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Purpose Detection of telomerase reverse transcriptase (TERT) promoter mutations is a crucial process in the integrated diagnosis of glioblastomas. However, the TERT promoter region is difficult to amplify because of its high guanine-cytosine (GC) content (> 80%). This study aimed to analyze the capturing of TERT mutations by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tissues.Materials and Methods We compared the detection rate of TERT mutations between targeted NGS and Sanger sequencing in 25 cases of isocitrate dehydrgenase (IDH)-wildtype glioblastomas and 10 cases of non-neoplastic gastric tissues. Our customized panel consisted of 232 essential glioma-associated genes.Results Sanger sequencing detected TERT mutations in 17 out of 25 glioblastomas, but all TERT mutations were missed by targeted NGS. After the manual visualization of the NGS data using an integrative genomics viewer, 16 cases showed a TERT mutation with a very low read depth (mean, 21.59; median, 25), which revealed false-negative results using auto-filtering. We optimized our customized panel by extending the length of oligonucleotide baits and increasing the number of baits spanning the coverage of the TERT promoter, which did not amplify well due to the high GC content.Conclusion Our study confirmed that it is crucial to consider the recognition of molecular bias and to carefully interpret NGS data.

Purpose We performed a prospective single-arm trial (NCT02782754) to explore the feasibility of reducing radiation therapy (RT) dose when induction chemotherapy is combined in the treatment of intracranial germinoma with beta-human chorionic gonadotropin levels Methods and Materials All patients aged 3 to 35 years from November 2012 to June 2018 were eligible for this study. Four cycles of induction chemotherapy were given before RT. Carboplatin/etoposide and cyclophosphamide/etoposide regimens were used in alternation every 3 weeks. A dose of 18 Gy of craniospinal RT for metastatic tumors, whole brain RT for basal ganglia tumors, or otherwise whole ventricular RT followed by 12.6 Gy of boost RT to the primary tumor bed was administered after induction chemotherapy. The primary endpoint of this study was progression-free survival. Results A total of 41 consecutive patients were enrolled (location: suprasellar in 12, pineal in 12, both suprasellar and pineal in 11, and basal ganglia in 6 patients). Eleven patients had leptomeningeal seeding. Toxicity during chemotherapy was mild, except for bone marrow suppression. Tumor status after induction chemotherapy was complete response in 33 patients and partial response in 8. All but 2 patients completed the scheduled treatment. All patients but 1 remained event free during a median follow-up of 3.4 (range, 0.3-7.0) years from diagnosis. The 1 patient experienced relapse and died of tumor bleeding. Late effects were not significant except for neuroendocrine dysfunction already present at diagnosis. Vertical growth and cognitive function were not significantly disturbed by treatment. Conclusions This study showed the feasibility of reducing RT dose/volume with induction chemotherapy in pathologically pure germinoma with elevated beta-human chorionic gonadotropin levels up to 200 mIU/mL.

Background In this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB). Methods Newly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues. Results In all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common. Conclusions The strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study., Tandem high‐dose chemotherapy (HDCT) after reduced‐dose craniospinal radiotherapy resulted in a low progression rate in high‐risk medulloblastoma. However, the high treatment‐related mortality rate indicates the need to modify the HDCT regimen and carefully select patients who may benefit from HDCT.

This study investigated distinct neuroimaging features measured by cortical thickness and subcortical structural shape abnormality in early-onset (EO, onset age65 years) and late-onset (LO, onset age ≥65 years) nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) patients. Cortical thickness and subcortical structural shape analyses were performed using a surface-based method from 38 patients with nfvPPA and 76 cognitively normal individuals. To minimize the effects of physiological aging, we used W-scores in comparisons between the groups. The EO-nfvPPA group exhibited more extensive cortical thickness reductions predominantly in the left perisylvian, lateral and medial prefrontal, temporal, posterior cingulate, and precuneus regions than the LO-nfvPPA group. The EO-nfvPPA group also exhibited significantly greater subcortical structural shape abnormality than the LO-nfvPPA group, mainly in the left striatum, hippocampus, and amygdala. Our findings suggested that there were differences in neuroimaging features between these groups by the age of symptom onset, which might be explained by underlying heterogeneous neuropathological differences or the age-related brain reserve hypothesis.

A late-onset treatment-related changes (TRCs), which represent radiographic radiation necrosis (RN), frequently occur after stereotactic radiosurgery (SRS) for brain metastases and often need surgical treatment. This study aimed to validate the true pathology and investigate clinical implication of surgically resected TRCs on advanced magnetic resonance imaging (MRI). Retrospective analyses of 86 patients who underwent surgical resection after radiosurgery of brain metastases were performed. Fifty-four patients displayed TRCs on preoperative MRI, comprising pure RN in 19 patients (TRC-RN group) and mixed viable tumor cells in 35 patients (TRC-PD group). Thirty-two patients revealed the consistent diagnosis of progressive disease in both MRI and histopathology (PD–PD group). The TRC-PD group showed larger prescription isodose volume (9.4 cm3) than the TRC-RN (4.06 cm3, p = 0.014) group and a shorter time interval from SRS to preoperative MRI diagnosis (median 4.07 months) than the PD–PD group (median 8.77 months, p = 0.004). Progression-free survival was significantly different among the three groups (p

Epidermal growth factor receptor (EGFR) amplification is one of the common alterations in IDH-wildtype glioblastoma. It is frequently associated with EGFRvIII mutation. To evaluate the correlation between EGFR overexpression, gene amplification, and EGFRvIII mutation, we performed immunohistochemical (IHC) analysis, fluorescence in situ hybridization by Vysis LSI EGFR/CEP7 dual color probe, and polymerase chain reaction studies in 76 patients diagnosed with glioblastomas (67 IDH-wildtype and 9 IDH-mutant). EGFR expression was scored ranging from 0 to 3+. Using formalin-fixed paraffin-embedded sections, real-time reverse transcription-polymerase chain reaction was carried out with primers specific for EGFRvIII and EGFR wildtype. In addition, we evaluated the impact of EGFR status on prognosis. EGFR gene amplifications and EGFRvIII mutations were identified in 30.3% and 15.5% of all cases, respectively. All the EGFR-amplified or EGFRvIII mutant cases were IDH-wildtype glioblastomas and tested positive with IHC. The sensitivity and specificity of EGFR IHC predicting EGFR gene amplification status were 100.0% and 46.5%, respectively. The EGFR-amplified cases tended to show more intense immunostaining (3+) in a considerable number of tumor cells (≥50%). Survival analyses of 37 IDH-wildtype glioblastoma patients revealed that none of the EGFR alterations significantly affected prognosis. EGFR IHC displayed high sensitivity and low specificity in predicting EGFR gene amplification, and interpretation of IHC results is a challenge. Therefore, EGFR IHC represents a possible screening tool for evaluation of EGFR gene amplification in clinical neuropathology, and both the intensity and proportion score facilitate interpretation of EGFR IHC.

