaningful association between the RNF213 c.14576G>A variant and MMS development (p = 0.0024). The crude odds ratio was calculated as 50.57 (95% CI 1.57-1624.41). All 3 patients with MMS and the c.14576G>A variant were diagnosed with MMS at an early age and had bilateral involvement. CONCLUSIONS The RNF213 c.14576G>A variant is more common in NF-1 patients who develop MMS than in NF-1 patients without MMS. This variant might be a susceptibility gene for the NF-1-moyamoya connection.
    No preview · Article · Feb 2016 · Journal of Neurosurgery Pediatrics
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    ABSTRACT: The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
    Full-text · Article · Jan 2016 · Nature
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    ABSTRACT: Background The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. During this process, the role of microRNAs (miRs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify the miR involved in leptomeningeal dissemination and to elucidate its biological functional mechanisms.Materials and methodsWe analyzed the miR expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. Differentially expressed miRs (DEmiRs) were validated in 29 medulloblastoma tissues and three medulloblastoma cell lines. The biological functions of the selected miRs were evaluated using in vitro and in vivo studies.ResultsA total of 12 DEmiRs were identified in medulloblastoma with seeding, including miR-192. The reduced expression of miR-192 was confirmed in the tumor seeding group and in the medulloblastoma cells. Overexpression of miR-192 inhibited cellular proliferation by binding DHFR. miR-192 decreased cellular anchoring via the repression of ITGAV, ITGB1, ITGB3, and CD47. Animals in the miR-192-treated group demonstrated a reduction of spinal seeding (P < 0.05) and a significant survival benefit (P < 0.05).Conclusions Medulloblastoma with seeding showed specific DEmiRs compared with those without. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring ability.
    Preview · Article · Oct 2015 · Oncotarget
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    ABSTRACT: The long-term clinical outcome of pediatric intracranial epepdymoma is poor with a high rate of recurrence. One of the main reasons for this poor outcome is the tumor's inherent resistance to chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. Knockdown of STAT3 was tried to confirm the effects of STAT3 inhibition in ependymoma cells. High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin, ifosfamide, and etoposide. Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. WP1066 effectively abrogated p-STAT3 expression. An increased apoptosis and decreased Survivin expression were observed after WP1066 treatment. Knockdown of STAT3 also decreased cell survival, supporting the critical role of STAT3 in sustaining ependymoma cells. In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoma BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application.
    Preview · Article · Oct 2015 · Translational oncology
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    ABSTRACT: Purpose: The aim of this study was to elucidate the differences in clinical and radiological manifestations and treatment outcomes of pediatric Chiari I malformation patients according to age. Methods: We retrospectively reviewed the patients who received surgery in our institution for symptomatic Chiari I malformations between January 1991 and December 2012. Fifty-four patients were identified, and their medical records were reviewed for clinical presentation, radiological findings, surgical treatment, and outcomes including complications. We divided the patients into 3 groups: Group I (n = 4) younger than 3 years old; Group II (n = 9) between 3 and 5 years old; and Group III (n = 41) older than 5 years old. Surveyed data were compared among the groups. The mean follow-up period was 82.8 months. Results: All of Group I patients presented with stem compression signs. Ventriculomegaly was common (3/4, 75 %), but no syrinx or scoliosis was observed. In Group II, scoliosis was the most common presentation (5/9, 56 %), and these patients rarely complained any other symptoms. Pain, such as headache (18/41, 44 %), was the predominant presentation in Group III. The incidences of syrinx and scoliosis were similar in Groups II and III. There were no differences in the treatment outcomes among the groups. The spinal curve did not improve in 4 of 5 Group II patients despite their early FMD surgeries. The incidence of complications related to cerebrospinal fluid leakage was higher in the young age group. Conclusions: The clinical and radiological manifestations of pediatric Chiari I malformation appeared to be different according to age.
