Brain and Spinal Tumors Originating from the Germ Line Cells.

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, ß-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations, hydrocephalus, and serum/CSF titer of ß-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life.

A multi-targeting bionanomatrix coating to reduce capsular contracture development on silicone implants.

BACKGROUND: Capsular contracture is a critical complication of silicone implantation caused by fibrotic tissue formation from excessive foreign body responses. Various approaches have been applied, but targeting the mechanisms of capsule formation has not been completely solved. Myofibroblast differentiation through the transforming growth factor beta (TGF-ß)/p-SMADs signaling is one of the key factors for capsular contracture development. In addition, biofilm formation on implants may result chronic inflammation promoting capsular fibrosis formation with subsequent contraction. To date, there have been no approaches targeting multi-facted mechanisms of capsular contracture development. METHODS: In this study, we developed a multi-targeting nitric oxide (NO) releasing bionanomatrix coating to reduce capsular contracture formation by targeting myofibroblast differentiation, inflammatory responses, and infections. First, we characterized the bionanomatrix coating on silicon implants by conducting rheology test, scanning electron microcsopy analysis, nanoindentation analysis, and NO release kinetics evaluation. In addition, differentiated monocyte adhesion and S. epidermidis biofilm formation on bionanomatrix coated silicone implants were evaluated in vitro. Bionanomatrix coated silicone and uncoated silicone groups were subcutaneously implanted into a mouse model for evaluation of capsular contracture development for a month. Fibrosis formation, capsule thickness, TGF-ß/SMAD 2/3 signaling cascade, NO production, and inflammatory cytokine production were evaluated using histology, immunofluorescent imaging analysis, and gene and protein expression assays. RESULTS: The bionanomatrix coating maintained a uniform and smooth surface on the silicone even after mechanical stress conditions. In addition, the bionanomatrix coating showed sustained NO release for at least one month and reduction of differentiated monocyte adhesion and S. epidermidis biofilm formation on the silicone implants in vitro. In in vivo implantation studies, the bionanomatrix coated groups demonstrated significant reduction of capsule thickness surrounding the implants. This result was due to a decrease of myofibroblast differentiation and fibrous extracellular matrix production through inhibition of the TGF-ß/p-SMADs signaling. Also, the bionanomatrix coated groups reduced gene expression of M1 macrophage markers and promoted M2 macrophage markers which indicated the bionanomatrix could reduce inflammation but promote healing process. CONCLUSIONS: In conclusion, the bionanomatrix coating significantly reduced capsular contracture formation and promoted healing process on silicone implants by reducing myfibroblast differentiation, fibrotic tissue formation, and inflammation. A multi-targeting nitric oxide releasing bionanomatrix coating for silicone implant can reduce capsular contracture and improve healing process. The bionanomatrix coating reduces capsule thickness, α-smooth muscle actin and collagen synthesis, and myofibroblast differentiation through inhibition of TGF-ß/SMADs signaling cascades in the subcutaneous mouse models for a month.

MiR-146a encapsulated liposomes reduce vascular inflammatory responses through decrease of ICAM-1 expression, macrophage activation, and foam cell formation.

Vascular insults can create an inflammatory cascade involving endothelial cell, smooth muscle cell, and macrophage activation which can eventually lead to vascular disease such as atherosclerosis. Several studies have identified microRNA 146a's (miR-146a) anti-inflammatory potential based on its role in regulating the nuclear factor kappa beta (NF-κß) pathway. Therefore, in this study, we introduced exogenous miR-146a encapsulated by liposomes to lipopolysaccharide (LPS) stimulated vascular cells and macrophages to reduce inflammatory responses. First, the miR-146a encapsulated liposomes showed uniform size (radius 96.4 ± 4.22 nm) and round shape, long term stability (at least two months), high encapsulation efficiency (69.73 ± 0.07%), and were well transfected to human aortic endothelial cells (HAECs), human aortic smooth muscle cells (SMCs), and human differentiated monocytes (U937 cells). In addition, we demonstrated that miR-146a encapsulated liposomes reduced vascular inflammation responses in HAECs and SMCs through inhibition of ICAM-1 expression and decreased monocyte adhesion. In macrophages, miR-146a liposome treatment demonstrated decreased production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), as well as reduced oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation. Thus, based on these results, miR-146a encapsulated liposomes may be promising for reducing vascular inflammation by targeting its multiple associated mediators.

