39 Tumor-associated epilepsy in patients with glioma 40 Brain tumors arising in the setting of chronic epilepsy 41 Low-grade gliomas: Role of relative cerebral blood. 18 Frozen Section Evaluation of Central Nervous System Lesions 19 Clinical Role of MicroRNAs in Different Brain Tumors.
Chang Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA USA, [email protected]. Bowen Jiang Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA USA, [email protected].
Astrocytomas: Diagnosis and Biomarkers
Methylation in Malignant Astrocytomas
Understanding the Word Epigenetics
DNA Methylation
The majority of CpG islands are associated with genes that are unmethylated in the germline and are often located within promoter regions of genes. How CpG islands remain unmethylated in non-embryonic cells is still unknown, but it is known that in cancer cells methylation of CpG islands contributes to gene silencing of tumor suppressor genes.
Relevance of DNA Methylation in Normal Cells
In mammals, DNA methylation is mainly found in cytosines of the dinucleotide sequence CpG and consists of the addition of a methyl group to the 5 position of cytosines, which changes the appearance of the largest DNA tuft to which DNA-binding proteins bind. CpG dinucleotides are not evenly distributed in the genome, but rather are concentrated in short CpG-rich DNA stretches called CpG islands, defined as DNA regions larger than 200 bp, with a C+G content >50% , and an observed/expected presence of CpG.
Epigenetics, Environment, Diet and Aging
Methylation of certain CpG island promoters during development, resulting in long-term transcriptional silencing, has been observed. It is known that age is a significant risk factor for cancer development, probably through methylation of CpG islands and silencing of tumor suppressor genes.
DNA Methylation in Human Disease and Cancer
In glioblastoma multiforme, the detection of methylation in the promoter of the MGMT (O6-methylguanine-DNA methyltransferase) gene predicts a favorable outcome in patients treated with alkylating agents (Hegi et al., 2005). One of the disadvantages of this technique is that the loss of a fragment in the RLGS profile can be due to deletion or methylation.
DNA Methylation in Astrocytic Tumors
The DNA in the tube gel is digested again with a more frequent cutting restriction enzyme and electrophoresed perpendicularly in a non-denaturing polyacrylamide gel. About 2000 fragments are created, with a high probability of containing gene and/or promoter sequences, making it possible to detect new hypermethylated sequences in the genome.
Genes Frequently Methylated, Relevance for Diagnosis and Prognosis
Methylated sequences are detected by comparing the fluorescent signal for each probe (Shames et al., 2007). While p14ARF methylation was associated with shorter survival, MGMT methylation indicated a better clinical outcome after chemotherapy (Kleihues et al., 1994).
Relevance of Methylation in the Clinic
The epithelial membrane protein 3 (EMP3) gene, whose methylation is considered an adverse prognostic marker in neuroblastoma, is frequently methylated in low-grade astrocytomas and secondary GBM (80%) but not in primary GBM (17%), suggesting that EMP3 methylation may be an early alteration in astrocytomas (Kunitz et al., 2007). Therefore, detection of MGMT methylation can be used as a predictive factor (Hegi et al., 2005).
Epigenetic Therapy
It has been demonstrated that it is possible to detect promoter methylation in total plasma of glioma patients (Weaver et al., 2006): they analyzed promoter methylation in 4 gene loci in tumor tissue and total plasma of patients with different glioma grades, and demonstrated that 90% of the patients showed methylation of at least one locus in the primary brain tumor and that in 67% of these patients, methylation was also found in blood. On the contrary, the detection of methylation of p14ARF promoter is associated with malignant progression and shorter survival;.
Future Directions
Tumors are known to release significant amounts of DNA, containing the genetic and epigenetic changes present in the primary tumor, into the systemic circulation, probably through apoptosis and cellular necrosis. As we previously mentioned, MGMT hypermethylation is associated with significantly longer survival in patients with GBM and low-grade gliomas treated with alkylating agents such as temozolomide.
Fan X, Inda MM, Tunon T, Castresana JS (2002) Improvement of the methylation-specific PCR technique for detection of p16 promoter hypermethylation in small amounts of tumor DNA. Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.
Deciphering the Function of Doppel Protein in Astrocytomas
Introduction
Further studies, which mirrored the studies of Moore et al. 1999) in mouse strains confirmed that doppel was virtually undetectable in the CNS and clearly distinct from the prion protein. Doppel's discovery, followed by its biochemical and structural characterization (Lührs et al., 2003), provided new hypothetical avenues into the molecular pathogenesis of the prion diseases, especially in the etiology of the ataxic correlated phenotype.