    No preview · Article · Aug 2015 · Child s Nervous System

  • No preview · Conference Paper · Aug 2015
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    Full-text · Article · Aug 2015 · Cancer Research
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    Ji Yeoun Lee · Seung-Ki Kim · Ji Hoon Phi · Kyu-Chang Wang
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    ABSTRACT: The majority of clinical studies on moyamoya disease (MMD) have focused on anterior circulation. The disease involvement of posterior circulation in MMD, mainly in the posterior cerebral artery (PCA), has been mentioned since the early 1980s, and it has been repeatedly emphasized as one of the most important factors related to poor prognosis in MMD. However, its clinical features and outcome have only been elucidated during the last few years. In this review, the angiographic definition of PCA stenosis is summarized. The clinical features are elucidated as being either early-onset or delayed-onset, according to the time of PCA stenosis diagnosis in reference to the anterior circulation revascularization surgeries. The surgical strategy and hypothesis on the mechanism of PCA stenosis is also briefly mentioned. It appears that some MMD patients may show PCA stenosis during the early or late course of the disease and that the presenting symptoms may vary. Because the hemodynamic compromise caused by PCA stenosis may respond well to surgical treatment, clinicians should be aware of the condition, especially during follow-up of MMD patients.
    Preview · Article · Jun 2015 · Journal of Korean Neurosurgical Society
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    Ji Hoon Phi · Kyu-Chang Wang · Ji Yeoun Lee · Seung-Ki Kim
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    ABSTRACT: Moyamoya-like vasculopathy develops in association with various systemic diseases and conditions, which is termed moyamoya syndrome. Relatively common diseases and conditions are related to moyamoya syndrome, including neurofibromatosis type 1, Down syndrome, thyroid disease, and cranial irradiation. Moyamoya syndrome shares phenotypical characteristics with idiopathic moyamoya disease. However, they differ in other details, including clinical presentations, natural history, and treatment considerations. The study of moyamoya syndrome can provide clinicians and researchers with valuable knowledge and insight. Although it is infrequently encountered in clinical practice, moyamoya-like vasculopathy can severely complicate outcomes for patients with various underlying diseases when the clinician fails to expect or diagnose moyamoya syndrome development. Furthermore, moyamoya syndrome could be used as a doorway to more enigmatic moyamoya disease in research. More comprehensive survey and investigation are required to uncover the secrets of all the moyamoya-like phenomena.
    Full-text · Article · Jun 2015 · Journal of Korean Neurosurgical Society
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    Hyun-Seung Kang · Kyu-Chang Wang · Seung-Ki Kim
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    ABSTRACT: Various approaches have been attempted in translational moyamoya disease research. One promising material for modeling and treating this disease is vascular progenitor cells, which can be acquired and expanded from patient peripheral blood. These cells may provide a novel experimental model and enable us to obtain insights regarding moyamoya disease pathogenesis. We briefly present the recent accomplishments in regard to the studies of vascular progenitor cells in moyamoya disease.
    Preview · Article · Jun 2015 · Journal of Korean Neurosurgical Society
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    Seung-Ki Kim · Kyu-Chang Wang

    Preview · Article · Jun 2015 · Journal of Korean Neurosurgical Society
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    ABSTRACT: Moyamoya disease (MMD) is a common cause of childhood stroke, in which the abnormal function of the endothelial colony-forming cell (ECFC) plays a key role in the pathogenesis of the disease. This study was designed to identify genes involved in MMD pathogenesis using gene expression profiling and to understand the defective function of MMD ECFCs. We compared gene expression profiles of ECFCs isolated from patients with MMD and normal controls. Among the differentially expressed genes, we selected a gene with the most downregulated expression, retinaldehyde dehydrogenase 2 (RALDH2). The activity of RALDH2 in MMD ECFCs was assessed by in vitro tube formation assay and in vivo Matrigel plug assay in the presence of all-trans retinoic acid. The transcriptional control of RALDH2 was tested using ChIP assays on acetyl-histone H3. Through the gene expression profiling of 7 MMD ECFCs, we were able to identify 537 differentially expressed genes. Notably, the expression of RALDH2 was markedly suppressed in MMD ECFCs. MMD ECFCs inefficiently formed capillary tubes in vitro and capillaries in vivo, a defect restored by all-trans retinoic acid treatment. Knockdown of RALDH2 mRNA in normal ECFCs also induced decreased activity of capillary formation in vitro. The decreased level of RALDH2 mRNA in MMD ECFCs was attributed to defective acetyl-histone H3 binding to the promoter region. From these results, we conclude that the expression of RALDH2 was epigenetically suppressed in ECFCs from patients with MMD, which may play a key role in their functional impairment. © 2015 American Heart Association, Inc.
