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1.  Prognosis of Glioblastoma With Oligodendroglioma Component is Associated With the IDH1 Mutation and MGMT Methylation Status1 
Translational Oncology  2014;7(6):712-719.
Glioblastoma (GBM) with oligodendroglioma component (GBMO) is a newly described GBM subtype in the 2007 World Health Organization classification. However, its biological and genetic characteristics are largely unknown. We investigated the clinicopathological and molecular features of 34 GBMOs and compared the survival rate of these patients with those of patients with astrocytoma, oligodendroglioma, anaplastic oligoastrocytoma (AOA), and conventional GBMs in our hospital. GBMO could be divided into two groups based on the presence of an IDH1 mutation. The IDH1 mutation was more frequently found in secondary GBMO, which had lower frequencies of EGFR amplification but higher MGMT methylation than the wild type IDH1 group, and patients with mutant IDH1 GBMO were on average younger than those with wild-type IDH1. Therefore, GBMO is a clinically and molecularly heterogeneous subtype, largely belonging to a proneural and classical subtype of GBM. The survival rate of GBMO patients itself was worse than that of AOA patients but not significantly better than that of conventional GBM patients. GBMO survival was independent of the dominant histopathological subtype i.e., astrocyte-dominant or oligodendroglioma -dominant, but it was significantly associated with the IDH1 mutation and MGMT methylation status. Therefore, GBMO should be regarded as a separate entity from AOA and must be classified as a subtype of GBM. However, further study is needed to determine whether it is a pathologic variant or a pattern of GBM because GBMO has a similar prognosis to conventional GBMs.
doi:10.1016/j.tranon.2014.10.002
PMCID: PMC4311043  PMID: 25500080
3.  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
4.  Clinicopathologic Analysis of Pituitary Adenoma: A Single Institute Experience 
Journal of Korean Medical Science  2014;29(3):405-410.
Pituitary adenoma (PA) is a common benign neuroendocrine tumor; however, the incidence and proportion of hormone-producing PAs in Korean patients remain unknown. Authors analyzed 506 surgically resected and pathologically proven pituitary lesions of the Seoul National University Hospital from 2006 to 2011. The lesions were categorized as: PAs (n = 422, 83.4%), Rathke's cleft cysts (RCCs) (n = 54, 10.6%), inflammatory lesions (n = 8, 1.6%), meningiomas (n = 4), craniopharyngiomas (n = 4), granular cell tumors (n = 1), metastatic renal cell carcinomas (n = 2), germinomas (n = 1), ependymomas (n = 1), and unsatisfactory specimens (n = 9, 1.8%). PAs were slightly more prevalent in women (M: F = 1:1.17) with a mean age of 48.8 yr (9-80 yr). Immunohistochemical analysis revealed that prolactin-producing PAs (16.6%) and growth hormone-producing adenomas (9.2%) were the most common functional PAs. Plurihormonal PAs and nonfunctioning (null cell) adenomas were found in 14.9% and 42.4% of patients with PAs, respectively. The recurrence rate of PAs was 11.1%, but nearly 0% for the remaining benign lesions such as RCCs. 25.4% of patients with PAs were treated by gamma-knife after surgery due to residual tumors or regrowth of residual tumor. In conclusion, the pituitary lesions and the proportions of hormone-producing PAs in Korean patients are similar to those of previous reports except nonfunctioning (null cell) PAs, which are unusually frequent.
