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1.  Snail plays an oncogenic role in glioblastoma by promoting epithelial mesenchymal transition 
Background: The factors affecting glioblastoma progression are of great clinical importance since dismal outcomes have been observed for glioblastoma patients. The Snail gene is known to coordinate the regulation of tumor progression in diverse tumors through induction of epithelial mesenchymal transition (EMT); however, its role in glioblastoma is still uncertain. Therefore, we aimed to further define its role in vitro. Methods and results: The small interfering RNA (siRNA) technique was employed to knock down Snail expression in three glioblastoma cell lines (KNS42, U87, and U373). Specific inhibition of Snail expression increased E-cadherin expression but decreased vimentin expression in all cell lines. In addition, inhibition of the expression of Snail significantly reduced the proliferation, viability, invasion, and migration of glioblastoma cells as well as increased the number of cells in the G1 phase. Conclusions: Knockdown of Snail suppresses the proliferation, viability, migration, and invasion of cells as well as inhibits cell cycle progression by promoting EMT induction. The findings suggest that expression of this gene facilitates glioblastoma progression. Therefore, these results indicate the clinical significance of Snail for use as a potential therapeutic target for glioblastoma.
PMCID: PMC4069885  PMID: 24966907
Epithelial mesenchymal transition (EMT); glioblastoma; small interfering RNA (siRNA); Snail
2.  Genetic Grouping of Medulloblastomas by Representative Markers in Pathologic Diagnosis1 
Translational Oncology  2013;6(3):265-272.
A recent analysis of the genetic features of medulloblastoma (MB) suggested classification into distinct subgroups according to gene expression profiles, including the Wingless signaling pathway-activated group (WNT group), the Sonic Hedgehog signaling pathway-activated group (SHH group), group 3, and group 4. To classify MB according to genetic features in practice, we analyzed 74 MBs using representative markers of each group. Based on immunohistochemistries (IHC), cytogenetic alterations, and a CTNNB1 mutation study, the patients were divided into the following three groups: cases showing nuclear β-catenin and/or CTNNB1 mutation and/or monosomy 6 were included in the WNT group (14/74, 18.9%); cases expressing GAB1 were included in the SHH group (15/74, 20.2%); cases that did not show positivity for markers of the WNT or SHH group were included in the non-WNT/SHH group (45/74, 60.6%). Immunoexpression of NPR3 seemed to lack sensitivity for classifying group 3, showing diffuse positivity in only two cases. KCNA1 was not specific to group 4 because it was expressed in all groups. Cases in the WNT group showed a slightly better survival than those in the SHH or non-WNT/SHH group, although additional cases are required for statistical significance. Isochromosome 17q (P = .002) and the large cell/anaplastic variant (P = .002) were demonstrated to be poor prognostic indicators in multivariate analysis. The representative IHC and cytogenetic data facilitated the division of MBs into the WNT and SHH groups; however, more specific markers should be added for the identification of group 3 and group 4 in practice.
PMCID: PMC3660794  PMID: 23730405
3.  Alpha Internexin Expression Related with Molecular Characteristics in Adult Glioblastoma and Oligodendroglioma 
Journal of Korean Medical Science  2013;28(4):593-601.
Alpha-internexin (INA) is a proneuronal gene-encoding neurofilament interacting protein. INA is overexpressed mostly in oligodendroglial phenotype gliomas, is related to 1p/19q codeletion, and is a favorable prognostic marker. We studied INA expression in oligodendrogliomas (ODGs) and glioblastomas (GBMs) to verify its association with several molecular phenotypes, 1p/19q codeletion, and epidermal growth-factor-receptor (EGFR) amplification. A total of 230 low- and high-grade ODG and GBM cases was analyzed for INA expression by immunohistochemical staining; and 1p/19q and EGFR gene status was examined by fluorescence in-situ hybridization. INA was positive in 80.3% of ODGs and in 34.3% of GBMs. 1p/19q codeletion was detected in 77.0% of ODGs and 5.5% of GBMs. INA and 1p/19q codeletion were strongly correlated (P < 0.001). The specificity of INA expression for 1p/19q codeletion was 70.8%, while sensitivity was 100%; positive predictive value was 72.5%, and negative predictive value was 29.2% in all 228 tumors. INA expression was correlated with better progression-free survival (PFS) and overall survival (OS) (P = 0.001). In conclusion, INA expression has high specificity and sensitivity to predict 1p/19q codeletion, and it is well correlated with PFS of both ODGs and GBMs. Therefore, INA expression could be a simple, reliable, and favorable prognostic and surrogate marker for 1p/19q codeletion and long term survival.