    No preview · Article · May 2015 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: Primary melanocytic lesions of the central nervous system originate from leptomeningeal melanocytes, with a spectrum ranging from well-differentiated benign meningeal melanocytomas to malignant melanomas. Atypical melanocytomas are borderline tumors, which have clinical and pathological characteristics between benign melanocytomas and malignant melanomas. Melanocytomas are rare in children and infrequently arise from the cavernous sinus. Approximately five patients with such an origin site have been reported. We report a 15-year-old girl with an atypical melanocytoma arising from the cavernous sinus. She underwent partial resection of the tumor and postoperative gamma knife surgery (GKS). She is stable 39 months after surgery. We discuss the first pediatric case with an intracranial atypical melanocytoma arising from the cavernous sinus.
    No preview · Article · May 2015 · Child s Nervous System
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    ABSTRACT: The location of a brain tumor is a fundamental characteristic, because various brain tumors develop in relatively specific locations. An atypical teratoid/rhabdoid tumor (AT/RT) is a highly age-specific tumor that occurs in infants and young children. However, AT/RTs develop in a variety of locations in the brain. This study aimed at uncovering the tumor location pattern of AT/RTs to enhance diagnoses. Neuroimages from 27 patients with a pathologically proven AT/RT were reviewed, and the specific tumor locations were described and categorized. The association of imaging characteristics and tumor location was analyzed. The posterior fossa was the most frequent locations accounting for 19 patients (70 %), followed by the diencephalon (four patients; 15 %), cerebrum (three patients; 11 %), and midbrain (one patient; 4 %). In the posterior fossa, the superior medullary velum (SMV) and cerebellopontine angle (CPA) areas were the most common sites (eight patients each) and three patients had a tumor in the inferior medullary velum (IMV) region. AT/RTs in the SMV area had a significantly higher chance of no/minimal enhancement compared with tumors in other locations (P = 0.001) and a lower likelihood of leptomeningeal tumor seeding at presentation (P = 0.053). The location spectrum of AT/RT follows a specific pattern, and some of the locations are linked with intriguing clinical characteristics. This information may not only help make correct preoperative diagnosis but also occasionally aid in postoperative pathological diagnosis.
    Full-text · Article · May 2015 · Child s Nervous System
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    Yun-Sik Dho · Seung-Ki Kim · Kyu-Chang Wang · Ji Hoon Phi
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    ABSTRACT: Congenital dermal sinus (CDS) is a type of occult spinal dysraphism characterized by a midline skin dimple. A 12-month-old girl presented with fever and ascending quadriparesis. She had a midline skin dimple in the upper sacral area that had been discovered in her neonatal period. Imaging studies revealed a holocord intramedullary abscess and CDS. Overlooking CDS or misdiagnosing it as benign sacrococcygeal dimple may lead to catastrophic infection and cause serious neurological deficits. Therefore, further imaging work-up or consultation with a pediatric neurosurgeon is recommended following discovery of any atypical-looking dimples in the midline.
    Preview · Article · Mar 2015 · Journal of Korean Neurosurgical Society
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    ABSTRACT: Purpose: Langerhans cell histiocytosis (LCH) arising from the skull base is a rare acute optic neuropathy cause. We describe a clinical approach for the purpose of optic nerve decompression and simultaneous lesion excision. This is the first case of visual improvement following decompression operation via endoscopic endonasal approach for acute optic neuropathy that is produced by LCH. Methods: An 11-year-old boy presented with a 2-week history of visual deterioration. Radiological evidence of compressive optic neuropathy by an expansile soft tissue mass around the optic canal was observed. The patient underwent an endoscopic endonasal optic nerve decompression and subtotal tumor removal. Results: His visual impairment improved dramatically after the operation. Conclusions: Acute optic neuropathy can be elicited by LCH arising in the sphenoid-ethmoid bone. Early decompression is the key to vision salvage. An endoscopic endonasal approach may be a good therapeutic option in this situation.