Graphical Abstract
doi:10.3346/jkms.2014.29.3.405
PMCID: PMC3945137  PMID: 24616591
Pituitary Gland; Pituitary Neoplasms; Pituitary Adenoma; Clinicopathological Study; Pituitary Hormone
5.  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
6.  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
7.  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
8.  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
9.  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
10.  Sporadic hemangioblastomas are characterized by cryptic VHL inactivation 
Hemangioblastomas consist of 10-20% neoplastic “stromal” cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0167-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-014-0167-x
PMCID: PMC4297409  PMID: 25589003
Central nervous system; Hemangioblastoma; Deep sequencing; Somatic gene alterations; Von Hippel-Lindau gene; Hypoxia-inducible signaling
11.  Prognosis Prediction of Measurable Enhancing Lesion after Completion of Standard Concomitant Chemoradiotherapy and Adjuvant Temozolomide in Glioblastoma Patients: Application of Dynamic Susceptibility Contrast Perfusion and Diffusion-Weighted Imaging 
PLoS ONE  2014;9(11):e113587.
Purpose
To assess the prognosis predictability of a measurable enhancing lesion using histogram parameters produced by the normalized cerebral blood volume (nCBV) and normalized apparent diffusion coefficient (nADC) after completion of standard concomitant chemoradiotherapy (CCRT) and adjuvant temozolomide (TMZ) medication in glioblastoma multiforme (GBM) patients.
Materials and Methods
This study was approved by the institutional review board (IRB), and the requirement for informed consent was waived. A total of 59 patients with newly diagnosed GBM who received standard CCRT with TMZ and adjuvant TMZ for six cycles underwent perfusion-weighted and diffusion-weighted imaging. Twenty-seven patients had a measurable enhancing lesion and 32 patients lacked a measurable enhancing lesion based on the Response Assessment in Neuro-Oncology (RANO) criteria in the follow-up MRI, which was performed within 3 months after adjuvant TMZ therapy was completed. We measured the nCBV and nADC histogram parameters based on the measurable enhancing lesion. The progression free survival (PFS) was analyzed by the Kaplan-Meier method with the use of the log-rank test.
Results
The median PFS of patients lacking measurable enhancing lesion was longer than for those with measurable enhancing lesions (17.6 vs 3.3 months, P<.0001). There was a significant, positive correlation between the 99th percentile nCBV value of a measurable enhancing lesion and the PFS (P = .044, R2 = .152). In addition, the median PFS was longer in patients with a 99th percentile nCBV value ≧4.5 than it was in those with a value <4.5 (4.4 vs 3.1 months, P = .036).
Conclusion
We found that the nCBV value can be used for the prognosis prediction of a measurable enhancing lesion after the completion of standard treatment for GBM, wherein a high 99th percentile nCBV value (≧4.5) suggests a better PFS for GBM patients.
doi:10.1371/journal.pone.0113587
PMCID: PMC4242641  PMID: 25419975
12.  Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations 
Acta neuropathologica  2014;128(1):111-122.
Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5′ arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 “hits” occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.
doi:10.1007/s00401-014-1285-z
PMCID: PMC4129448  PMID: 24839956
DICER1; Pituitary blastoma; miRNA; Pediatric tumors
13.  A Case Report of Preoperative and Postoperative 7.0T Brain MRI in a Patient with a Small Cell Glioblastoma 
Journal of Korean Medical Science  2014;29(7):1012-1017.
A 45-yr-old female patient was admitted with one-month history of headache and progressive left hemiparesis. Brain magnetic resonance imaging (MRI) demonstrated a mass lesion in her right frontal lobe. Her brain tumor was confirmed as a small cell glioblastoma. Her follow-up brain MRI, taken at 8 months after her initial surgery demonstrated tumor recurrence in the right frontal lobe. Contrast-enhanced 7.0T brain magnetic resonance imaging (MRI) was safely performed before surgery and at the time of recurrence. Compared with 1.5T and 3.0T brain MRI, 7.0T MRI showed sharpened images of the brain tumor contexture with detailed anatomical information. The fused images of 7.0T and 1.5T brain MRI taken at the time of recurrence demonstrated no significant discrepancy in the positions of the anterior and the posterior commissures. It is suggested that 7.0T MRI can be safely utilized for better images of the maligant gliomas before and after surgery.