Purpose Targeted next-generation sequencing (NGS) panels for solid tumors have been useful in clinical framework for accurate tumor diagnosis and identifying essential molecular aberrations. However, most cancer panels have been designed to address a wide spectrum of pan-cancer models, lacking integral prognostic markers that are highly specific to gliomas. Materials and methods To address such challenges, we have developed a glioma-specific NGS panel, termed "GliomaSCAN," that is capable of capturing single nucleotide variations and insertion/deletion, copy number variation, and selected promoter mutations and structural variations that cover a subset of intron regions in 232 essential glioma-associated genes. We confirmed clinical concordance rate using pairwise comparison of the identified variants from whole exome sequencing (WES), immunohistochemical analysis, and fluorescence in situ hybridization. Results Our panel demonstrated high sensitivity in detecting potential genomic variants that were present in the standard materials. To ensure the accuracy of our targeted sequencing panel, we compared our targeted panel to WES. The comparison results demonstrated a high correlation. Furthermore, we evaluated clinical utility of our panel in 46 glioma patients to assess the detection capacity of potential actionable mutations. Thirty-two patients harbored at least one recurrent somatic mutation in clinically actionable gene. Conclusion We have established a glioma-specific cancer panel. GliomaSCAN highly excelled in capturing somatic variations in terms of both sensitivity and specificity and provided potential clinical implication in facilitating genome-based clinical trials. Our results could provide conceptual advance towards improving the response of genomically guided molecularly targeted therapy in glioma patients.

Achieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.

Background Infants and very young children with malignant brain tumors have a poorer survival and a higher risk for neurologic deficits. The present study evaluated the feasibility and effectiveness of multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in minimizing use of radiotherapy (RT) in very young children with non-metastatic malignant brain tumors. Methods Twenty consecutive patients younger than 3 years were enrolled between 2004 and 2017. Tandem HDCT/auto-SCT was performed after six cycles of induction chemotherapy. Local RT was administered only to patients with post-operative gross residual tumor at older than 3 years. Since September 2015, early post-operative local RT for patients with atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor was administered. Results All 20 enrolled patients underwent the first HDCT/auto-SCT, and 18 proceeded to the second. Two patients died from toxicity during the second HDCT/auto-SCT, and four patients experienced relapse/progression (one localized and three metastatic), three of whom remained alive after salvage treatment including RT. A total of 17 patients remained alive at a median 7.8 (range, 2.5−15.7) years from diagnosis. Nine survivors received no RT, six survivors received local RT alone, and two survivors who experienced metastatic relapse after tandem HDCT/auto-SCT received both local and craniospinal RT. The 5-year overall, event-free, and craniospinal RT-free survival rates were 85.0% ± 8.0%, 70.0% ± 10.2%, and 75.0% ± 9.7%, respectively. Neuroendocrine and neurocognitive functions evaluated 5 years after tandem HDCT/auto-SCT were acceptable. Conclusion Our results suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal therapy including tandem HDCT/auto-SCT while minimizing RT, particularly craniospinal RT., Graphical Abstract

Dermoid cysts may occur in the orbit, most commonly in the superolateral area. Malignant transformation of such lesions has been previously reported; however, most turn out to be squamous cell carcinoma. The authors' patient initially presented with mild proptosis and limitation in extraocular movements. Preliminary biopsy showed whitish amorphous material and abundant hairs filling the thin-walled cyst, consistent with dermoid cyst. The patient underwent tumor resection via lateral orbitotomy with bone window and transorbital endoscopic approach for the dural involvement. Final biopsy showed dermoid cyst with pilosebaceous malignant transformation showing p53 expression and 30% of Ki-67 index. Adjuvant radiotherapy was performed. To the best of the authors' knowledge, this is the first reported case of this type. Despite its rarity, there should always be a high index of suspicion and complete work-up for an accurate diagnosis.

OBJECTIVEThe authors conducted this retrospective study to investigate the clinical outcomes of intracranial solitary fibrous tumor (SFT) and hemangiopericytoma (HPC), defined according to the 2016 WHO classification of central nervous system (CNS) tumors.METHODSHistopathologically proven intracranial SFT and HPC cases treated in the period from June 1996 to September 2014 were retrospectively reviewed and analyzed. Two neuropathologists reviewed pathological slides and regraded the specimens according to the 2016 WHO classification. Factors associated with progression-free survival (PFS) and overall survival (OS) were statistically evaluated with uni- and multivariate analyses.RESULTSThe records of 47 patients—10 with SFT, 33 with HPC, and 4 with anaplastic HPC—were reviewed. A malignant transition from conventional SFT to WHO grade III SFT/HPC was observed in 2 cases, and 13 HPC cases were assigned grade III SFT/HPC. Mean and median follow-ups were 114.6 and 94.7 months, respectively (range 7.1–366.7 months). Gross-total resection (GTR) was significantly associated with longer PFS and OS (p = 0.012 for both), and adjuvant radiation therapy versus no such therapy led to significantly longer PFS (p = 0.018). Extracranial metastases to the liver, bone, lung, spine, and kidney occurred in 10 patients (21.3%). Grade III SFT/HPC was strongly correlated with the development of extracranial metastases (p = 0.031).CONCLUSIONSThe 2016 WHO classification of CNS tumors reflected the different types of pathological malignant progression and clinical outcomes better than prior classifications. Gross-total resection should be the primary treatment goal in patients with SFT/HPC, regardless of the pathological grade, and radiation can be administered as adjuvant therapy for patients with SFT/HPC that shows an aggressive phenotype or that is not treated with GTR.

Background Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features. Methods We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs. Results Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target. Conclusions Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients. Key points 1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.

This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

Fibromyxomas are rare tumors that are not commonly seen in the orbit. The authors present a case of orbital fibromyxoma. A 42-year-old male presented with proptosis of the right eye that began 1 month prior. Magnetic resonance imaging revealed the presence of an orbital mass in the right eye, with low signal intensity on T1-weighted images and heterogeneous high-signal intensity on T2-weighted images. The patient underwent excisional biopsy of the orbital tumor through a Krönlein approach. The tumor originated from the inferior rectus muscle. Histopathologic analysis demonstrated scattered spindle cells, with both fibrous and myxoid stroma. Immunohistochemical staining was positive for Vimentin and negative for S-100 protein and CD34. The tumor was diagnosed as orbital fibromyxoma. The patient showed no evidence of recurrence over 18 months of follow-up after operation.

AIMS: Clear cell meningioma is a rare subtype of meningioma and shows not only unusual histology, but also unique clinical features. Recently, SMARCE1 mutations have been shown to cause spinal and cranial clear cell meningiomas. We present 12 cases which were diagnosed with a clear cell meningioma in a single institution between 1997 and 2014, and investigate their SMARCE1 mutation status.METHODS AND RESULTS: To investigate the SMARCE1 mutation status of these tumours, we used a combination of Sanger sequencing and multiplex ligation dependent probe amplification analysis and also performed SMARCE1 immunohistochemical staining. We found both SMARCE1 mutational hits, including novel SMARCE1 mutations, in six out of eight tested patients. Immunohistochemical analysis showed loss of SMARCE1 protein staining in all but two cases. Two individuals who were originally diagnosed with clear cell meningioma were negative for SMARCE1 mutations, but tested positive for NF2 mutations. As a result, these two tumours were reanalyzed and eventually reclassified, as a microcystic and a mixed growth pattern meningioma with focal clear cell areas, respectively.CONCLUSIONS: These results expand the spectrum of pathogenic variants in SMARCE1 and show that mutation screening can help facilitate meningioma classification. This may have implications for prognosis and future clinical management of patients, since clear cell meningiomas are classed as grade II tumours, while microcystic and meningothelial meningiomas are classed as grade I. This article is protected by copyright. All rights reserved.