Doppel Gene Expression Analysis in Astrocytomas: A Novel Potential
2.2 (Comincini et al., 2006b): this alternative post-transcriptional pathway could directly regulate the excess of potentially harmful transcripts. Furthermore, as illustrated (inset b), the cellular localization of the doppel protein shifts from plasma membrane to the cytosol, especially within lysosome organelles (Sbalchiero et al., 2008).
Doppel Protein in Astrocytomas
The first characterization map of the interactome of members of the prion protein family was recently reported (Watts et al., 2009). In this scenario, other studies have pointed to the direct involvement of the proapoptotic protein Bax in promoting dopel-induced apoptosis in transgenic mouse Purkinje cells deficient in prion protein expression.
Conclusion
Del Vecchio I, Azzalin A, Guidi E, Amati G, Caramori T, Uboldi C, Comincini S, Ferretti L (2005) Mappatura funzionale della regione del promotore del doppio gene bovino. Travaglino E, Comincini S, Benatti C, Azzalin A, Nano R, Rosti V, Ferretti L, Invernizzi R (2005) Overexpression of the Doppel protein in acute myeloid leukemias and myeloid-plastic syndros.
Astrocytic Tumors: Role of Antiapoptotic Proteins
Subsequent signaling is mediated by the cytoplasmic portion of the death receptor, which contains a conserved sequence called the death domain (DD). However, such activation corresponds to a simultaneous and parallel activation of the transcription factor nuclear factor (NF)-κB.
The p53
On the other hand, hypophosphorylated Rb represents the active form and can inhibit cell cycle progression by binding and inhibiting transcription factors of the E2F family. E2F is a transcription factor believed to integrate cell cycle progression with the transcriptional apparatus through its cyclic interactions with important cell cycle regulators such as Rb, cyclins, and cyclin-dependent kinases.
The Bcl-2 Family of Proteins
In GBM cells, a mutant form of the Bcl-2 protein, called Bcl-2L12, has been described in association with resistance to apoptosis and propensity for necrosis. A direct physical interaction appears to underlie the process of Bcl-2L12 inhibition of caspase-7, whereas Bcl-2L12-induced transcriptional regulation of the small heat shock protein alpha B-crystallin is required to neutralize the activation of caspase-3 (Stegh . et. al., 2008).
Inhibitor of Apoptosis Proteins
Its BIR domains are more distantly related to the BIR domains of class 1 IAPs. Furthermore, survivin's subcellular compartments in mitochondria appear to play a role in the anti-apoptotic function of the protein.
Deregulation of the Wnt/ β -Catenin/Tcf Signaling Pathway in Astrocytomas
Anaplastic astrocytoma (III) has a higher frequency of TP53 mutations, deletion of p16 and p19, RB alterations and LOH on chromosome 19q (50%) (Nupponen and Joensuu, 2006). Most glioblastomas are primary glioblastomas that develop rapidly without evidence of a less malignant precursor lesion.
Molecular Pathogenesis of Glioblastomas
In contrast, IDH1 mutations are very rare (<5%) or absent in pilocytic astrocytomas and primary glioblastomas. Almost 60% of the low-grade astrocytomas have both TP53 and IDH1 mutations (Ohgaki and Kleihues, 2009).
Wnt Signaling Pathway
4 Deregulation of the Wnt/β-catenin/Tcf signaling pathway in astrocytomas 37 the sequence in which the genetic changes are acquired is not. Dvl-Fzd complex formation and LRP phosphorylation by CK1γ, which facilitates Axin translocation to the membrane and inactivation of the kill box.
Cellular Origin-Neural Stem Cells-Wnt Signaling
This ongoing degradation of β-catenin prevents its nuclear translocation, allowing the DNA-binding Tcf/Lef proteins to interact with transcriptional co-repressors to block β-catenin target gene expression. In the nucleus, β-catenin transforms the Tcf/Lef proteins into potent transcriptional activators there through activation of its target genes ( Moon et al., 2004 ).