Graphical Abstract
doi:10.3346/jkms.2014.29.7.1012
PMCID: PMC4101769  PMID: 25045237
Pre- and post-operative 7.0T MRI; Small Cell Glioblastoma
14.  Low-Dose Whole Brain Radiotherapy with Tumor Bed Boost after Methotrexate-Based Chemotherapy for Primary Central Nervous System Lymphoma 
Purpose
The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL).
Materials and Methods
We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively.
Results
With a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025).
Conclusion
Low-dose WBRT with tumor bed boost after methotrexate-based chemotherapy might be an effective method for management of PCNSL.
doi:10.4143/crt.2014.46.3.261
PMCID: PMC4132445  PMID: 25038761
Radiotherapy; Methotrexate; Central nervous system; Lymphoma
15.  Therapeutic effect of anti-C-X-C motif chemokine 10 (CXCL10) antibody on C protein-induced myositis mouse 
Arthritis Research & Therapy  2014;16(3):R126.
Introduction
C-X-C motif chemokine 10 (CXCL10) is a chemokine that plays a critical role in the infiltration of T cells in autoimmune diseases and is reported to be expressed in muscle tissue of polymyositis. To determine the therapeutic efficacy of CXCL10 blockade, we investigated the role of CXCL10 and the effect of anti-CXCL10 antibody treatment in C protein-induced myositis (CIM), an animal model of polymyositis.
Methods
CIM was induced with human skeletal muscle C protein fragment in female C57BL/6 mice. Immunohistochemistry of CXCL10 and C-X-C motif chemokine receptor 3 (CXCR3) and measurement of serum CXCL10 were performed. Cell surface markers and interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in CIM lymph node cells was investigated by flow cytometry. Mice with CIM were treated with anti-CXCL10 antibody or control antibody (anti-RVG1) and the inflammation in muscle tissue was assessed.
Results
Immunohistochemistry showed increased expression of CXCL10 and CXCR3 in the inflammatory lesions of muscle in CIM. Especially, CD8+ T cells invading myofiber expressed CXCR3. Serum level of CXCL10 was increased in CIM compared to the level in normal mice (normal mouse, 14.3 ± 5.3 pg/ml vs. CIM, 368.5 ± 135.6 pg/ml, P < 0.001). CXCR3 positivity in CD8+ T cells was increased compared to that of CD4+ T cells in the lymph node cells of CIM (CXCR3+ among CD8+ T cell, 65.9 ± 2.1% vs. CXCR3+ among CD4+ T cell, 23.5 ± 4.7%, P <0.001). Moreover, IFN-γ+ cells were increased among CXCR3+CD8+ T cells compared to CXCR3–CD8+ T cells (CXCR3+CD8+ T cell, 28.0 ± 4.2% vs. CXCR3-CD8+ T cell, 9.5 ± 1.5%, P = 0.016). Migration of lymph node cells was increased in response to CXCL10 (chemotactic index was 1.91 ± 0.45). CIM mice treated with anti-CXCL10 antibody showed a lower inflammation score in muscles than those with anti-RVG1 (median, anti-CXCL10 treatment group, 0.625 vs. anti-RVG1 treatment group, 1.25, P = 0.007).
Conclusions
CXCL10/CXCR3 expression was increased in the inflammation of CIM model and its blockade suppressed inflammation in muscle.
doi:10.1186/ar4583
PMCID: PMC4095607  PMID: 24939012
16.  Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma 
Oncotarget  2014;5(10):3399-3407.