doi:10.3346/jkms.2013.28.4.593
PMCID: PMC3617314  PMID: 23579442
Glioblastoma; Oligodendroglioma; Alpha-internexin, humans; 1p/19q Codeletion; EGFR protein, Human
4.  Ultrastructural Studies of Gastrointestinal Stromal Tumors 
Journal of Korean Medical Science  2004;19(2):234-244.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract (GIT). Although interstitial cells of Cajal has been suggested as origin of this tumor, the cytological and ultrastructural features of GISTs are heterogeneous and unclear. A total 10 cases of normal gastrointestinal tissue (control), 13 GISTs of the stomach (8), small intestine (3), mesocolon (1) and liver (1), and 2 gastrointestinal autonomic nervous tumor (GANT) of small intestine were ultrastructurally studied. Normal interstitial cells of Cajal (ICC) were abundantly present around the myenteric plexuses or individually scattered through the wall of GIT. ICC was characterized by slender cytoplasmic processes, well-developed endoplasmic reticulum (ER), mitochondria, Golgi apparatus, caveolae and intermediate filaments. The GISTs and GANTs had overlapping ultrastructures. The most common and important ultrastructural features of GISTs were rich villous cytoplasmic processes, dispersed intermediate filaments and abundant SER, and those of GANTs were neurosecretory granules and skenoid fibers. Compared with ICC, the GISTs and GANTs had remarkably reduced caveolae and gap junctions. Our study suggested that ultrastructural analysis gives much information to investigate lineage differentiation of neoplastic cells and make a differential diagnosis of these tumors from other mesenchymal tumors and between GISTs and GANTs.
doi:10.3346/jkms.2004.19.2.234
PMCID: PMC2822305  PMID: 15082897
Gastrointestinal Neoplasms; Stromal Tumors; Autonomic Pathways; Microscopy, Electron; Immunohistochemistry; Proto-Oncogene Protein c-Kit
5.  Study on User Interface of Pathology Picture Archiving and Communication System 
Objectives
It is necessary to improve the pathology workflow. A workflow task analysis was performed using a pathology picture archiving and communication system (pathology PACS) in order to propose a user interface for the Pathology PACS considering user experience.
Methods
An interface analysis of the Pathology PACS in Seoul National University Hospital and a task analysis of the pathology workflow were performed by observing recorded video. Based on obtained results, a user interface for the Pathology PACS was proposed.
Results
Hierarchical task analysis of Pathology PACS was classified into 17 tasks including 1) pre-operation, 2) text, 3) images, 4) medical record viewer, 5) screen transition, 6) pathology identification number input, 7) admission date input, 8) diagnosis doctor, 9) diagnosis code, 10) diagnosis, 11) pathology identification number check box, 12) presence or absence of images, 13) search, 14) clear, 15) Excel save, 16) search results, and 17) re-search. And frequently used menu items were identified and schematized.
Conclusions
A user interface for the Pathology PACS considering user experience could be proposed as a preliminary step, and this study may contribute to the development of medical information systems based on user experience and usability.
doi:10.4258/hir.2014.20.1.45
PMCID: PMC3950265  PMID: 24627818
Radiology Information Systems; User-Computer Interface; Task Performance and Analysis; Workflows
6.  Immunohistochemical Classification of Primary and Secondary Glioblastomas 
Korean Journal of Pathology  2013;47(6):541-548.
Background
Glioblastomas may develop de novo (primary glioblastomas, P-GBLs) or through progression from lower-grade astrocytomas (secondary glioblastomas, S-GBLs). The aim of this study was to compare the immunohistochemical classification of glioblastomas with clinically determined P-GBLs and S-GBLs to identify the best combination of antibodies for immunohistochemical classification.
Methods
We evaluated the immunohistochemical expression of epidermal growth factor receptor (EGFR), p53, and isocitrate dehydrogenase 1 (IDH-1) in 150 glioblastoma cases.