Angiomatosis is a complex vascular malformation that denotes a clinically extensive hemangioma, which either involves multiple tissue planes or extensively infiltrates 1 type of tissue. It is a rare condition characterized by diffuse proliferation of blood vessels admixed with fat and fibrotic tissue. Typically, this process involves the limbs in multiple tissue planes, including dermis, subcutis, muscle, and bone. In this report, the authors present the first case of angiomatosis infiltrating the orbit, controlled effectively with a combination of systemic steroids, radiation, and beta-blocker therapy. The characteristic imaging and histologic features and management options are discussed.

The extremely invasive phenotypes and genotypes related to progression of gliomatosis cerebri (GC) remain unclear although GC has been removed as an independent entity from the 2016 WHO classification. Hence, categorization of GC under the current WHO molecular classification is essential, and the molecular subgroups that might contribute to GC progression should be compared with the histopathological differences between initial and new lesions identified during follow-up. Analyses of IDH1/2 and TERTp mutations and 1p/19q co-deletion, and immunohistochemistry of IDH1-R132H, ATRX, p53 and galectin-3 were performed. Anaplastic astrocytoma, IDH-wildtype (AA-IDHwt) was the common molecular subgroup (52.8%), followed by diffuse astrocytoma, IDH-wildtype (DA-IDHwt) and AA, IDH-mutant (AA-IDHmt) (each 16.9%), DA-IDHmt (7.9%), glioblastoma (GBM)-IDHwt (3.3%) and GBM-IDHmt (2.2%). Approximately 92% of the AA-IDHwt lesions progressed to histologically confirmed GBM in the newly enhanced lesions harboring the TERTp mutation and expressing galectin-3. Similar to primary GBMs, GC-related GBMs that progressed from the IDHwt subgroups showed microvascular proliferation, palisading necrosis or thrombotic occlusion, implying that a subset of IDHwt subgroups may evolve to overt GBM. Molecular subgrouping did not provide the perfect prediction for the survival of GC patients. The AA-IDHwt group showed worse overall and progression-free survival (PFS) than the AA-IDHmt group. Biopsy plus radiotherapy, chemotherapy and temozolomide treatment for DA-IDHwt, and resection plus radiotherapy and temozolomide treatment for AA-IDHwt prolonged PFS. In conclusions, majority of GC was of the AA-IDHwt subgroup, which progressed to GBM. Molecular subgroups may assist in the selection of treatment modalities, because "GC pattern" still remains as a special growth of gliomas in WHO 2016 classification without established treatment guideline.

Background Chordomas are aggressive bone tumors that have a predilection for the axial skeleton including the skull base and spinal/sacral bones. However, the histopathological and clinical differences between skull base chordoma (SBC) and sacral/spinal chordoma (SC) are unclear as previous studies have been focused on patient prognosis and treatment outcome. This study aimed to evaluate the clinicopathologic features and prognosis of chordoma according to its location. Methods Patients with chordomas were enrolled, and the histopathologic features were compared according to the tumor location. Results A total of 52 patients were enrolled. SBCs had more abundant chondroid matrix and diffuse growth pattern, while SCs had non-chondroid, myxoid matrix and a lobulating pattern, typical of chordoma. Old age and residual tumors were risk factors for shorter overall survival in SBCs. The chondroid matrix was an independent risk factor for shorter disease-free survival in the overall population. Conclusion Chordomas have different histopathologic features depending on the anatomical location., Graphical Abstract

With the aim to investigate the outcome of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) for high-grade gliomas (HGGs), we retrospectively reviewed the medical records of 30 patients with HGGs (16 glioblastomas, 7 anaplastic astrocytomas, and 7 other HGGs) between 2006 and 2015. Gross or near total resection was possible in 11 patients. Front-line treatment after surgery was radiotherapy (RT) in 14 patients and chemotherapy in the remaining 16 patients including 3 patients less than 3 years of age. Eight of 12 patients who remained progression free and 5 of the remaining 18 patients who experienced progression during induction treatment underwent the first HDCT/auto-SCT with carboplatin + thiotepa + etoposide (CTE) regimen and 11 of them proceeded to the second HDCT/auto-SCT with cyclophosphamide + melphalan (CyM) regimen. One patient died from hepatic veno-occlusive disease (VOD) during the second HDCT/auto-SCT; otherwise, toxicities were manageable. Four patients in complete response (CR) and 3 of 7 patients in partial response (PR) or second PR at the first HDCT/auto-SCT remained event free: however, 2 patients with progressive tumor experienced progression again. The probabilities of 3-year overall survival (OS) after the first HDCT/auto-SCT in 11 patients in CR, PR, or second PR was 58.2% ± 16.9%. Tumor status at the first HDCT/auto-SCT was the only significant factor for outcome after HDCT/auto-SCT. There was no difference in survival between glioblastoma and other HGGs. This study suggests that the outcome of HGGs in children and adolescents after HDCT/auto-SCT is encouraging if the patient could achieve CR or PR before HDCT/auto-SCT., Graphical Abstract

In this study, we investigated the distribution of human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) administered via intracerebroventricular (ICV) injection in a canine model. Ten beagles (11–13 kg per beagle) each received an injection of 1 × 106 cells into the right lateral ventricle and were sacrificed 7 days after administration. Based on immunohistochemical analysis, hUCB-MSCs were observed in the brain parenchyma, especially along the lateral ventricular walls. Detected as far as 3.5 mm from the cortical surface, these cells migrated from the lateral ventricle toward the cortex. We also observed hUCB-MSCs in the hippocampus and the cervical spinal cord. According to real-time polymerase chain reaction results, most of the hUCB-MSCs were found distributed in the brain and the cervical spinal cord but not in the lungs, heart, kidneys, spleen, and liver. ICV administered hUCB-MSCs also enhanced the endogenous neural stem cell population in the subventricular zone. These results highlighted the ICV delivery route as an optimal route to be performed in stem cell-based clinical therapies for neurodegenerative diseases.