Activation of Wnt/ β -Catenin/Tcf Signaling Pathway Components
Within this complex, β-catenin is sequentially phosphorylated by CK1α and GSK3β, resulting in its recognition by ubiquitin ligases and subsequent degradation in proteasomes. The Wnt/β-catenin/Tcf pathway is activated when Wnt ligands bind to their cognate specific receptor complex containing members of the Frizzled family and LRP5 or LRP6.
Wnt Signaling Antagonists
Knockdown of Dkk-3 resulted in increased cell survival index compared to control cells and reciprocally, overexpression of Dkk-3 decreased the survival index in a time-dependent manner. In contrast, forced expression of Dkk-3 does not alter the cell survival index in normal astrocytes.
Wnt Ligands and Frizzled Receptors
Dkk-3 expression levels were found to be lower in human malignant glioma tissues compared to normal brain tissues and also Dkk-3 expression levels were lower in glioma cell lines compared to astrocytes normal human. Overexpression of Dkk-3 induces apoptosis in GBM cell lines through the activation of phosphor-JUN, caspase-9, and caspase-3 and also resulted in the reduction and degradation of β-catenin.
Dishevelled and FRAT-1
Comparison of relative levels of β-catenin and AXIN1 revealed that they were significantly inversely proportional. However, significant positive correlation was observed between levels of β-catenin and 2-year patient survival.
Lef-1 and Tcf-4
Furthermore, pygopus 2 showed positive correlation with cyclin D1 expression in human glioma samples. In summary, several investigations investigating the Wnt/β-catenin/Tcf signaling pathway in astrocytomas indicate that this pathway is aberrantly activated in human astrocytomas and is involved in the progression leading to metastasis.
Subependymal Giant Cell Astrocytoma: Role of mTOR Pathway and Its Inhibitors
TORC2 was originally known to be rapamycin-insensitive, but recent studies indicate that it is also targeted by rapamycin (Loewith et al., 2002). Another major dysregulation caused by TSC1/TSC2 loss is the inhibition of autophagy (Jung et al., 2010).
Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex
Therefore, it has been suggested that giant cells and dysmorphic neurons in SEGA originate from the subventricular zone (Kim et al., 2001). There was minimal expression of p53 and high expression of Bax along with low Bcl-2 proteins in these tumors (Kim et al., 2001).
Genes Regulating mTOR Activity in Subependymal Giant Cell Astrocytoma
Long-term treatment with everolimus, like sirolimus, was shown to disrupt mTORC2 assembly and function (Gibbons et al., . 2009). Long-term treatment with temsirolimus, like sirolimus, was shown to disrupt mTORC2 assembly and function (Gibbons et al., 2009).
Temsirolimus has also been shown to arrest the cell cycle in G1 phase and inhibit angiogenesis. An important aspect of the antitumor effect of rapamycin and its progeny, everolimus and temsirolimus, is their potential to act both directly on tumor cells, by inhibiting growth, and indirectly, by inhibiting angiogenesis.
Lessons from Preclinical Studies
TSC1 knockout mice are characterized by renal tumors, hepatic heamangiomas, and heamangiosarcomas of various localizations, but tumor development is sex-dependent. The mice with neuron-specific TSC1 knockout show many enlarged and dysplastic neurons, as well as cortical dysplasia.
Targeting mTOR in Subependymal Giant Cell Astrocytoma
In addition, the authors showed that treatment with everolimus was associated with a clinically significant reduction in seizure frequency. This study will evaluate the antitumor activity and clinical benefits of everolimus in growing SEGA associated with TSC.
Conclusions
JM, Chiron C, Delalande O (2007) Subependymal giant cell astrocytomas in pediatric tuberous sclerosis: when to operate. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant cell astrocytomas in tuberous sclerosis.
Role of Progesterone Receptor Isoforms in Human Astrocytomas Growth
Astrocytomas
Hulleman and Helin (2005), mentioned that the average survival of patients with astrocytomas grade I could be long after surgery and treatment, while grade II is about 7 years, and patients with astrocytomas grade III have a median survival half of that time, about 3.5 years. Treatment for patients with astrocytomas depends on many factors, including the size and location of the tumor, its rate of growth, and the symptoms the patient is experiencing.
Genomic Mechanism of Action of Progesterone (P)
Patients with grade IV astrocytomas (glioblastomas) have a very poor prognosis, with average survival reported between 9 and 11 months. 2004), classified the glioblastomas into glioblastomas that develop from a previously diagnosed astrocytoma and glioblastomas that appear to develop de novo. Various strategies have been used to treat astrocytomas, including extended surgical resection, fractionated and targeted radiation, and intracavitary and/or intraarterial chemotherapy that result in prolonged and not always significant survival for patients and compromise brain function.