Results
According to clinical history, the glioblastomas analyzed in this study consisted of 146 P-GBLs and 4 S-GBLs. Immunohistochemical expression of EGFR, p53, and IDH-1 was observed in 62.6%, 49.3%, and 11.1%, respectively. Immunohistochemical profiles of EGFR(+)/p53(-), IDH-1(-)/EGFR(+)/p53(-), and EGFR(-)/p53(+) were noted in 41.3%, 40.2%, and 28.7%, respectively. Expression of IDH-1 and EGFR(-)/p53(+) was positively correlated with young age. The typical immunohistochemical features of S-GBLs comprised IDH-1(+)/EGFR(-)/p53(+), and were noted in 3.6% of clinically P-GBLs. The combination of IDH-1(-) or EGFR(+) was the best set of immunohistochemical stains for identifying P-GBLs, whereas the combination of IDH-1(+) and EGFR(-) was best for identifying S-GBLs.
Conclusions
We recommend a combination of IDH-1 and EGFR for immunohistochemical classification of glioblastomas. We expect our results to be useful for determining treatment strategies for glioblastoma patients.
doi:10.4132/KoreanJPathol.2013.47.6.541
PMCID: PMC3887156  PMID: 24421847
Glioblastoma; Immunohistochemistry; IDH1 protein, human; Genes, erbB-1; Genes, p53
7.  Xanthogranulomatous cholecystits in 2-month-old infant 
Xanthogranulomatous cholecystitis (XGC) is a rare form of chronic cholecystitis that is accompanied by xanthomatous histiocytes and chronic inflammation. A 2-month-old boy presented with a right upper abdominal palpable mass. Cholecystectomy with liver wedge resection was done, under the impression that the mass might be a hepatic tumor or liver abscess. Pathologic examination showed XGC with abscess formation. Most cases of XGC were observed in adult and only a few cases were reported in children. We describe a very rare case of XGC in infancy.
doi:10.4174/jkss.2013.85.4.191
PMCID: PMC3791363  PMID: 24106687
Xanthogranulomatous cholecystitis; Cholecystitis; Infant; Cholecystectomy
8.  Supratentorial Intracerebral Schwannoma : Its Fate and Proper Management 
Intracerebral schwannomas are rare and there have been none reported in Korea. We present the case of a 25-year-old man with newly developed right-side weakness and recent seizure aggravation. His seizures started approximately 9 years prior to admission. At that time, a 1 cm diameter intra-axial enhancing mass at the left precentral gyrus was found on magnetic resonance image (MRI). After 9 years of observation and treatment with antiepileptic medication, an MRI taken due to symptom aggravation revealed peri-tumoral cyst formation with tumor enlargement. The tumor was surgically removed. Subsequently, right-side weakness diminished and there was good seizure control. Pathologic diagnosis was schwannoma. Schwannoma is a very rare tumor and there are no pathognomonic findings on radiologic images; thus, it is challenging to make a correct diagnosis. However, considering the natural course and excellent prognosis after surgical treatment of this kind of intra-axial mass with benign features, early surgery for diagnosis and proper treatment is highly recommended.
doi:10.3340/jkns.2013.54.4.340
PMCID: PMC3841278  PMID: 24294459
Intracerebral schwannoma; Supratentorial; Precentral gyrus; Treatment; Seizure
9.  Differential Diagnosis and Management of a Pituitary Mass with Renal Cell Carcinoma 
The small pituitary mass was incidentally found in 40-years-old women with renal cell carcinoma. The endocrinological and ophthalmological evaluation revealed no deficit and the short-term follow-up was recommended. In 6 months later, the visual disturbance was reported and the size of mass was increased. The tumor was removed totally via the trans-sphenoid approach. The post-operative endocrinological insufficiency was not noticed. During one year of follow-up period, there was no evidence of recurrence without adjuvant radiotherapy. The clinical features of pituitary metastasis from renal cell carcinoma were similar to those of pituitary adenoma. The possibility of pituitary metastasis should be kept in mind in patients with sellar mass and renal cell carcinoma.
doi:10.3340/jkns.2013.54.2.132
PMCID: PMC3809440  PMID: 24175029
Pituitary; Metastasis; Renal cell carcinoma
10.  ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma 
BMC Cancer  2013;13:291.
Background
The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma.