Hemangiopericytoma (HPC) in the central nervous system (CNS) is a rare disease with distinctive biological/clinical characteristics compared with meningioma. Cases of HPCs of the CNS were collected, and clinicopathological records were retrospectively reviewed and analyzed. Immunohistochemistry (IHC) for proliferative markers (Ki-67, PHH3) and STAT6 were performed. A total of 140 cases were collected, with mean follow-up of 77 months (median 58.8 months; range 0.53–540.5 months). 1-, 5-, 10-, and 20-year survival rates were 99.1, 94.0, 74.4, and 61.9 %, respectively. Thirty-nine patients (27.9 %) had recurrent disease. Mean and median times to recurrence were 62.9 and 47.3 months with 1-, 5-, 10-, and 20-year recurrence-free survival rates of 98.3, 78.3, 50.1, and 11.0 %, respectively. Thirteen patients (9.3 %) developed extracranial metastases. No adjuvant radiation therapy, higher histologic grades, failure of gross-total resection, and cases with gamma-knife surgery (GKS) were factors associated with shorter disease-free survival (log-rank test, p = 0.02, 0.00, 0.02, 0.00), among which high histologic grade and cases with GKS were significant in multivariable analysis. Strong nuclear STAT6 expression was noted in HPCs in 62 cases of HPCs (60/62, 96.8 %), whereas diffuse weak positivity was demonstrated in all meningioma cases. The survival rate in patients with HPC of the CNS is comparable to that of previously reported series. Recurrence remains a critical clinical issue of the disease. Identification of NAB2-STAT6 fusion transcript with surrogate IHC marker is a valuable diagnostic tool in the differential diagnosis of the disease.

Purpose We prospectively evaluated the effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in improving the survival of patients with atypical teratoid/rhabdoid tumors while reducing the risks of late adverse effects from radiotherapy (RT). Materials and Methods For young children (< 3 years old), tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. RT was deferred until after 3 years of age unless the tumor showed relapse or progression. For older patients (> 3 years old), RT including reduced-dose craniospinal RT (23.4 or 30.6 Gy) was administered either after two cycles of induction chemotherapy or after surgery, and tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. Results A total of 13 patients (five young and eight older) were enrolled from November 2004 to June 2012. Eight patients, including all five young patients, had metastatic disease at diagnosis. Six patients (four young and two older) experienced progression before initiation of RT, and seven were able to proceed to HDCT/auto-SCT without progression during induction treatment. Three of six patients who experienced progression during induction treatment underwent HDCT/auto-SCT as salvage treatment. All five young patients died from disease progression. However, four of the eight older patients remain progression-freewith a median follow-up period of 64 months (range, 39 to 108 months). Treatment-related late toxicities were acceptable. Conclusion The required dose of craniospinal RT might be reduced in older patients if the intensity of chemotherapy is increased. However, early administration of RT should be considered to prevent early progression in young patients.

According to the 2016 World Health Organization classification of tumors of the central nervous system, detecting 1p/19q co-deletion became essential in clinical neuropathology for gliomas with oligodendroglioma-like morphology. Here, we assessed genomic profiles of glioblastoma in 80 cases including 1p/19q status using fluorescent in situ hybridization (FISH), array-comparative genomic hybridization (aCGH), and/or whole exome sequencing (WES). Paraffin-embedded tumor tissues were subjected to FISH analysis, and the corresponding frozen tissues from the same tumors were evaluated for aCGH and/or WES for 1p/19q co-deletion and other genetic parameters, which included IDH1-R132H, ATRX, TP53, CIC, and NOTCH1 mutations and MGMT methylation status. We also evaluated correlations between 1p/19q co-deletion status and molecular markers or clinical outcomes. The FISH analyses revealed 1p/19q co-deletion in two cases, isolated deletion of 1p in six cases, and 19q in two cases, whereas the aCGH and WES results showed isolated deletion of 19q in four cases and 19 monosomy in only one case. Eleven cases showed discordant 1p/19q results between aCGH/WES and FISH analysis, and in most of them, 1p and/or 19q deletion on FISH analysis corresponded to the partial deletions at 1p36 and/or 19q13 on aCGH/WES. Our cohort exhibited IDH1-R132H mutations (5.4%), MGMT promotor methylation (34.6%), and mutations in ATRX (9.5%), TP53 (33.3%), and NOTCH1 (3.8%) but not in CIC (0%). In addition, MGMT methylation and ATRX mutation were significantly associated with clinical prognosis. In glioblastomas, partial deletions of 1p36 and/or 19q13 were uncommon, some of which appeared as 1p and/or 19q deletions on FISH analysis.

The co-occurrence of Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) is extremely rare and almost all cases were reported in adults. We describe a case of intracranial LCH and ECD that was confirmed by histopathological and molecular studies. A three-year-old boy presented with headache and right exophthalmos and brain magnetic resonance images (MRI) revealed multiple intracranial tumors. Whole body MRI showed osteolytic lesions typical of LCH in flat bones and osteosclerotic changes typical of ECD in long bones. Histologically, the biopsy samples from the posterior fossa and occipital skull mass revealed areas of both LCH and ECD. Immunohistochemically, the LCH contained CD1a-positive Langerhans cells and the ECD had CD1a-negative, CD68-positive foamy histiocytes. BRAF V600E mutations were detected in both the LCH and ECD areas. The coexistence of LCH and ECD in the same biopsy and the BRAF V600E mutation status in both histologic types support the recent re-classification of the histiocytic disorder into LCH, ECD, and “mixed histiocytosis”, which reflects tumorigenesis for all three from a common progenitor cell.

We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.

AIM Leptomeningeal enhancement (LME) on preoperative brain magnetic resonance imaging (MRI) does not always indicate leptomeningeal seeding (LMS). With Stupp's regimen, authors have treated glioblastoma patients with LME on preoperative brain MRI but here we tried to find the clinical impact of LME. METHODS From 2005 to 2015, 290 patients with glioblastoma have been treated with Stupp's regimen at Samsung Medical Center. Among these, 33 patients showed LME on preoperative brain MRI. We compared the clinical outcomes between the patients with or without LME on preoperative brain MRI and analyzed the clinical results according to changes of LME at following MRI. RESULTS The median survival was 23 months, and 2-year overall survival (OS) and disease-free survival (DFS) rate was 46.3% and 19.6%, respectively. Prognostic factors for OS and DFS were Karnofsky performance status, extent of resection and adjuvant chemotherapy. MGMT promoter methylation status was a significant prognostic factor for DFS. However, LME was not a significant prognostic factor for OS (P = 0.156) or DFS (P = 0.193). Among the 33 patients with LME on preoperative MRI, 21 (63.6%) showed persistent LME at the next MRI. A statistically significant difference in 2-year survival was evident between patients with and without persistent LME (OS, 17.3% and 70.1%, respectively, P = 0.044; DFS, 5.3% and 54.0%, respectively, P = 0.006). The most common pattern of failure was local recurrence. However, patients with persistent LME displayed a higher incidence of LMS than patients without LME. CONCLUSION LME on preoperative brain MRI did not affect the clinical results in glioblastoma patients treated with the Stupp's regimen. However, persistence of LME was associated with poor survival and high possibility of LMS. For these patients, the postoperative adjuvant treatment should focus on palliative aim or more aggressive treatment scheme should be followed to overcome the disastrous results.

Lipoblastoma is a rare tumor that is not commonly seen in the orbit. The authors present clinical features, histopathologic findings, changes in the radiologic findings over time, and the radiological–pathological correlation of orbital lipoblastoma in an infant. A 3-month-old male infant presented with a palpable mass on the left upper eyelid. The patient was observed for 1 year with magnetic resonance imaging. At the age of 15 months, the patient underwent excisional biopsy. Histopathologic examination showed features of hypocellular lobules with a mixture of adipocytes of various stages of maturity and myxoid stroma separated by prominent fibrous septa, confirming a diagnosis of orbital lipoblastoma. [ J Pediatr Ophthalmol Strabismus . 2017;54:e67–e70.]