Establishment of quantitative indicators for an efficient treatment on masticatory muscle pain.

BACKGROUND: Although several studies have investigated effective treatments for masticatory muscle pain (MMP), no unified conclusion has been drawn regarding the effectiveness of these treatments. OBJECTIVES: This study aimed to define quantitative indicators for predicting the outcome of MMP treatment. MATERIALS AND METHODS: In total, patients aged 20-70 years were recruited and divided into the MMP (n = 24) and control (n = 36) groups, based on the presence of MMP according to the Diagnostic Criteria for Temporomandibular Disorders. At pretreatment, the MMP group was assessed using quantitative indicators such as subjective pain levels, pain duration, graded chronic pain scale (GCPS), and perceived stress scale (PSS). Salivary alpha-amylase (sAA) and interleukin-6 (IL-6) levels were analyzed. The masticatory muscle palpation score and the range of mouth opening were measured. At posttreatment, subjective pain levels, mouth opening, and treatment/medication duration were examined. The PSS and sAA levels were assessed in the control group. RESULTS: sAA levels in the MMP group were significantly higher than those in the control group (p < .05). The masseter muscle palpation score (MPS) showed a positive correlation with IL-6 levels (ρ = 0.503, p < .05) and a negative correlation with nonsteroidal anti-inflammatory drug (NSAID) treatment period (ρ = -0.462, p < .05). The temporalis muscle palpation score (TPS) was positively correlated with pain duration and GCPS grade (ρ = 0.483, p < .05, and ρ = 0.445, p < .05, respectively). CONCLUSIONS: Treatment with NSAIDs was effective in the MMP group with high MPS and IL-6 levels, but not in the MMP group with high TPS, pain duration, and GCPS grade.

Evaluation of children's pain expression and behavior using audio visual distraction.

OBJECTIVES: Dental anxiety distresses children and their families with consequent poor oral health and costly pediatric dental services. Children's behaviors could be modified using a distraction technique for improved dental treatment. The study evaluates the effects of an audio-visual distraction on children's behaviors and pain expressions during dental treatment. MATERIAL AND METHODS: One hundred healthy children, between 4 and 6 years of age, were randomly assigned to one of two groups: audio visual distraction (AVD, N = 61) group and control (CTR, N = 39) group. The pre and post pain expression was collected using a faces pain rating scale from the participated children. Children's behavior was evaluated using the Frankl behavior rating scale by the assigned dentist. Data was analyzed using chi-squared tests and analysis of variance. RESULTS: The AVD group demonstrated more "definitely positive" behavior (91.8%) compared to the CTR group (35.9%) based on the Frankl scale evaluation from pre- and post-treatment (p < 0.0001). The pain rating scale did not demonstrate a significant difference in post-treatment pain scales (p = 0.2073) or changes in pain (p = 0.1532) between the AVD group and CTR group. CONCLUSIONS: The AVD is an effective distraction tool for young children during dental treatment regardless of child's subjective pain expression.

Regulation of extracellular and intracellular prolactin on cell proliferation and survival rate through GHR/JAK2/STAT3 pathway in NSCLC.

Styrene increases serum prolactin (PRL) concentration. Hyperprolactinemia is associated with poor prognosis in lung cancer patients, but the mechanism of PRL action is unclear. The aims of this study were to (i) investigate the mechanism of PRL-action receptor in NSCLC cells (ii) measure whether PRL was secreted by NSCLC cells and its stimulatory mechanism in vitro and in vivo. We found that cell proliferation was increased after treatment of a pharmacological dose of PRL in A549 cells, which through up regulation of growth hormone receptor (GHR) and downstream of JAK2/STAT3/VEGF pathway. All NSCLC cells in the present study secreted PRL and expressed GHR, but not PRLR. Inhibition of GHR protein level led to decrease the PRL-induced cell proliferation. PRL was detected in NSCLC cells culture medium. Knockdown of intracellular PRL downregulated JAK2/STAT3 protein activities and GHR and VEGF protein levels. Furthermore, knockdown of intracellular PRL reduced the cell proliferation and the ability of colony-forming. In lung cancer tissues, PRL, GHR and VEGF levels were higher in the tumor tissues than in normal tissues and the protein expressions of these three proteins are positively correlated, respectively. High expression levels of both PRL and GHR cause a poor survival rate in lung cancer patients. Taken together, our results suggested that extracellular and intracellular PRL were involved in cell proliferation through GHR. Combination of in vitro and in vivo results, GHR and PRL are important targets for suppressing NSCLC cell proliferation, which might improve the survival rate in NSCLC patients.