Methods
ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels.
Results
Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas.
Conclusions
High ID3 expression is associated with medullolbastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma.
doi:10.1186/1471-2407-13-291
PMCID: PMC3686661  PMID: 23768125
ID3; Medulloblastoma; Seeding; Prognosis; Survival; Group 4
11.  5-Aminolevulinic Acid Fluorescence Discriminates the Histological Grade of Extraventricular Neurocytoma 
Extraventricular neurocytomas are rare brain tumors that have a diverse range of clinical characteristics. We describe two cases involving fluorescence-guided resection of extraventricular neurocytoma using 5-aminolevulinic acid (5-ALA) and evaluate the efficacy of the technique. We found that the tumor reactions to 5-ALA differed depending on the histologic grade. This finding shows that the 5-ALA fluorescence reaction may potentially be used as a biomarker of the clinical behavior of these tumors. To our knowledge, this is the first report in which fluorescence-guided resection was utilized for the resection of extraventricular neurocytomas.
doi:10.14791/btrt.2013.1.1.45
PMCID: PMC4027114  PMID: 24904890
Extraventricular neurocytoma; Fluorescence guided surgery; 5-aminolevulinic acid
12.  Analysis of the BRAFV600E Mutation in Central Nervous System Tumors1 
Translational Oncology  2012;5(6):430-436.
BRAFV600E mutations are involved in the development of melanoma, colon cancer, and papillary thyroid carcinoma. These mutations are also found in primary brain tumors at low to moderate frequencies. In this study, we investigated a series of brain tumors to determine the prevalence and associated clinicopathologic features of BRAFV600E mutations. By direct sequencing, we analyzed 223 brain tumors, including 51 gangliogliomas (GGs), 45 pilocytic astrocytomas (PAs), 12 pleomorphic xanthoastrocytomas (PXAs), 35 glioblastomas (GBs), 28 anaplastic astrocytomas (AAs), 44 oligodendroglial tumors (ODGs), 3 anaplastic oligoastrocytomas, and 5 diffuse astrocytomas. Thirty-six cases (16.1%) exhibited the BRAFV600E mutation, including 66.7% of PXAs, 23.5% of GGs, 15.6% of PAs, and 9.7% of the malignant gliomas; the latter included 14.3% of AAs, 8.6% of GBs, and 4.5% of ODGs. Copy number aberration at the 7q34 (BRAF) locus was found in 73.1% of PAs and 50% of PXAs. 9p Homozygous deletion was found in 66.7% of PXAs, but it was not correlated with the BRAFV600E mutation. Patients' age, sex, histologic grade, and progression-free survival were also not correlated with the BRAFV600E mutation. The BRAFV600E mutation in brain tumors did not have prognostic value but is certainly a diagnostic marker and therapeutic target, not only for pediatric low-grade gliomas but also for malignant gliomas, even though the rate of mutation was not high. These results should be verified in a larger study with more cases and a longer follow-up period to overcome the limitation of small sample size.
PMCID: PMC3542839  PMID: 23323158
13.  Development of a canine model for recurrent laryngeal injury by harmonic scalpel 
Laboratory Animal Research  2012;28(4):223-228.
Various energy devices had been used in thyroid surgery. Aim of study is to develop canine model for recurrent laryngeal nerve injury by harmonic scalpel and to evaluate feasibility of using this model for evaluating the safety use of harmonic scalpel during thyroid surgery. Nine dogs were divided into 3 groups according to distance between harmonic scalpel application and recurrent laryngeal nerve; group 1 (1 mm), 2 (2 mm), and 3 (3 mm). Vocal cord function was assessed pre- and postoperatively using video laryngoscopy. Harmonic scalpel was applied adjacent to left recurrent laryngeal nerve and, two weeks later, right recurrent laryngeal nerve at assigned distances. Recurrent laryngeal nerves were evaluated for subacute and acute morphologic changes. Laryngoscopy demonstrated 3 abnormal vocal cords in group 1, 1 in group 2, and no in group 3 (P=0.020). Subacute histologic changes were observed in nerves with abnormal function. Acute histologic changes were observed 5/8 (62.5%) in group 1, 1/7 (14.3%) in group 2, and not in group 3. We developed canine model for recurrent laryngeal injury. The functional outcomes matched with the histologic changes. These warrant further study to determine the safety margin for energy device in vicinity of recurrent laryngeal nerve.