Glioblastoma with an oligodendroglial component (GBMO) is recognized as a subgroup of glioblastoma (GBM); however, the molecular and clinicopathological characteristics of GBMO are obscure. We evaluated the methylation status of MGMT, IDH1/2 mutation, deletions of 1p and 19q and expression of IDH1, p53, p16, CD151, and galectin3 proteins in 42 GBMOs (32 primary and 10 secondary tumors). Our aims were to correlate our molecular findings with clinicopathologic features, and to compare molecular-to-clinical correlations in the 42 GBMOs with the corresponding correlations in 45 GBMs. GBMO was subdivided into two subgroups according to the predominant cell component comprising >50 % of tumors: the astrocytic predominant type (GBMO-A) and oligodendroglioma predominant type (GBMO-O). Methylation of MGMT, IDH1/2 mutation, and co-deletion of 1p and 19q were found in 31.0, 26.2, and 17.9 % of patients with GBMO, respectively. Clinicopathological and molecular characteristics did not differ significantly between GBMO-A and GBMO-O. However, patients with GBMO-O experienced better outcomes than patients with GBMO-A (p = 0.007). On multivariate analysis the predominant cell type was an independent prognostic factor in overall survival [hazard ratio 4.2 (95 % confidence interval 1.4–12.8), p = 0.011]. When compared to patients with classic GBM, those with GBMO were younger (49.21 vs. 57.47, p = 0.003) and more frequently had tumors with IDH1 mutation (23.8 vs. 4.4 %, p = 0.009). Survival was similar in patients with GBMO and with classic GBM. Based on these results, GBMO may represent a subgroup of GBM that is associated with IDH1 mutation and younger age, although similar to classic GBM in prognosis.

A case of intracranial malignant peripheral nerve sheath tumor (MPNST) with uncommon features due to recurrence is reported. The primary tumor showed typical histopathological features of MPNST with wavy nuclei and S-100 positivity. The patient's latest recurrent tumor resembled undifferentiated sarcoma with lipoblast-like multivacuolated cells and hyaline globules (HGs). Ultrastructurally, the vacuolated spaces contained granular materials derived from cystic dilation of the rough endoplasmic reticulum. The HG consisted of round osmophilic inclusions with or without a limiting membrane. The HGs and lipoblast-like multivacuolated cells may have been caused by the degeneration of tumor cells in myxoid stroma and abundant vasculature.

A set of proteins reflecting the prognosis of patients have clinical significance since they could be utilized as predictive biomarkers and/or potential therapeutic targets. With the aim of finding novel diagnostic and prognostic markers for glioblastoma (GBM), a tissue microarray (TMA) library consisting of 62 GBMs and 28 GBM-associated normal spots was constructed. Immunohistochemistry against 78 GBM-associated proteins was performed. Expression levels of each protein for each patient were analyzed using an image analysis program and converted to H-score [summation of the intensity grade of staining (0-3) multiplied by the percentage of positive cells corresponding to each grade]. Based on H-score and hierarchical clustering methods, we divided the GBMs into two groups (n=19 and 37) that had significantly different survival lengths (p0.05). In the two groups, expression of nine proteins (survivin, cyclin E, DCC, TGF-β, CDC25B, histone H1, p-EGFR, p-VEGFR2/3, p16) was significantly changed (q0.05). Prognosis-predicting potential of these proteins were validated with another independent library of 82 GBM TMAs and a public GBM DNA microarray dataset. In addition, we determined 32 aberrant or mislocalized subcellular protein expression patterns in GBMs compared with relatively normal brain tissues, which could be useful for diagnostic biomarkers of GBM. We therefore suggest that these proteins can be used as predictive biomarkers and/or potential therapeutic targets for GBM.

Neuroblastoma (NB) is one of the most common malignant pediatric tumors that show aggressive behavior. Most advanced-stage NBs have proven refractory to many treatment modalities, and a fundamental alternative therapy, such as inhibition of biological pathways, is now being explored. Anaplastic lymphoma kinase (ALK) has recently been identified as an activation mutation in familial or high-risk sporadic NBs. We examined the prevalence of the ALK mutation in 54 NB cases (23 pre-treatment cases and 31 cases for which specimens were available before and after treatment) and the presence of the ALK mutation in various pediatric tumors. We detected the ALK mutation (F1174C and R1275Q) in 2 (3.7%) of the 54 NB specimens. Both cases showed poorly differentiated and advanced-stage NBs. No ALK mutations were detected in other pediatric tumors. The frequency of the ALK mutation was somewhat lower than that expected in Korean patients with NBs. The mutation detected in the present study was one of the hotspot mutations, including positions of F1174 and R1275 reported previously. The results of the present study suggest the possibility of potential roles of ALK inhibitors in the therapeutics of a small population of neuroblastoma carrying mutated ALK kinases.

Pilomyxoid astrocytoma (PMA) is a recently described astrocytic tumor that has been previously diagnosed as pilocytic astrocytoma (PA). The purpose of this study was to describe the imaging features of PMAs in comparison with PAs.We retrospectively reviewed CT/MR images and medical records of 10 patients with PMA and 38 patients with PA. The mean ages of patients with PMA and PA were 10 and 15 years, respectively. Imaging features including location, composition, enhancement pattern, presence of calcification, hemorrhage, and leptomeningeal dissemination were compared in patients with two tumor types.Six PMAs (60%) occurred at the suprasellar area and the cerebellum was the most common (45%) site of PA. Solid component was dominant in eight PMAs (80%) and in 19 PAs (50%). All of the PMAs containing solid mass (n=8) included non-enhancing portion while 12/37 (32%) PAs included non-enhancing solid portion (p0.05). Leptomeningeal dissemination was noted in five PMAs (50%) and one PA (3%) (p0.05). Other imaging findings were not significantly different.A younger age, more frequent occurrence at the suprasellar area, mainly solid mass containing non-enhancing portion, and more frequent leptomeningeal dissemination are helpful differential features of PMAs as compared to PAs.

In this study, we evaluated the results of multimodal treatment that included tandem HDCT/auto-SCT in children with anaplastic ependymomas. Fourteen patients with anaplastic ependymomas were enrolled from 2006 to 2014. Six cycles of induction chemotherapy were administered to all patients before they underwent tandem HDCT/auto-SCT. Patients who were older than 3 years of age were administered RT after two cycles of induction chemotherapy. In patients under 3 years of age, RT was either omitted or delayed until they reached 3 years of age, if the patients experienced CR after tandem HDCT/auto-SCT. All patients, including two who experienced disease progression during induction treatment, underwent the first HDCT/auto-SCT, and 13 subsequently underwent the second HDCT/auto-SCT. One patient died from hepatic VOD during the second HDCT/auto-SCT; other toxicities occurring during tandem HDCT/auto-SCT were manageable. Relapses or progression occurred in seven patients, and five of seven of them remain alive till date after salvage treatment, including surgery and RT. The 5-year overall and event-free survival rates were 85.1% ± 9.7% and 50.0% ± 13.4%, respectively. These findings suggest that multimodal treatment including tandem HDCT/auto-SCT could be a feasible option for improving survival in children with anaplastic ependymomas.