Transcriptional Activity of PR Isoforms
In the unligated form, PR is associated with chaperone proteins such as the heat shock proteins HSP70 and HSP90. PR is then phosphorylated (yellow triangles) and forms a complex with coregulators such as the coactivator protein SRC-1.
Regulation of PR Isoforms Expression
PR interacts with progesterone responsive elements (PREs) in the promoter region of steroid target genes, the basal transcription machinery is recruited and the gene is transcribed. transcription initiation factors, CBP/p300, histone. genes involved in cell cycle and apoptosis such as BIRC3 or PCNA were up-regulated by PR-B while Bcl-X was up-regulated by PR-A. The transcription factors TCF8 and DSIPI are regulated by PR-B and PR-A, respectively. 2000), showed that PR-B is necessary for normal mammary gland development, while PR-A is essential for uterine development and reproductive function. 2000), revealed that P up-regulation of calcitonin and amphiregulin genes is PR-A dependent. Papers by Liu et al. 2003), it is assumed that in many cancer cell lines one or both PR isoforms are silenced by methylation.
Role of P in Astrocytomas Proliferation
Numerous transcription factor binding sites may be distant from the proximal promoter and still play a role in the regulation of gene expression. Recently, Bonéy-Montoya et al. 2010), identified eight regions associated with ERα, located 48–311 kb upstream of the PR-B transcription start site that possess one or more EREs and each of them consists of one consensus ERE half-site.
PR Isoforms Regulation and Function in Astrocytomas
At the mRNA level, PR-B expression was higher than that of PR-A in human astrocytomas grade III and IV. This differential PR isoform expression should thus be involved in P effects in U373 and D54 cell growth.
Conclusion and Perspectives
Pinski J, Halmos G, Shirahige Y, Wittliff JL, Schally AV (1993) Inhibition of growth of the human malignant glioma cell line (U87MG) by the steroid hormone antagonist RU486. Horwitz KB (2002) Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells.
Astrocytic Tumors: Role of Carbonic Anhydrase IX
Carbonic Anhydrase IX
The expression and localization of CA IX has been studied in head and neck squamous cell carcinoma (HNSCC) (Beasley et al., 2001). Recent studies have also clearly shown that CA IX is highly expressed in some malignant gliomas (Haapasalo et al., 2006).
Immunohistochemical and Analytical Methods
In addition, CA IX has also been suggested to reduce the intracellular pH gradient in the hypoxic core of three-dimensional tumor spheroids grown from cancer-derived cell lines (Swietach et al., 2008). However, when CA IX inhibition was studied in RNAi-treated breast cancer cells, the invasive capacity of the cells appeared to be slightly reduced compared to the control, but this difference was not considered significant (Robertson et al., 2004).
Evaluation of Carbonic Anhydrase IX in Astrocytic Tumors
Another potential mechanism for the function of CA IX was suggested by the finding that CA IX modulates E-cadherin-mediated cell adhesion by reducing the binding of this cell adhesion molecule to beta-catenin (Pastorekova et al.). molecules could potentially promote cell motility and invasion.
Prognostic Significance and Role of Carbonic Anhydrase IX in Astrocytomas
However, others have described a link between CA IX expression and proliferation (Proescholdt et al., 2005). Our findings on the prognostic significance of CA IX in astrocytic tumors have been confirmed by Korkolopoulou et al.
Development of Cysts in Pilocytic Astrocytomas: Role of Eosinophilic Granular Bodies (Method)
In addition to degradation of cellular macromolecules, lysosomal proteases have been implicated in a variety of pathological processes such as the progression of degenerative neurological disorders (Dumontel et al., 1999; Stahl et al., 2007). Our results show that EGBs can be observed by immunostaining with antibodies against LAMP-1, LAMP-2 and cathepsin D (Tung et al., 2010).
Eosinophilic Granular Bodies Staining with Antibodies Against LAMP-1,
Cathepsin D is a major lysosomal proteinase that plays an important role in the progression of various cancers including brain cancer (Sivaparvathi et al., 1996; Rochefort and Liaudet-Coopman, 1999; Rochefort et al., 2000). We recently studied the content of EGBs and analyzed their morphologies in tumor specimens from pilocytic astrocytomas.