doi:10.5625/lar.2012.28.4.223
PMCID: PMC3542380  PMID: 23326282
Recurrent laryngeal nerve; canine model; harmonic scalpel; safety margin; nerve damage; ultrasonic shears
14.  Experience with 5-Aminolevulinic Acid in Fluorescence-Guided Resection of a Deep Sylvian Meningioma 
The 5-aminolevulinic acid (5-ALA)-induced tumor fluorescence is a useful intraoperative marker for the diagnosis and the detection of various malignancies, but its use in meningioma is only reported infrequently. In meningioma, a complete resection of the tumor mass is crucial for the prevention of recurrence and postoperative morbidities. Deep sylvian meningioma is a rare type of meningioma where complete tumor removal is complicated by its deep anatomical location and close involvement with the middle cerebral artery. From our experience, 5-ALA-mediated fluorescence facilitated a safe excision whilst preserving critical neurovascular structures. To our best knowledge, this is first report from use of 5-ALA in a deep sylvian meningioma.
doi:10.3340/jkns.2012.52.6.558
PMCID: PMC3550426  PMID: 23346330
5-aminolevulinic acid; Resection; Deep sylvian meningioma; Meningioma without dural attachment
15.  The Return of an Old Worm: Cerebral Paragonimiasis Presenting with Intracerebral Hemorrhage 
Journal of Korean Medical Science  2012;27(11):1428-1432.
Paragonimiasis is caused by ingesting crustaceans, which are the intermediate hosts of Paragonimus. The involvement of the brain was a common presentation in Korea decades ago, but it becomes much less frequent in domestic medical practices. We observed a rare case of cerebral paragonimiasis manifesting with intracerebral hemorrhage. A 10-yr-old girl presented with sudden-onset dysarthria, right facial palsy and clumsiness of the right hand. Brain imaging showed acute intracerebral hemorrhage in the left frontal area. An occult vascular malformation or small arteriovenous malformation compressed by the hematoma was initially suspected. The lesion progressed for over 2 months until a delayed surgery was undertaken. Pathologic examination was consistent with cerebral paragonimiasis. After chemotherapy with praziquantel, the patient was monitored without neurological deficits or seizure attacks for 6 months. This case alerts practicing clinicians to the domestic transmission of a forgotten parasitic disease due to environmental changes.
doi:10.3346/jkms.2012.27.11.1428
PMCID: PMC3492682  PMID: 23166429
Cerebral Paragonimiasis; Intracerebral Hemorrhage; Diagnosis
16.  The Changes in MGMT Promoter Methylation Status in Initial and Recurrent Glioblastomas12 
Translational Oncology  2012;5(5):393-397.
To evaluate the mechanism of the development of therapeutic resistance after temozolomide treatment, we focused on changes in O6-methylguanine DNA methyltransferase (MGMT) and mismatch repair (MMR) between initial and recurrent glioblastomas. Tissue samples obtained from 24 paired histologically confirmed initial and recurrent adult glioblastoma patients who were initially treated with temozolomide were used for MGMT and MMR gene promoter methylation status and protein expression analysis using methylation-specific multiplex ligation probe amplification (MS-MLPA), methylation-specific polymerase chain reaction (MSP), and immunohistochemical staining. There was a significant decrease in the methylation ratio of the MGMT promoter determined by MS-MLPA, which was not detectable with MSP, and MGMT protein expression changes were not remarkable. However, there was no epigenetic variability in MMR genes, and a relatively homogeneous expression of MMR proteins was observed in initial and recurrent tumors. We conclude that the development of reduced methylation in the MGMT promoter is one of the mechanisms for acquiring therapeutic resistance after temozolomide treatment in glioblastomas.
PMCID: PMC3468928  PMID: 23066447
17.  Effects of Electrical Stimulation Rate on Speech Recognition in Cochlear Implant Users 
Korean Journal of Audiology  2012;16(1):6-9.
Background and Objectives
The stimulus signals delivered in cochlear implant (CI) systems are generally derived by sampling the temporal envelope of each channel at some constant rate and using its intensity to control the stimulation current level delivered to the corresponding electrode site. The objective of the study was to investigate speech recognition performance of cochlear implant users in quiet and noisy environments using either moderate or high rates of electrical stimulations.