    Full-text · Article · Jan 2015 · Child s Nervous System
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    ABSTRACT: TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0174-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2014
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    ABSTRACT: Purpose: Cranial distraction osteogenesis (DO) has many advantages for correcting skull deformities: Thus, DO is extensively used for the treatment of skull deformities. However, diverse, unexpected complications are associated with this procedure. In this study, we present the surgical outcomes and complications of DO. Moreover, we propose a modified protocol for DO to reduce complications. Methods: This is a retrospective study on managed patients that underwent DO between March 2008 and May 2013. Their clinical courses were reviewed. Distraction protocols were individually inspected, and the final surgical outcomes, including complications, were evaluated. Results: During the study period, a total of ten patients (seven boys and three girls) were treated at our institute. The median distraction period was 20.5 days (ranging from 17 to 50 days). The range of total distraction length was 19-22 mm. The median consolidation period was 96 days (ranging from 0 to 343 days). All patients achieved the goals of distraction. At follow-up evaluations, all patients, except one, showed good surgical outcomes in both head shape and neurologic symptoms. There were six patients with wound complications during the treatment period. Among them, the distractors were removed early in three patients. Interestingly, even these three patients, without a sufficient consolidation period, showed good outcomes. Conclusions: Although DO has many merits for correcting skull deformities, it frequently causes severe wound complications. To reduce these complications, we propose a modified protocol with a minimal or even no consolidation period.
    No preview · Article · Dec 2014 · Child s Nervous System
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    ABSTRACT: Background: Atypical teratoid/rhabdoid tumors (AT/RT) are among the most malignant pediatric brain tumors. Cells from brain tumors with high aldehyde dehydrogenase (ALDH) activity have a number of characteristics that are similar to brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT. Methods: Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. The therapeutic effect of DSF against BTICs from AT/RT was confirmed in vitro and in vivo. Results: AT/RT cells displayed a high expression of ALDH. DSF demonstrated a more potent cytotoxic effect on ALDH(+) AT/RT cells compared with standard anticancer agents. Notably, treatment with DSF did not have a considerable effect on normal neural stem cells or fibroblasts. DSF significantly inhibited the ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, and proliferation potential and induced apoptosis and cell cycle arrest in ALDH(+) AT/RT cells. Importantly, DSF reduced the metabolism of ALDH(+) AT/RT cells by increasing the nicotinamide adenine dinucleotide ratio of NAD(+)/NADH and regulating Silent mating type Information Regulator 2 homolog 1 (SIRT1), nuclear factor-kappaB, Lin28A/B, and miRNA let-7g. Animals in the DSF-treated group demonstrated a reduction of tumor volume (P < .05) and a significant survival benefit (P = .02). Conclusion: Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application.
    No preview · Article · Nov 2014 · Neuro-Oncology
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    Kyu-Chang Wang
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    ABSTRACT: Thank you, Dachling, for the introduction. It is my great honor to be introduced by Dr. Pang.Prologue: Do you know this man?Do you know the man in Fig. 1?Fig. 1Mr. Ki-Moon Ban, the current secretary general of the United Nations (from the webpage of the United Nations, http://www.un.org/)Yes, he is Mr. Ki-Moon Ban who was born in 1944 in Korea before its liberation from Japan. At the age of 17, he had an opportunity to visit San Francisco as a winner of an English essay contest sponsored by the Red Cross. There, he met President John F. Kennedy and dreamed of being a diplomat. He, then, entered Seoul National University, majoring in international relations, and earned a master’s degree from the John F. Kennedy School of Government at Harvard University. In 2007, he became the secretary general of the United Nations (UN). He is now in his second term [1].Do you know the man in Fig. 2?Fig. 2Dr. Jong-Wook Lee, a former director general of the World Health Organization (courtesy of Jun-Woo ...
    Preview · Article · Nov 2014 · Child s Nervous System

Publication Stats

3k Citations
612.20 Total Impact Points

Institutions

  • 2003-2015
    • Seoul National University
      • • Department of Pediatrics
      • • College of Medicine
      Sŏul, Seoul, South Korea
  • 1995-2015
    • Seoul National University Hospital
      • • Department of Pediatric Neurosurgery
      • • Department of Neurosurgery
      • • Department of Internal Medicine
      Sŏul, Seoul, South Korea
  • 2010
    • Chung-Ang University
      Sŏul, Seoul, South Korea