Eosinophilic Granular Bodies Staining with PAS, H&E and Antibodies Against
The Origin of Eosinophilic Granular Bodies and Possible Role of Eosinophilic
LAMP-1 and LAMP-2 play important roles in lysosomal biogenesis and in maintaining the structural integrity of the lysosomal compartment (Eskelinen et al., 2003). Cathepsin D plays an important role in mediating cell apoptosis (Deiss et al., 1996; Roberg and Ollinger, 1998).
Immunohistochemistry Using Anti-LAMP-1 and Anti-LAMP-2
Because cathepsin D and possibly other lysosomal proteinases are present in the EGB in microcysts of pilocytic astrocytomas, the extracellular digestive abilities of cathepsin D and other lysosomal proteinases may be involved in the digestion of the extracellular matrix in the surrounding brain tissue. Therefore, the presence of eosinophilic granular bodies in pilocytic astrocytoma cysts may be involved to some extent in the development of the tumor cyst.
Protocol
Discussion
Tibbetts KM, Emnett RJ, Gao F, Perry A, Gutmann DH, Leonard JR (2009) Histopathologic predictors of pilocytic astrocytoma event-free survival. White JB, Piepgras DG, Scheithauer BW, Parisi JE (2008) Rate of spontaneous bleeding in histologically proven cases of pilocytic astrocytoma.
Role of Synemin in Astrocytoma Cell Migration
In general, each class of IF proteins is specific to a type of tissue or cell (Omary, 2009). Therefore, changes in the expression of IF proteins during the malignant transformation, such as those found for synemin in astrocytomas, have the potential to significantly contribute to malignant behavior.
Synemin: An Unusual IF Protein Present in Astrocytoma Cells
A further example of the ability of IF proteins to facilitate signal propagation was observed in injured axons, where vimentin bound to and promoted the spatial translocation of activated MAP kinases such as Erk1 and Erk2 (Perlson et al., 2005). Synemin is also upregulated in many central nervous system pathologies, as evidenced by the induction of α- and β-synemin in reactive astrocytes that appear in response to physical or metabolic trauma (Jing et al.
Importance of Synemin for Astrocytoma Cell Motility
The experimental conditions were similar to those described in Pan et al. 2008) for cells treated with synemin shRNAs. However, downregulation of synemin did not affect the adhesion of astrocytoma cells to the substrate (Pan et al., 2008).
Role of IF Proteins Other Than Synemin in Cell Motility
Vimentin −/− mice were also instrumental in elucidating vimentin contribution to the transendothelial migration of lymphocytes ( Nieminen et al., 2006 ). Several experimental studies have shown that high GFAP levels correlate with low motility (for review see: Rutka et al., 1997).
Prospects for Synemin and Other IF Proteins in Astrocytoma Therapy
Jing R, Pizzolato G, Robson RM, Gabbiani G, Skalli O (2005) The intermediate filament protein synemin is present in human reactive and malignant astrocytes and associates with ruffled membranes in astrocytoma cells. Pan Y, Jing R, Pitre A, Williams BJ, Skalli O (2008) The intermediate filament protein synemin contributes to the migratory properties of astrocytoma cells by influencing actin cytoskeleton dynamics.
Diffuse Astrocytomas: Immunohistochemistry of MGMT Expression
Several factors limit the standardization of MGMT IHC and the determination of cut-off levels for prognostic evaluation. The following chapter provides an overview of commonly used antibodies, technical aspects of MGMT IHC, and results of studies investigating MGMT IHC in diffuse astrocytomas.
MGMT Immunohistochemistry – Technical Considerations
For this reason, assessment of MGMT status as a potential predictor of response to alkylating agents is particularly important. IHC of MGMT offers several advantages, such as performance in formalin-fixed, paraffin-embedded tissue and the ability to detect MGMT expression in individual cells.
MGMT Immunohistochemistry Compared to MGMT Promoter
MGMT Immunohistochemistry in Glioma Cells and Non-neoplastic Cells
Clone MT3.1 showed poorer concordance and thus may be less useful for assessment of MGMT protein expression by IHC. In the same study, only weak to slight concordance was observed for the presence of MGMT positive hematogenous cells.
MGMT Immunohistochemistry and Patient Outcome
JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Yuan Q, Matsumoto K, Nakabeppu Y, Iwaki T (2003) A comparative immunohistochemistry of O6-methylguanine-DNA methyltransferase and p53 in diffuse infiltrating astrocytomas.