Materials and Methods
Six post-lingually deafened adult users of the Nucleus CI24 cochlear implant (Contour® electrode array, Cochlear™, Macquarie Park, Australia) with the Freedom® speech processor participated in the study. Stimulation rates of 900 and 2400 pulses-per-second/channel (pps/ch) were used after both stimulation programs were balanced for loudness. Monosyllabic word and sentence recognition scores in quiet and noisy environments were evaluated for each stimulation program after two months of practice. Subjects were also asked to respond to a questionnaire to examine their preference to any stimulation rate in different hearing conditions.
Results
Word recognition scores for monosyllabic words in quiet conditions with the 900 stimulation rate was better than that of the 2400 stimulation rate, although no significant differences between them were found for sentence test in noise. A survey questionnaire indicated that most subjects preferred the 900 stimulation rate to the 2400 stimulation rate, especially in quiet conditions.
Conclusions
Most subjects indicated a preference for 900 pps/ch rate in quiet conditions. It is recommended to remap at 900 pps/ch for those CI users whose performance in quiet conditions is less than ideal.
doi:10.7874/kja.2012.16.1.6
PMCID: PMC3936531  PMID: 24653862
Cochlear implants; Speech perception; Rehabilitation of hearing impaired
18.  Inhibition of the Ca2+ release channel, IP3R subtype 3 by caffeine slows glioblastoma invasion and migration and extends survival 
Cancer Research  2010;70(3):1173-1183.
Ca2+ signaling is an important determining factor in many cellular processes, especially in cancer cell proliferation, motility and invasion. Glioblastoma is the deadliest brain cancer with its average survival time of less than a year, with the most prominent cellular feature being the ability of these cells to migrate to and invade the neighboring tissue. We hypothesized that disturbing the Ca2+ signaling pathway would decrease the propensity for these cells to migrate. Thus, we investigated the detailed Ca2+ signaling pathway of the glioblastoma cells in response to various receptor tyrosine kinases (RTK) and G-protein coupled receptor (GPCR) agonists. Here we report that caffeine, which is a well-known activator of ryanodine receptors (RyRs), paradoxically inhibits inositol-1, 4, 5-triphospate receptor(IP3R)-mediated Ca2+ increase by selectively targeting IP3R subtype 3(IP3R3), whose mRNA expression is significantly increased in glioblastoma cells. Consequently, by inhibiting IP3R3-mediated Ca2+ release, caffeine was found to inhibit the invasion and migration of various glioblastoma cell lines in scrape motility, Matrigel invasion, soft agar, and brain slice implantation assays. In a mouse xenograft model of glioblastoma, caffeine intake via drinking water greatly increased mean survival duration of subject animals. These findings propose IP3R3 as a novel target for glioblastoma treatment and that caffeine may be a useful adjunct therapy that slows glioblastoma invasion and migration by selectively targeting IP3R3.
doi:10.1158/0008-5472.CAN-09-2886
PMCID: PMC3273964  PMID: 20103623
19.  Usefulness of MS-MLPA for detection of MGMT promoter methylation in the evaluation of pseudoprogression in glioblastoma patients 
Neuro-Oncology  2010;13(2):195-202.
Pseudoprogression is a major diagnostic dilemma in current treatment protocols for malignant gliomas that involve concurrent chemoradiotherapy. We hypothesized that methylation-specific multiplex ligation probe amplification (MS-MLPA), an assay that permits semiquantitative evaluation of promoter methylation, may be used to diagnose pseudoprogression based on the quantification of the methylation status of the O6-methylguanine DNA methyltransferase (MGMT) promoter. We examined the methylation ratio of the MGMT promoter with MS-MLPA in 48 samples from glioblastoma patients. The results were compared with those from methylation-specific polymerase chain reaction (MSP), and protein levels were confirmed by immunohistochemical staining. We then evaluated the correlation between those molecular signatures and clinical outcomes. With regard to radiological progression after chemoradiotherapy, the diagnostic accuracy of the MS-MLPA method was 80% (using a cut-off value of 0.2). These results are better than those obtained with MSP (diagnostic accuracy of 68%). Combining the MS-MLPA and MSP methods resulted in a diagnostic accuracy of 93% for the identification of pseudoprogression among patients to whom these results were coherent. These results demonstrate that MS-MLPA is a useful method to predict radiological progression vs pseudoprogression in glioblastoma patients and that the interpretation of these results in combination with MSP results will provide good practical guidelines for clinical decision making in glioblastoma treatment.