Purpose Obtaining brain tissue is critical to definite diagnosis and to furthering understanding of neurodegenerative diseases. The present authors have maintained the National Neuropathology Reference and Diagnostic Laboratories for Dementia in South Korea since 2016. We have built a nationwide brain bank network and are collecting brain tissues from patients with neurodegenerative diseases. We are aiming to facilitate analyses of clinic-pathological and image-pathological correlations of neurodegenerative disease and to broaden understanding thereof. Materials and methods We recruited participants through two routes: from memory clinics and the community. As a baseline evaluation, clinical interviews, a neurological examination, laboratory tests, neuropsychological tests, and MRI were undertaken. Some patients also underwent amyloid PET. Results We recruited 105 participants, 70 from clinics and 35 from the community. Among them, 11 died and were autopsied. The clinical diagnoses of the autopsied patients included four with Alzheimer's disease (AD), two with subcortical vascular dementia, two with non-fluent variant primary progressive aphasia, one with leukoencephalopathy, one with frontotemporal dementia (FTD), and one with Creutzfeldt-Jakob disease (CJD). Five patients underwent amyloid PET: two with AD, one with mixed dementia, one with FTD, and one with CJD. Conclusion The clinical and neuropathological information to be obtained from this cohort in the future will provide a deeper understanding of the neuropathological mechanisms of cognitive impairment in Asia, especially Korea.

Objective: Dysembryoplastic neuroepithelial tumors (DNTs) are benign cortical tumors that are frequently associated with the medically intractable focal epilepsy. In this study, the authors delineate the clinical characteristics of DNTs in children and evaluate the role of cortical dysplasia (CD) in the epileptogenicity to find out the optimum surgical strategy. Methods: A retrospective analysis was performed for clinical data of children with DNT, who underwent surgery between 1996 and 2006. The adopted surgical methods were uniform according to the tumor location and included intraoperative electrocorticography (ECoG)-guided resection. The prognostic factors were evaluated for the two prognostic group categorized by the seizure outcome at one year after surgery. Results: Of 22 patients, the overall seizure free rate was 90.9% and the other two patients belonged to Engel class II during the mean follow-up period of 44.1 months. There was no worsening of the seizure after one year of surgery. Associated CD was found in 18 cases (81.8%) and in the 80% (8 of 10 cases) of the additionally resected areas according to the electrophysiologic studies. Conclusions: The CD associated with DNT appears to have its own epileptogenicity. Therefore, complete removal of the CD with tumor itself is important for patient outcome. A thorough surgical approach can be accomplished by comprehensive presurgical evaluations and extensive surgery with the aid of the intraoperative ECoG or intracranial recording. 2008 Elsevier B.V. All rights reserved.

Meningioangiomatosis (MA) is a rare lesion appearing sporadically or as a part of neurofibromatosis 2. The occurrences of meningiomas arising from MA (MA-M) have raised doubts about the traditional concept of a hamartomatous origin for MA. Cytogenetic or molecular studies on MA, with or without meningiomas, are limited because of the rarity of MA. The current study was to evaluate the loss of heterozygosity (LOH) in seven cases of MA-M and two cases of pure MA. LOH on six chromosomes (1p32, 9p21, 13q14, 16q22, 17p, and 22q12) were investigated using 13 sets of microsatellite markers, including D1S193, D1S463, D22S193, D22S929, D22S282, TP53, D17S796, D16S421, D16S512, D13S118, D13S153, D9S162, and D9S104. PCR was performed using each marker and polymorphic analysis was accomplished by silver staining. Immunohistochemical stain for Ki-67 was carried out and labeling index was measured by using a semiquantitative manual counting method. The meningioma portions of MA-Ms showed LOH for loci on chromosomes 22q12, 9p21, and 1p32 in 57.1% (4/7), 28.6% (2/7), and 28.6% (2/7) of cases, respectively. The MA portions of MA-M had a LOH for loci on 22q12 in 28.6% (2/7) of cases, whereas each pure MA harbored one LOH on either chromosome 22q12 or 9p21. The proliferation indices of MA-Ms were significantly higher in the meningioma than in the MA components. Our data suggest that both the meningioma and the MA undergo the same overlapping clonal process, with the MA-M while undergoing additional genetic alterations that confer a greater proliferative potential.

Objective: Gliomatosis cerebri (GC) is defined as a diffuse neoplastic glial cell infiltration of the brain with the preservation of anatomical architecture and the sparing of neurons and can be classified into Type 1 (diffuse) and Type 2 (mass forming) GCs macroscopically. There is little information on subtypes of GC. The aim of this study was to evaluate the clinicopathologic findings of GCs and to compare the clinicopathologic findings between Type 1 and Type 2 GCs. Material: A total of 33 cases of GC were obtained from pathology file of Samsung Medical Center. The diagnosis was based on magnetic resonance imaging findings and histological confirmation for all patients. Fifteen cases were classified into Type 1 and 18 were Type 2 based on the MR images. Methods: Clinical information included patients' age, sex, tumor extent, treatment modality and survival. Pathologic features included the amount of rod cells and cytologic anaplasia such as multinucleated tumor giant cells, endothelial cell proliferation, or mitosis. Immunohistochemical study was performed for GFAP, O1, Gal-C, Ki-67, and p53. Clinicopathologic comparison between subtypes and statistical analysis were performed. Results: Median age at diagnosis was older (56 years) in Type 1 than in Type 2 (44 years). Male to female ratio was about 1.54:1. Mean survival time was shorter (21 months) in Type 2 than in Type 1 GCs (24 months) (p = 0.0447). Histologically, 33 cases of GC were classified into two histologic grades (low and high grade) by cytologic anaplasia. High-grade GC was more common in Type 2 than Type 1 (p = 0.027). Immunohistochemical results demonstrated that the infiltrating tumor cells were undifferentiated cells with astrocytic or oligodendroglial differentiation. Ki-67 labeling index was correlated with subtypes (p = 0.0096). Pathologic features were not correlated with survival. Conclusions: Type 1 and 2 GCs are somewhat different in clinical presentation and pathologic features. The age group, survival time, histologic grade, and Ki-67 labeling index were significantly correlated with subtypes of GCs. Type 2 GC was correlated with poor survival but histologic grade was not.

Teratoid Wilms' tumor is a rare variant of Wilms' tumor (WT) that has been reported exclusively in pediatric patients. The present paper describes a teratoid WT in a 50-year-old Korean man with a giant right renal mass. Radical nephrectomy was performed under the impression that the mass was a renal cell carcinoma. Grossly, the removed kidney contained a giant well-encapsulated mass measuring 24 x 18 x 10 cm with cystic changes, necrosis, and hemorrhage. On microscopy triphasic patterns of WT and prominent heterologous components were seen, including rhabdomyoblasts, neuroepithelial tissue, fat, cartilage, and various types of mature epithelium. This is the first reported case of a teratoid WT occurring in an adult kidney.