Central Nervous System Germ Cell Tumors
An Epidemiology Review
Histological Classification
Although this tumor is not classified as a secreting germ cell tumor, a mild increase in serum and/or cerebrospinal fluid levels of β-HGC has been reported ( Keene et al., 2007 ). These tumor cells often stain positive for β-HCG (De Girolami et al., 2008) and may have elevated serum and/or cerebrospinal fluid levels of β-HCG.
Discriptive Epidemiology Based on Tumor Location and Clinical
Rarely, germ cell tumors have been reported in the cerebellum and the cerebellar pontine angle (Matsutami et al., 1997). Tumors occur more frequently in the pineal region in men than in women, especially for germinomas (Goodwin et al., 2009).
Incidence
In addition, at the time of presentation, there have been reports of discrete germ cell tumors in more than one location within the brain parenchyma. Although the majority of people with CNS germ cell tumors tend to present around adolescence (10-12 years), this can sometimes occur into the third decade (Goodwin et al., 2009).
RAF Fusion Genes and MAPK Activation in Pilocytic Astrocytomas
Mutations in NF1 abrogate its function, resulting in Ras activation and downstream ERK/MAPK signaling. Many subsequent studies have since implicated changes in the MAPK pathway in the development of intermittent PA, as described below.
Molecular Genetic Development of Pilocytic Astrocytoma
In addition, a BRAF fusion gene arising from an interstitial deletion between BRAF and the FAM131B gene (which is located distal to BRAF) is present in 3 cases of PA, suggesting that multiple mechanisms may result in the fusion of BRAF in PA (Cin et al. ., 2011). Compared to normal fetal brain control samples, tumor samples with a BRAF fusion gene showed a significant upregulation of MEK/ERK phosphorylation, consistent with a constitutively active BRAF kinase domain (Forshew et al., 2009).
MAPK Activation via RAF1 Fusion Genes
PA with simple genomic rearrangements implicating non-homologous end joining or microhomology-induced replication as possible mechanisms for tandem duplication and subsequent fusion gene formation (Cin et al., 2011; Lawson et al., 2011). In addition, the fusion gene construct with the most commonly reported breakpoint (KIAA1549ex16-BRAFex9) was shown to have increased kinase activity compared to the wild-type protein in vitro and to transform NIH3T3 cells in a colony-forming assay, demonstrating that the gene fusion has direct transformation properties (Jones et al., 2008).
Alternative Mechanisms of MAPK Activation in Pilocytic Astrocytoma
Targeted Therapy Against the MAPK Pathway
Sorafenib is efficacious in certain types of cancer such as renal cell carcinoma, however its anti-tumor activity is believed to derive in part from off-target effects on vascularization rather than disruption of Raf kinases per se (Dhillon et al., 2007). One of the most promising candidates to date is the inhibitor PLX4032 which shows potent in-vitro activity against the BRAF V600E mutation (Bollag et al., 2010).
Summary
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumors of the central nervous system. The significance of atypia and histological malignancy in pilocytic astrocytoma of the cerebellum: a clinicopathological and flow cytometric study.
Biomarker Discovery in Central Nervous System Neoplasms: Past, Present and Future
At Duke, we conducted a systematic investigation of the surface antigen profiles of human glial tumors using a large panel of glioma cell lines (Wikstrand et al., 1977). Until the 1980s, only a few genes altered in human cancer were precisely defined.
Summary and Future Prospects
Wikstrand CJ, Mahaley MS, Bigner DD (1977) Surface antigenic properties of human glia brain tumor cells. Yuan CT, Wikstrand CJ, Bigner DD (2001) EGF mutant receptor VIII as a molecular target in cancer therapy.
Astrocytomas: Role of Taurine in Apoptosis Using Magnetic Resonance Spectroscopy
However, it is generally accepted that lipid droplet production occurs during both apoptotic and necrotic cell death ( Delikatny et al., 2002 ). The TUNEL method (Gavrieli et al., 1992) was then used to stain one slide from each biopsy.
Results
The main findings of this study were:. i) the taurine concentration in glioma biopsies correlated with the number of TUNEL-stained apoptotic cells (Fig. 14.1) independently of the presence of necrosis; And. ii) the approximately 2.8 ppm Lip/MM peak of PUFAs correlated with the number of TUNEL-stained apoptotic cells, but only in the non-necrotic biopsies. However, in the necrotic biopsies there was a correlation between the percentage of necrosis and the approx.