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors.

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan.

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

Pulp-Dentin Tissue Healing Response: A Discussion of Current Biomedical Approaches.

Dental pulp tissue exposed to mechanical trauma or cariogenic process results in root canal and/or periapical infections, and conventionally treated with root canal procedures. The more recent regenerative endodontic procedure intends to achieve effective root canal disinfection and adequate pulp-dentin tissue regeneration; however, numerous limitations are reported. Because tooth is composed of vital soft pulp enclosed by the mineralized hard tissue in a highly organized structure, complete pulp-dentin tissue regeneration has been challenging to achieve. In consideration of the limitations and unique dental anatomy, it is important to understand the healing and repair processes through inflammatory-proliferative-remodeling phase transformations of pulp-dentin tissue. Upon cause by infectious and mechanical stimuli, the innate defense mechanism is initiated by resident pulp cells including immune cells through chemical signaling. After the expansion of infection and damage to resident pulp-dentin cells, consequent chemical signaling induces pluripotent mesenchymal stem cells (MSCs) to migrate to the injury site to perform the tissue regeneration process. Additionally, innovative biomaterials are necessary to facilitate the immune response and pulp-dentin tissue regeneration roles of MSCs. This review highlights current approaches of pulp-dentin tissue healing process and suggests potential biomedical perspective of the pulp-dentin tissue regeneration.

Candida Infection Associated with Salivary Gland-A Narrative Review.

Candida species are common global opportunistic pathogens that could repeatedly and chronically cause oral mucosa infection and create an inflammatory environment, leading to organ dysfunction. Oral Candida infections may cause temporary or permanent damage to salivary glands, resulting in the destruction of acinar cells and the formation of scar tissue. Restricted function of the salivary glands leads to discomfort and diseases of the oral mucosa, such as dry mouth and associated infection. This narrative review attempts to summarize the anatomy and function of salivary glands, the associations between Candida and saliva, the effects of Candida infection on salivary glands, and the treatment strategies. Overall, clinicians should proactively manage Candida infections by educating patients on oral hygiene management for vulnerable populations, conducting frequent checks for a timely diagnosis, and providing an effective treatment plan.

Loss of BCAT1 Expression is a Sensitive Marker for IDH-Mutant Diffuse Glioma.

BACKGROUND: IDH mutation is an important prognostic factor of diffuse astrocytomas. Although the majority of IDH mutations could be identified by immunohistochemical (IHC) stain for R132H-mutant IDH1, DNA sequencing would be required for IHC negative cases to determine their IDH mutation status. This approach is not cost-effective for tumors with low IDH mutation rates. OBJECTIVE: To investigate whether BCAT1 could be used as a surrogate marker for IDH mutations, because BCAT1 is an enzyme related to IDH genes. METHODS: A group of 120 anaplastic astrocytomas were immunostained for BCAT1, ATRX, and R132H-mutant IDH1. Staining results correlated with the results of DNA sequencing of IDH1/IDH2. RESULTS: DNA sequencing showed IDH1/2 mutations in 50.8% of cases of which 73.8% had IDH1 R132H mutation. Several IDH1 noncodon 132 mutations, ie, G97D, S122N, G123E, I130K, and G131S, which had uncertain prognostic significance, were identified. IHC stain for R132H-mutant IDH1 identified 93.3% of IDH1 R132H mutations and 70.5% of all IDH mutations. BCAT1 loss was seen in 65.8% of cases, its sensitivity to identify IDH mutations was 96.7%. The sensitivity reached 100% for IDH1 codon 132 and IDH2 codon 172 mutations. CONCLUSION: Positive BCAT1 stain could be used to exclude diffuse gliomas with IDH1 codon 132 and IDH2 codon 172 mutations. Selecting cases with negative BCAT1 and R132H-mutant IDH1 staining for DNA sequencing of IDH1/2 genes could improve the cost-effectiveness of detecting IDH mutations particularly in tumors with low IDH mutation rates, and confine the need of 1p/19q assay in IDH-mutant tumors.

Irradiation-Induced Secondary Tumors following Pediatric Central Nervous System Tumors: Experiences of a Single Institute in Taiwan (1975-2013).