Dysembryoplastic neuroepithelial tumors (DNTs) are benign glial-neuronal neoplasms with characteristic cliniopathologic features. Three histologic forms of DNTs have been described (simple, complex, and non-specific). The developmental origin of the tumors remains controversial. To determine the developmental origin and nature of the histologic forms of DNTs, immunohistochemical studies of nestin, TrkA, TrkB, p75, and NeuN were conducted in 40 cases of DNTs, including 11, 9, and 20 simple, complex, and non-specific forms, respectively. Nestin positivity of oligodendroglia-like cells (OLCs) was present in 50 and 27.3% of simple and complex forms, respectively. In the non-specific form of DNT, 94.7% of the cases were positive for nestin. Most DNTs exhibited diffuse, strong staining for TrkA and TrkB, irrespective of the histologic subtypes. Both p75 and NeuN positivity were found in about one-half of the simple, complex, and non-specific forms, respectively. Our study suggests that OLCs are a heterogeneous population of cells, and higher expression of nestin in the non-specific form of DNTs compared to the simple or complex forms suggests that the non-specific form has an earlier developmental origin than the simple or complex forms.

Some basal ganglia germinomas are difficult to diagnose in early stage of disease due to vague initial presentation without discernable mass lesion on brain imaging. We performed this study to determine the usefulness of 11C-methionine positron emission tomography (MET PET) for the diagnosis and monitoring of disease activity. MET PET was performed in three consecutive patients; they presented with cerebral hemiatrophy without definite mass lesions on brain image. The maximum standard tracer uptake values (max SUVs) were calculated and used for the quantitative evaluation of the abnormal MET uptake. A pathological diagnosis was made after stereotactic biopsy using MET PET/computed tomography. The max SUVs significantly decreased after treatment. Basal ganglia germinoma should be considered in the differential diagnosis of patients with progressive hemiparesis and hemiatrophy on magnetic resonance imaging. The MET PET was useful for diagnosis, and it can be valuable in evaluation of treatment effects and monitoring for tumor recurrence.

Intracerebral granular cell tumors (GCTs) are a rare finding. We report here on a case of cerebral GCT in a 47-year-old man who suffered with severe headache. The tumor appeared as a relatively well-defined, enhancing mass at the periventricular white matter of the left occipital lobe of the brain. Histologically, the tumor was entirely composed of granular cells. Some of the tumor cells showed peripherally accentuated cytoplasmic granules with central clearing, which produced a unique "targetoid" appearance. The granular cells of the current case were positive for neuron-specific enolase (NSE), S-100 protein, GFAP, vimentin, CD 68, lysozyme, and alpha-1-antitrypsin. These wide immunoexpressions were not observed for the previously reported cerebral GCTs. Interestingly, this case showed "targetoid" or "reversed targetoid" immunoreactive patterns in NSE, CD68, GFAP, and vimentin. Despite these wide immunoexpressions and the lack of any association with astrocytoma, the histogenesis of cerebral GCTs is still suggested to be of a glial origin, based on the tumor location, the GFAP positivity and the ultrastructural findings, of which the latter showed intermediate filaments, and these are reminiscent of neoplastic astrocytes.

Aims The endothelium has emerged recently as a therapeutic target in the treatment of hypertension because endothelial dysfunction and subsequent vascular rarefaction cause target organ damage and further elevate blood pressure (BP). It led us to hypothesize that one of the endothelial survival factors, a potent derivative of angiopoietin-1 (cartilage oligomeric matrix protein, COMP-Ang-1), could be a novel class of antihypertensive agents that maintain endothelial integrity and function, thereby preventing the development of hypertension and target organ damage. Methods and results To study the role of COMP-Ang-1 in preventing hypertension and target organ damage, a COMP-Ang-1 plasmid was electroporated into adductor muscles of 6 weeks old, pre-hypertensive, spontaneously hypertensive rats (SHRs), and the secretion of its expressed protein into the bloodstream was confirmed by western blotting. In comparison with sham and reporter gene transfer, COMP-Ang-1 gene transfer significantly prevented increases in systolic BP and reduced microvascular rarefaction and tissue damage in the heart and kidney. However, overexpression of soluble Tie2 receptor completely abolished these beneficial effects of COMP-Ang-1 gene transfer on SHRs, indicating that expressed COMP-Ang-1 protein has antihypertensive effects in SHRs by binding Tie2 receptors on the vascular endothelium. In particular, COMP-Ang-1 gene-transferred SHRs had significantly higher plasma levels of nitrite than other controls, which was found to be due to that expressed COMP-Ang-1 protein promoted nitrite synthesis by activating endothelial nitric oxide synthase, one of the Tie2 downstream-signalling molecules. Conclusion The present study suggests a new potential of endothelial survival factor, COMP-Ang-1, as an antihypertensive agent that effectively reduces the hypertension-associated cardiovascular and renal damage, as well as prevents the further elevation of BP.

We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

Background Wnt5a, a non-canonical Wnt ligand, has been shown to play tumor-promoting or tumor-suppressive roles in different neoplasms. Increased Wnt5a expression and Wnt5a-dependent invasive activity that is mediated by one of its receptors, Ryk, have been reported in glioblastomas. Methods We investigated the protein expression of Wnt5a, its receptors Ryk and Ror2, and the canonical Wnt pathway marker β-catenin in 186 cases of glioblastoma and its variants. Associations with clinicopathological and molecular variables and prognosis were analyzed. Results All glioblastoma cases expressed Wnt5a, Ryk and Ror2 with a different grade. The expression of both Ryk and Ror2 correlated with that of Wnt5a in glioblastomas. The expression of β-catenin did not correlate with any of Wnt5a, Ryk or Ror2. Wnt5a expression was significantly different among subgroups of the glioblastoma. However, none of Wnt5a, Ryk or Ror2 had a prognostic impact on glioblastoma. For β-catenin, a shorter progression-free survival was noted in the glioblastoma with oligodendroglioma component (GBMO) subgroup. Conclusions Our results corroborated previous findings of Ryk-mediated Wnt5a effect, and suggested a role for Ror2 in the Wnt5a machinery in glioblastoma.

Mesenchymal hamartoma (MH) of the liver is an uncommon benign lesion related to ductal plate malformation. It is usually cystic and mainly composed of myxoid mesenchymal tissue with tortuous or cystic bile ducts. In order to characterize the clinicopathological features of MH, the Korean Gastrointestinal Pathology Study Group collected a total of 17 MH cases diagnosed in 7 hospitals from 1992 to 2002 and compared the clinicopathologic findings of cystic MH with those of solid variant. Among the 17 cases, 7 (41%) were solid. The solid form showed a higher serum level of alpha-fetoprotein (AFP), the smaller bile ducts, and more frequent proliferation of vessels. Serum AFP level was related to the amount of hepatocytes. Two of seven solid cases harbored a larger amount of evenly distributed hepatocytes and proliferation of small duct with focal hepatocyte-bile duct transition. These histologic findings are similar to those of mixed hamartoma. Therefore, the mixed hamartoma and the MH of both solid and cystic types could be the variants of one disease spectrum. And hepatocytes within MH might be rather a genuine tumor component than entrapped into the tumor. In conclusion, MH can show various clinicopathological features and recognition of these features will facilitate accurate diagnosis of MH.