doi:10.1093/neuonc/noq162
PMCID: PMC3064622  PMID: 21075779
glioblastoma; MS-MLPA; MGMT; pseudoprogression
20.  Atypical Extraventricular Neurocytoma 
The authors report a case of atypical extraventricular neurocytoma (EVN) transformed from EVN which had been initially diagnosed as an oligodendroglioma 15 years ago. An 8-year-old boy underwent a surgical resection for a right frontal mass which was initially diagnosed as oligodendroglioma. When the tumor recurred 15 years later, a secondary operation was performed, followed by salvage gamma knife treatment. The recurrent tumor was diagnosed as an atypical EVN. The initial specimen was reviewed and immunohistochemistry revealed a strong positivity for synaptophysin. The diagnosis of the initial tumor was revised as an EVN. The patient maintained a stable disease state for 15 years after the first operation, and was followed up for one year without any complications or disease progression after the second operation. We diagnosed an atypical extraventricular neurocytoma transformed from EVN which had been initially diagnosed as an oligodendroglioma 15 years earlier. We emphasize that EVN should be included in the differential diagnosis of oligodendroglioma.
doi:10.3340/jkns.2011.50.4.381
PMCID: PMC3243844  PMID: 22200023
Atypical extraventricular neurocytoma; Differential diagnosis; Oligodendroglioma; Recurrence
21.  Early Motor Balance and Coordination Training Increased Synaptophysin in Subcortical Regions of the Ischemic Rat Brain 
Journal of Korean Medical Science  2010;25(11):1638-1645.
The aim of this study was to evaluate the effect of early motor balance and coordination training on functional recovery and brain plasticity in an ischemic rat stroke model, compared with simple locomotor exercise. Adult male Sprague-Dawley rats with cortical infarcts were trained under one of four conditions: nontrained control, treadmill training, motor training on the Rota-rod, or both Rota-rod and treadmill training. All types of training were performed from post-operation day 1 to 14. Neurological and behavioral performance was evaluated by Menzies' scale, the prehensile test, and the limb placement test, at post-operation day 1, 7, and 14. Both Rota-rod and treadmill training increased the expression of synaptophysin in subcortical regions of the ischemic hemisphere including the hippocampus, dentate gyrus, and thalamus, but did not affect levels of brain-derived neurotrophic factor or tyrosin kinase receptor B. The Rota-rod training also improved Menzies' scale and limb placement test scores, whereas the simple treadmill training did neither. The control group showed significant change only in Menzies' scale score. This study suggests that early motor balance and coordination training may induce plastic changes in subcortical regions of the ischemic hemisphere after stroke accompanied with the recovery of sensorimotor performance.
doi:10.3346/jkms.2010.25.11.1638
PMCID: PMC2967002  PMID: 21060754
Stroke; Motor Skills; Neuronal Plasticity; Synaptophysin
22.  Primary Culture of Central Neurocytoma: A Case Report 
Journal of Korean Medical Science  2010;25(5):798-803.
A seventeen-year-old female patient was admitted with sudden-onset of headache and vomiting. Brain magnetic resonance imaging demonstrated a heterogeneously enhancing tumour in the left lateral ventricle. The tumour was removed and confirmed as a central neurocytoma (CN). For the residual tumour in the left lateral ventricle, gamma knife stereotactic radiosurgery was done at fifteen months after the initial surgery. Tumour recurred in the 4th ventricle at 5 yr after initial surgery. The tumour was removed and proved as a CN. In vitro primary culture was done with both tumours obtained from the left lateral ventricle and the 4th ventricle, respectively. Nestin, a neuronal stem cell marker was expressed in reverse Transcriptase-Polymerase Chain Reaction of both tumors. Both tumours showed different morphology and phenotypes of neuron and glia depending on the culture condition. When cultured in insulin, transferrin selenium and fibronectin media with basic fibroblast growth factors, tumour cells showed neuronal morphology and phenotypes. When cultured in the Dulbeco's Modified Essential Media with 20% fetal bovine serum, tumors cells showed glial morphology and phenotypes. It is suggested that CN has the characteristics of neuronal stem cells and potential to differentiate into mature neuron and glial cells depending on the environmental cue.