PURPOSE: Complications can occur following a prolonged latency period after radiation therapy for cancer, and this is a growing concern because secondary tumors are potentially fatal. Few studies have examined secondary tumors in patients who received radiation therapy as children. METHODS AND MATERIALS: This retrospective study examined 1697 pediatric patients with central nervous system tumors who received treatment at Taipei Veterans General Hospital from January 1, 1975, to December 31, 2013. Secondary tumors developed in 27 of 681 patients who received cranial irradiation. Overall survival was estimated using the Kaplan-Meier method, and the significance of differences was determined by the log-rank test. RESULTS: The overall cumulative incidence of secondary tumors at 25 years was 3.96%, and there were similar numbers of male patients (n = 16) and female patients (n = 11). The mean age at diagnosis was 8.8 years (range, 3-16.5 years), the median dose of cranial irradiation was 52.5 Gy (mean, 53.4 Gy), the mean latency period was 14.6 years (range, 2-33 years), and the mean age at diagnosis of a secondary tumor was 23.1 years. The secondary tumors were mainly meningiomas (n = 13), sarcomas (n = 7), and high-grade gliomas (n = 6), and the mean latency periods were 19.66, 8.00, and 10.83 years, respectively. The overall survival rate from these secondary tumors was significantly different (P < .05). Age at irradiation of <7 years and craniospinal irradiation significantly increased the risk of a secondary tumor (P < .05). Secondary tumors developed in 11 of 128 patients (8.6%) with primary medulloblastomas, which was higher than the overall cumulative incidence. CONCLUSIONS: Clinicians should consider the increased risk of secondary tumors in long-term cancer survivors who received craniospinal irradiation as children. Using a selective dose de-escalation strategy or deferring radiation therapy for young patients at highest risk of secondary cancers should be studied.

Aggressive natural killer (NK)-cell leukaemia and extranodal NK/T-cell lymphoma are two distinct diseases that differ in their clinical presentation and cytogenetic findings.

AIMS: Aggressive natural killer (NK)-cell leukaemia (ANKCL) and extranodal NK/T-cell lymphoma (ENKTCL) with secondary bone marrow involvement are rare bone marrow NK/T-cell neoplasms and share similar features. This study aimed to distinguish these two entities. METHODS AND RESULTS: We studied bone marrow NK/T-cell neoplasms by classifying them into those with no extramedullary mass (group 1, eight cases) and those with extramedullary mass (group 2, 13 cases). The two groups showed similar clinical presentations and pathological features. Fever and cytopenia were the most common clinical presentations in both groups. The neoplastic cells varied from small and relatively monotonous cells to large pleomorphic cells. In six cases (two in group 1, and four in group 2), the neoplastic infiltrate was inconspicuous, consisting of ≤10% of marrow cells in the interstitium, which were hardly identified by haematoxylin and eosin staining alone. Nearly all patients rapidly died, regardless of the neoplastic infiltrate volume. All of the group 1 patients fulfilled the World Health Organisation 2017 diagnostic criteria of ANKCL, and their survival was significantly worse than that of the group 2 patients (P = 0.035). In addition, there was a significant association between being in group 1 and chromosome 7 abnormalities. Chromosome 6q deletion, which is commonly reported in ENKTCL, was seen in two of our group 2 patients, and was not observed in any of our group 1 patients. CONCLUSION: ANKCL with no extramedullary mass should be distinguished from ENKTCL with bone marrow involvement, as the former shows distinct outcomes and genetic features.

The MGMT promoter single-nucleotide polymorphism rs1625649 had prognostic impact on patients with MGMT methylated glioblastoma.

Promoter methylation is the most significant mechanism to regulate O6-methylguanine-DNA-methyltransferase (MGMT) expression. Single-nucleotide polymorphisms (SNPs) in the MGMT promoter region may also play a role. The aim of this study was to evaluate the clinical significance of SNPs in the MGMT promoter region of glioblastoma. Genomic DNAs from 118 glioblastomas were collected for polymerase chain reaction (PCR) amplification. Sanger sequencing was used to sequence the MGMT promoter region to detect SNPs. The results were correlated with MGMT status and patient survival. Rs1625649 was the only polymorphic SNP located at the MGMT promoter region in 37.5% of glioblastomas. Homozygous rs1625649 (AA genotype) was correlated with a higher MGMT methylation level and a lower protein expression, but the result was not statistically significant. In patients with MGMT methylated glioblastoma, cases with homozygous rs1625649 (AA genotype) were significantly associated with a lack of MGMT protein expression and a better progression-free survival (PFS) than the cases with wild type rs1625649 (CC genotype) or heterozygous rs1625649 (CA genotype). The survival impact was significant in multivariate analyses. In conclusion, the MGMT promoter homozygous rs1625649 (AA genotype) was found to correlate with a better PFS in patients with MGMT methylated glioblastoma.