We investigated the role of somatic mutations and a common single nucleotide polymorphism (SNP) in the hTERT promoter region on hTERT expression and clinical outcomes. The hTERT promoter region was sequenced from 48 glioblastomas. hTERT expression was analyzed by quantitative real time-PCR. The association between hTERT promoter genetic changes and other genomic events and clinical variables common in gliomas were examined. C228T and C250T somatic mutations were found in 60.4% of glioblastomas, and a common SNP (T349C) was found in 66.6%. Somatic mutations and the SNP likely have opposing effects on hTERT expression. hTERT expression was significantly higher in the C228T or C250T mutated tumors. Tumors with the T349C genotype showed lower hTERT expression when C228T or C250T mutations were present. However, no significant survival differences were observed among the groups with or without hTERT promoter mutations and SNP. There was a significant association between genetic changes in the hTERT promoter and patient age as well as MGMT promoter methylation and EGFR amplification. hTERT expression is modulated by somatic mutations in the hTERT promoter as well as a common polymorphism. However, hTERT related genomic changes have limited value as an independent prognostic factor for clinical outcomes in glioblastomas.
PMCID: PMC4102818  PMID: 24930669
Glioblastoma; hTERT; promoter mutation; hTERT expression; single nucleotide polymorphism; rs2853669
17.  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
18.  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
19.  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
20.  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
21.  Cerebral Blood Volume Calculated by Dynamic Susceptibility Contrast-Enhanced Perfusion MR Imaging: Preliminary Correlation Study with Glioblastoma Genetic Profiles 
PLoS ONE  2013;8(8):e71704.
Purpose
To evaluate the usefulness of dynamic susceptibility contrast (DSC) enhanced perfusion MR imaging in predicting major genetic alterations in glioblastomas.
Materials and Methods
Twenty-five patients (M:F = 13∶12, mean age: 52.1±15.2 years) with pathologically proven glioblastoma who underwent DSC MR imaging before surgery were included. On DSC MR imaging, the normalized relative tumor blood volume (nTBV) of the enhancing solid portion of each tumor was calculated by using dedicated software (Nordic TumorEX, NordicNeuroLab, Bergen, Norway) that enabled semi-automatic segmentation for each tumor. Five major glioblastoma genetic alterations (epidermal growth factor receptor (EGFR), phosphatase and tensin homologue (PTEN), Ki-67, O6-methylguanine-DNA methyltransferase (MGMT) and p53) were confirmed by immunohistochemistry and analyzed for correlation with the nTBV of each tumor. Statistical analysis was performed using the unpaired Student t test, ROC (receiver operating characteristic) curve analysis and Pearson correlation analysis.
Results
The nTBVs of the MGMT methylation-negative group (mean 9.5±7.5) were significantly higher than those of the MGMT methylation-positive group (mean 5.4±1.8) (p = .046). In the analysis of EGFR expression-positive group, the nTBVs of the subgroup with loss of PTEN gene expression (mean: 10.3±8.1) were also significantly higher than those of the subgroup without loss of PTEN gene expression (mean: 5.6±2.3) (p = .046). Ki-67 labeling index indicated significant positive correlation with the nTBV of the tumor (p = .01).
Conclusion
We found that glioblastomas with aggressive genetic alterations tended to have a high nTBV in the present study. Thus, we believe that DSC-enhanced perfusion MR imaging could be helpful in predicting genetic alterations that are crucial in predicting the prognosis of and selecting tailored treatment for glioblastoma patients.
doi:10.1371/journal.pone.0071704
PMCID: PMC3747204  PMID: 23977117
22.  Cerebral Blood Volume Analysis in Glioblastomas Using Dynamic Susceptibility Contrast-Enhanced Perfusion MRI: A Comparison of Manual and Semiautomatic Segmentation Methods 
PLoS ONE  2013;8(8):e69323.
Purpose
To compare the reproducibilities of manual and semiautomatic segmentation method for the measurement of normalized cerebral blood volume (nCBV) using dynamic susceptibility contrast-enhanced (DSC) perfusion MR imaging in glioblastomas.