doi:10.3346/jkms.2010.25.5.798
PMCID: PMC2858845  PMID: 20436722
Neurocytoma; Cell Culture Techniques; Neuronal Stem Cells
23.  Methylation Status of the O6-Methylguanine-Deoxyribonucleic Acid Methyltransferase Gene Promoter in World Health Organization Grade III Gliomas 
Objective
We analyzed the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter in World Health Organization (WHO) grade III gliomas in association with other molecular markers to evaluate their prevalence.
Methods
The samples of a total of 36 newly WHO grade III glioma patients including 19 anaplastic oligodendrogliomas (AO), 7 anaplastic oligoastrocytomas (AOA), and 10 anaplastic astrocytomas (AA) were analyzed. The methylation status of the MGMT gene promoter was confirmed by methylation-specific polymerase chain reaction. The 1p/19q chromosomal deletion status and EGFR amplification were assessed by Fluorescence In-Situ Hybridization. MGMT, EGFR, EGFRvIII, and p53 expression were analyzed by immunohistochemical staining.
Results
The MGMT gene promoter was methylated in 32 (88.9%) and unmethylated in 4 (11.2%). Among them, all of the AO and AOA had methylated MGMT gene promoter without exception. Significant associations between MGMT gene promoter hypermethylation and 1p/19q deletion was observed (p = 0.003). Other molecular markers failed to show significant associations between MGMT gene promoter statuses.
Conclusion
There was extensive epigenetic silencing of MGMT gene in high grade gliomas with oligodendroglial component. Together with frequent 1p/19q co-deletion in oligodendroglial tumors, this may add plausible explanations supporting the relative favorable prognosis in oligodendroglial tumors compared with pure astrocytic tumors.
doi:10.3340/jkns.2009.46.4.385
PMCID: PMC2773399  PMID: 19893731
MGMT gene promoter; Methylation; 1p/19q; Oligodendroglioma; Methylation-specific PCR
24.  A case of non-gestational choriocarcinoma arising in the ovary of a postmenopausal woman 
Journal of Gynecologic Oncology  2009;20(3):192-194.
Primary ovarian choriocarcinoma arising from a germ cell is an extremely rare occurrence, especially in postmenopausal women, and the prognosis is poor. Non-gestational choriocarcinoma of the ovary (NGCO) accounts for 0.6% or less of all ovarian neoplasms. It is important to distinguish gestational choriocarcinomas of the ovary (GCO) from other carcinomas because of the poor prognosis of NGCO. We describe a case of NGCO with lung metastasis in a 55 year old woman, which we present together with a brief review of the literature.
doi:10.3802/jgo.2009.20.3.192
PMCID: PMC2757566  PMID: 19809555
Nongestational choriocarcinoma; Ovary; Postmenopause
25.  Clinical Characteristics and Treatment Results of Pediatric Osteosarcoma: The Role of High Dose Chemotherapy with Autologous Stem Cell Transplantation 
Purpose
In this study, we investigated the clinical characteristics and treatment results of osteosarcoma during the past 7 years, and evaluated the role of high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT).
Materials and Methods
We retrospectively analyzed the clinical data of patients who were diagnosed as osteosarcoma at our center from January, 2000 to December, 2007.
Results
The 5-year overall survival and event-free survival of the patients were 72.6% and 55.9%, respectively. Seventeen (41.5%) patients showed disease progression during treatment or relapse after the end of treatment. The patients who had metastasis at diagnosis or who had a lower grade of necrosis after neoadjuvant chemotherapy showed decreased overall and event-free survival. Four patients received ASCT after HDCT, and 3 of them are alive without disease.
Conclusions
The patients who relapsed or had refractory osteosarcoma or who had metastasis at diagnosis or a lower grade of necrosis after neoadjuvant chemotherapy showed poor prognosis. HDCT with ASCT could be an alternative treatment option for these patients.
doi:10.4143/crt.2008.40.4.172
PMCID: PMC2697476  PMID: 19688126
Osteosarcoma; Autologous stem cell transplantation; High dose chemotherapy; Pediatrics

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