Detection of human cytomegalovirus in glioblastoma among Taiwanese subjects.

The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) has been debated for more than a decade. We investigated the presence of HCMV genes, RNA and protein in GBMs and their relationships with tumor progression. Results of quantitative PCR for HCMV UL73, nested PCR for HCMV UL144, in situ hybridization (ISH) for RNA transcript, and immunohistochemistry (IHC) for protein expression and their relationship to the prognosis of 116 patients with GBM were evaluated. Nine (7.8%) cases revealed a low concentration of HCMV UL73, and only 2 of the 9 (1.7%) cases showed consistent positivity on repeat PCR testing. HCMV UL144, ISH and IHC assays were all negative. The HCMV UL73 positive cases did not show significant difference in the clinicopathological characters including age, gender, Karnofsky performance status, extent of resection, bevacizumab treatment, isocitrate dehydrogenase 1 mutation, O6-methylguanine-DNA-methyltranferase status and Ki67 labeling index, and did not reveal prognostic significance. As only one HCMV gene was detected at low concentration in 7.8% of GBMs and there was no evidence of transcription, protein expression or prognostic impact, we cannot conclude a relationship between HCMV and GBM in Taiwanese patients.

Large cell/anaplastic medulloblastoma is associated with poor prognosis-a retrospective analysis at a single institute.

PURPOSE: Medulloblastoma (MB) is the most commonly occurring malignant pediatric brain tumor worldwide. However, a recent study found that the treatment outcomes in those with high-risk disease receiving conventional treatment were suboptimal. This study aimed to assess outcomes and treatment strategies for specific histologic subtypes of pediatric MB. METHODS: A total of 114 pediatric patients (age < 20 years) diagnosed with MB between March 1998 and August 2011 were retrospectively reviewed; 52 that were treated with surgery followed by adjuvant radiotherapy (RT) and chemotherapy (CHT) were included. RESULTS: The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 73 and 69%, respectively. Median time to relapse was 17 months with a median survival time of 6 months after relapse. Patients of average risk had a better 5-year OS rate compared with high-risk patients (p = 0.027). The 5-year RFS of high-risk patients was lower compared with average risk (p = 0.038). A greater proportion of patients with large cell/anaplastic (LC/A) MB had recurrence than classic MB with 5-year RFS rate of 34 and 76%, respectively (p = 0.001), and OS rate of 56 and 76%, respectively (p = 0.04). CONCLUSION: High-risk group and histology of LC/A were the most significant factors associated with worse OS and RFS. Patients with LC/A-MB had higher relapse rates and worse survival than those with classic MB. LC/A-MB carries a high risk for recurrence and should be treated with the more aggressive strategies.

Comparative Assessment of 4 Methods to Analyze MGMT Status in a Series of 121 Glioblastoma Patients.

The O-methylguanine-DNA-methyltranferase (MGMT) status is a powerful predictor of response to temozolomide for newly diagnosed glioblastoma (GBM) patients, and it is commonly assessed by immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP), quantitative real-time MSP (qMSP), and/or pyrosequencing (PSQ). This study was to compare their predictive power of prognosis in 121 newly diagnosed GBM patients using multivariate Cox regression with bootstrapping. MGMT status tested by IHC, MSP, qMSP, or PSQ all showed significant correlation with the progression-free survival and overall survival of GBM patients. The predictive power of IHC for progression-free survival and overall survival was lower than those of the methylation assays, but their differences were not significant. Performing additional methylation assay, especially PSQ, could better predict the prognosis of patients with IHC- tumors. MGMT status tested by IHC, MSP, qMSP, or PSQ all showed prognostic significance. An additional MGMT methylation assay, of which PSQ appeared to be the best, could improve the predictive power for GBM patients with MGMT IHC- tumors.

Thyroid transcription factor-1 distinguishes subependymal giant cell astrocytoma from its mimics and supports its cell origin from the progenitor cells in the medial ganglionic eminence.