The authors report the clinical presentations, radiological findings, and treatment outcome of thymic carcinoma patients with cerebral metastasis. The authors retrospectively reviewed the medical records of 49 patients with thymic carcinoma and 6 of them (12.2%) developed brain metastasis. There were 4 men and 2 women with a mean age of 48 years (ranging from 33 to 56 years). The pathological types of thymic carcinoma which developed brain metastasis were thymic carcinoma type C of the WHO classification in three patients, type B3 in one and carcinoid tumor in two patients. Surgical resection was performed as an initial treatment for brain lesions in three patients. Five patients received whole brain radiation therapy (WBRT) and radiosurgery was performed in one of them. The survival time was from 2 months in a patient with no treatment for brain lesions to 9 months in a patient who is still alive after surgical resection combined with WBRT and radiosurgery. There is high probability of metastasis particularly in thymic carcinoma type C or carcinoid tumor. Frequent surveillance and aggressive therapeutic approach are necessary to improve survival in these patients with cerebral involvement.

Background We report on our experience with epilepsy surgery in the treatment of localization-related epilepsy caused by dysembryoplastic neuroepithelial tumor (DNT) aimed at achieving the best seizure control. Methods A retrospective analysis was performed on the pathological reports as well as on clinical data of 24 case patients with medically intractable epilepsy with DNT treated surgically between 1995 and 2000 at the Samsung Medical Center. Resective surgery was performed using subdural electrodes or intraoperative electrocorticography in all patients. Results The mean follow-up period was 57.2 months. Two patients had rare seizures transiently after surgery but remained free from seizures after 6 months. Others remained completely free from seizures. There was a strong tendency of temporal lobe involvement (19 cases; 79.2%). Size of tumors located at medial temporal regions was significantly smaller than those at lateral temporal or frontal lobes (P < .05). A rather radical resection (tumor plus surrounding tissue showing active epileptogenicity) was performed in all but one case where only focal lesionectomy was done. In 20 of the 24 cases (83.3%), association of cortical dysplasia (CD) was found on pathological examination. Conclusions We conclude that DNT is frequently associated with CD, with a wide area of epileptogenic activity that might be related to the presence of CD around the DNT. Comprehensive preoperative investigations for accurate localization of epileptogenic activity, meticulous brain mapping, and a rather radical resection of pathological areas might be essential for the achievement of excellent seizure control in DNT-associated epilepsy.

To analyze the clinicopathologic characteristics of childhood non-Hodgkin's lymphoma (NHL) associated with Epstein-Barr virus (EBV), EBER in situ hybridization was performed in 80 cases of NHLs. EBER-positive lymphomas account for 25% (20/80) and include NK/T-cell lymphoma (6/6), aggressive NK-cell leukemia (1/1), peripheral T cell lymphoma (5/11), diffuse large B-cell lymphoma (5/14), hydroa-like T-cell lymphoma (1/1), marginal zone B-cell lymphoma (1/2), and post-transplantation lymphoproliferative disorder (1/1). Other types including 19 cases of Burkitt's lymphoma were negative. For 9 EBER-positive cases, immunohistochemical staining for LMP-1, and EBNA-2 was performed to determine the EBV latency pattern. Two of nine EBER-positive cases expressed both LMP-1 and EBNA-2. Clinically, patients with EBV-positive B-cell lymphomas were cured with chemotherapy, whereas EBV-associated NK- and T cell lymphomas pursued fatal clinical course. In conclusion, EBVs infected in childhood NHLs are frequently associated not only with NK- and T- cell lymphomas but also large B-cell lymphomas.

HUlip is a human homologue of a C. elegans gene, unc-33, that is developmentally regulated during maturation of the nervous system. HUlip is highly expressed only in the fetal brain and spinal cord, and is undetected in the adult brain. The purpose of this study was to investigate the pattern of hUlip expression in the developing human brain and nervous system tumors. Ten human brains at different developmental stages and 118 cases of nervous system tumor tissues were examined by immunohistochemistry. Twelve related tumor cell lines were also analyzed by northern blotting and immunoblotting. HUlip was expressed in late fetal and early postnatal brains; strongly in the neurons of the brain stem, basal ganglia/thalamus, and dentate gyrus of the hippocampus, and relatively weakly in the cerebral and cerebellar cortex. Among tumors, hUlip expression was easily detected in tumor cells undergoing neuronal differentiation such as ganglioneuroblastomas and ganglioneuromas. Furthermore, hUlip immunoreactivity was also found in various brain tumors showing neuronal differentiation: central neurocytomas (6 of 6 cases were positive), medulloblastomas (5/11), atypical teratoid rhabdoid tumor (1/1) and gangliogliomas (4/7). Some astrocytic tumors also showed weak positivity: astrocytomas (1 of 5 cases), anaplastic astrocytomas (2/5), and glioblastomas (3/11). Subependymal giant cell astrocytomas and subependymomas, which are of controversial histogenetic origin, showed strong hUlip immunoreactivity. The results of this study indicate that the expression of hUlip protein is distinctly restricted to the late fetal and early postnatal periods of human nervous system development and to certain subsets of nervous system tumors. The exact function of hUlip needs to be further clarified; yet the results of our study strongly imply that hUlip function is important in human nervous system development and its aberrant expression in various types of nervous system tumors suggests a role of hUlip as an oncofetal neural antigen.

Pulmonary hypertension (PH) is characterized by structural and functional changes in the lung including proliferation of vascular smooth muscle cells (VSMCs) and excessive collagen synthesis. Although connective tissue growth factor (CTGF) is known to promote cell proliferation, migration, adhesion, and extracellular matrix production in various tissues, studies on the role of CTGF in pulmonary hypertension have been limited. Here, we examined CTGF expression in the lung tissues of male Sprague Dawley rats treated with monocrotaline (MCT, 60 microg/kg), a pneumotoxic agent known to induce PH in animals. Establishment of PH was verified by the significantly increased right ventricular systolic pressure and right ventricle/left ventricle weight ratio in the MCT-treated rats. Histological examination of the lung revealed profound muscular hypertrophy in the media of pulmonary artery and arterioles in MCT-treated group. Lung parenchyma, vein, and bronchiole did not appear to be affected. RT-PCR analysis of the lung tissue at 5 weeks indicated significantly increased expression of CTGF in the MCT-treated group. In situ hybridization studies also confirmed abundant CTGF mRNA expression in VSMCs of the arteries and arterioles, clustered pneumocytes, and infiltrated macrophages. Interestingly, CTGF mRNA was not detected in VSMCs of vein or bronchiole. In saline-injected control, basal expression of CTGF was seen in bronchial epithelial cells, alveolar lining cells, and endothelial cells. Taken together, our results suggest that CTGF upregulation in arterial VSMC of the lung might be important in the pathogenesis of pulmonary hypertension. Antagonizing the role of CTGF could thus be one of the potential approaches for the treatment of PH.