Materials and Methods
Twenty-two patients (11 male, 11 female; 27 tumors) with histologically confirmed glioblastoma (WHO grade IV) were examined with conventional MR imaging and DSC imaging at 3T before surgery or biopsy. Then nCBV (means and standard deviations) in each mass was measured using two DSC MR perfusion analysis methods including manual and semiautomatic segmentation method, in which contrast-enhanced (CE)-T1WI and T2WI were used as structural imaging. Intraobserver and interobserver reproducibility were assessed according to each perfusion analysis method or each structural imaging. Interclass correlation coefficient (ICC), Bland-Altman plot, and coefficient of variation (CV) were used to evaluate reproducibility.
Results
Intraobserver reproducibilities on CE-T1WI and T2WI were ICC of 0.74–0.89 and CV of 20.39–36.83% in manual segmentation method, and ICC of 0.95–0.99 and CV of 8.53–16.19% in semiautomatic segmentation method, repectively. Interobserver reproducibilites on CE-T1WI and T2WI were ICC of 0.86–0.94 and CV of 19.67–35.15% in manual segmentation method, and ICC of 0.74–1.0 and CV of 5.48–49.38% in semiautomatic segmentation method, respectively. Bland-Altman plots showed a good correlation with ICC or CV in each method. The semiautomatic segmentation method showed higher intraobserver and interobserver reproducibilities at CE-T1WI-based study than other methods.
Conclusion
The best reproducibility was found using the semiautomatic segmentation method based on CE-T1WI for structural imaging in the measurement of the nCBV of glioblastomas.
doi:10.1371/journal.pone.0069323
PMCID: PMC3738566  PMID: 23950891
23.  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
24.  True Progression versus Pseudoprogression in the Treatment of Glioblastomas: A Comparison Study of Normalized Cerebral Blood Volume and Apparent Diffusion Coefficient by Histogram Analysis 
Korean Journal of Radiology  2013;14(4):662-672.
Objective
The purpose of this study was to differentiate true progression from pseudoprogression of glioblastomas treated with concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ) by using histogram analysis of apparent diffusion coefficient (ADC) and normalized cerebral blood volume (nCBV) maps.
Materials and Methods
Twenty patients with histopathologically proven glioblastoma who had received CCRT with TMZ underwent perfusion-weighted imaging and diffusion-weighted imaging (b = 0, 1000 sec/mm2). The corresponding nCBV and ADC maps for the newly visible, entirely enhancing lesions were calculated after the completion of CCRT with TMZ. Two observers independently measured the histogram parameters of the nCBV and ADC maps. The histogram parameters between the true progression group (n = 10) and the pseudoprogression group (n = 10) were compared by use of an unpaired Student's t test and subsequent multivariable stepwise logistic regression analysis to determine the best predictors for the differential diagnosis between the two groups. Receiver operating characteristic analysis was employed to determine the best cutoff values for the histogram parameters that proved to be significant predictors for differentiating true progression from pseudoprogression. Intraclass correlation coefficient was used to determine the level of inter-observer reliability for the histogram parameters.
Results
The 5th percentile value (C5) of the cumulative ADC histograms was a significant predictor for the differential diagnosis between true progression and pseudoprogression (p = 0.044 for observer 1; p = 0.011 for observer 2). Optimal cutoff values of 892 × 10-6 mm2/sec for observer 1 and 907 × 10-6 mm2/sec for observer 2 could help differentiate between the two groups with a sensitivity of 90% and 80%, respectively, a specificity of 90% and 80%, respectively, and an area under the curve of 0.880 and 0.840, respectively. There was no other significant differentiating parameter on the nCBV histograms. Inter-observer reliability was excellent or good for all histogram parameters (intraclass correlation coefficient range: 0.70-0.99).
Conclusion
The C5 of the cumulative ADC histogram can be a promising parameter for the differentiation of true progression from pseudoprogression of newly visible, entirely enhancing lesions after CCRT with TMZ for glioblastomas.
doi:10.3348/kjr.2013.14.4.662
PMCID: PMC3725362  PMID: 23901325
Apparent diffusion coefficient; Cerebral blood volume; Glioblastoma multiforme; Histogram analysis; Pseudoprogression
25.  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

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