Subependymal giant cell astrocytoma is a benign brain tumor mostly associated with tuberous sclerosis complex. However, it may be misinterpreted as other high-grade brain tumors due to the presence of large tumor cells with conspicuous pleomorphism and occasional atypical features, such as tumor necrosis and endothelial proliferation. In this study, we first investigated thyroid transcription factor-1 (TTF-1) expression in a large series of subependymal giant cell astrocytomas and other histologic and locational mimics to validate the diagnostic utility of this marker. We then examined TTF-1 expression in non-neoplastic brain tissue to determine the cell origin of subependymal giant cell astrocytoma. Twenty-four subependymal giant cell astrocytoma specimens were subjected to tissue microarray construction. For comparison, a selection of tumors, including histologic mimics (21 gemistocytic astrocytomas and 24 gangliogliomas), tumors predominantly occurring at the ventricular system (50 ependymomas, 19 neurocytomas, and 7 subependymomas), and 134 astrocytomas (3 pleomorphic xanthoastrocytomas, 45 diffuse astrocytomas, 46 anaplastic astrocytomas, and 40 glioblastomas) were used. Immunohistochemical stain for TTF-1 was positive in all 24 subependymal giant cell astrocytomas, whereas negative in all astrocytomas, gangliogliomas, ependymomas, and subependymomas. Neurocytomas were positive for TTF-1 in 4/19 (21%) of cases using clone 8G7G3/1 and in 9/19 (47%) of cases using clone SPT24. In the three fetal brains that we examined, TTF-1 expression was seen in the medial ganglionic eminence, a transient fetal structure between the caudate nucleus and the thalami. There was no BRAFV600E mutation identified by direct sequencing in the 20 subependymal giant cell astrocytomas that we studied. In conclusion, TTF-1 is a useful marker in distinguishing subependymal giant cell astrocytoma from its mimics. Expression of TTF-1 in the fetal medial ganglionic eminence indicates that subependymal giant cell astrocytoma may originate from the progenitor cells in this region.

Clinical considerations and surgical approaches for low-grade gliomas in deep hemispheric locations: thalamic lesions.

BACKGROUND: Tumors with epicenter in the thalamus occur in about 4 % of pediatric brain tumors. The histological diagnosis is mainly gliomas. Among them, low-grade glioma (LGG) constituted of a significant entity of the tumors (Cuccia et al., Childs Nerv Syst 13:514-521, 1997; Puget et al., J Neurosurg 106:354-362, 2007; Bernstein et al., J Neurosurg 61:649-656, 1984; Bilginer et al., Childs Nerv Syst 30:1493-1498, 2014). Since Kelly's report in 1989, >90 % resection of thalamic tumors were achieved in reported series (Ozek and Ture, Childs Nerv Syst 18:450-6, 2002; Villarejo et al., Childs Nerv Syst 10:111-114, 1994; Moshel et al., Neurosurgery 61:66-75, 2007; Albright, J Neurosurg 100(5 Suppl Pediatrics): 468-472, 2004; Kelly, Neurosurgery 25:185-195, 1989; Drake et al., Neurosurgery 29: 27-33, 1991). MATERIALS AND METHODS: Sixty-nine cases of thalamic tumors in children were retrospectively reviewed. There were 25 cases of LGGs. We analyzed our experience and correlated it with reported series. RESULTS: Summing up of 4 reported series and the present series, there were 267 cases of thalamic tumors in children. Among these tumors, 107 (40.1 %) were LGGs and 91 (34.1 %) were low-grade astrocytomas (LGAs). In the present series, all of the 25 LGGs were LGAs that consisted of 11 pilocytic astrocytomas (PAs) and 14 diffuse astrocytomas (DAs). Six cases received biopsy sampling only. The remaining 19 cases received different degrees of surgical resection via several approaches. Radical (>90 %) resection was achieved better in PAs comparing with DAs. There was no operative mortality. Two patients had increased neurological deficits. In a mean follow-up period of 11.9 years, three patients died of tumor progression and one patient died of anaplastic change. The 5- and 10-year overall survival (OS) was 87.1 and 87.1 %, respectively. CONCLUSION: Thalamic LGGs are mainly LGAs and are indolent. The rate of >90 % resection was relatively low in the present series. By applying contemporary diagnostic MRI studies, surgical facilities, and appropriate approaches in selective cases, we may try maximum neuroprotective radical (>90 %) resection.