Declaration
However, there are still no PC factors associated with apoptosis in the necrotic biopsy group. GB, Gribbestad IS (2007) Metabolic mapping using high-resolution magic angle spinning 1H MR spectroscopy for assessment of apoptosis in cervical carcinomas.
Imaging of Hypoxia-Inducible Factor-1-Active Regions in Tumors Using a POS and 123 I-IBB Method
The transcription factor hypoxia-inducible factor-1 (HIF-1) has been reported as one of the critical components of hypoxic responses (Eltzschig and Carmeliet, 2011).
In Vivo Molecular Imaging
Development of an Oxygen-Dependent Degradable Probe
Imaging of HIF-1-Active Tumors Using
123 I-IPOS
After 24-hour incubation of cells with 125I-IPOS under normoxic (20% O2) or hypoxic (0.1% O2) conditions, more than 2-fold higher radioactivity accumulated in hypoxic cells than in normoxic cells. In vivo evaluation (biodistribution, planar imaging, metabolite analysis, comparison between probe accumulation and HIF-1 transcriptional activity, autoradiography and immunohistochemical analysis) of 125I-IPOS was then performed.
Pretargeting Approach
High-performance liquid chromatography (HPLC) analysis with size exclusion revealed that more than 80% of the intracellular radioactivity came from intact125I-IPOS and that approximately 70% of the radioactivity in the reoxygenated medium came from125I-IBB and other small particles . molecules (Kudo et al., 2009). Size exclusion analysis of radioactive species in tumors revealed that more than 77% of intracellular radioactivity originated from intact125I-IPOS.
Imaging of HIF-1-Active Tumors Based on the Pretargeting Approach
Harada H, Kizaka-Kondoh S, Hiraoka M (2005) Optical imaging of tumor hypoxia and evaluation of the efficacy of a hypoxia-targeted drug in living animals. Kuchimaru T, Kadonosono T, Tanaka S, Ushiki T, Hiraoka M, Kizaka-Kondoh S (2010) In vivo imaging of HIF-active tumors by an oxygen-dependent degradation protein probe with a switchable labeling system.
Diffuse Low-Grade Astrocytomas: P53-Mediated Inhibition of Angiogenesis
Furthermore, all types of astrocytomas depend on solid blood vessels for survival and growth (Wesseling et al., 1997). Furthermore, angiogenesis was found to be correlated with aggressiveness and clinical recurrence within each astrocytoma group (Leon et al., 1996).
Immunohistochemical Examination of Microvessel Density and Human
CF III/VIIa signaling has a role in angiogenesis and apoptosis (Belting et al., 2005). PAI-1 inhibits tissue plasminogen activator and urokinase-type serine proteases (Kunz et al., 1995).
Spontaneous Regression of Cerebellar Astrocytomas
Although referred to as spontaneous, the cause for such a phenomenon may involve a combination of factors in any individual case. Recognition of this phenomenon may encourage a more conservative approach to subtotal resection of the tumor, involving surveillance during follow-up of patients, if the tumor is asymptomatic.
Criteria for Regression
In some patients, only a subtotal resection can be safely achieved, and it is in this population that the issue of spontaneous regression becomes important.
Incidence and Time Course of Regression
The first-line treatment for CA is surgical resection, which, if completed, is generally curative. Eleven of these did not receive adjuvant treatment and five of the 11 tumors (45%) regressed during the follow-up period ranging from 7 to 66 months (mean 32 months) (Saunders et al., 2005).
Imaging Surveillance
Mechanisms of Regression
Activation of the host immune system after infection may be a factor, but there are no such reports associated with these regressions. Exposure of hidden antigenic sites on the tumor to the immune system after surgery may be a factor, but this is probably not a major factor, as such regressions can occur after years of stability (Steinbok et al., 2006).
Associated Factors Influencing Regression
Gunny RS, Hayward RD, Phipps KP, Harding BN, Saunders DE (2005) Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Schmandt SM, Packer RJ, Vezina LG, Jane J (2000) Spontaneous regression of low-grade astrocytomas in childhood.
Subependymal Giant Cell Astrocytoma: Gene Expression Profiling
They are believed to be caused by structural changes in the brain, namely the aforementioned SEGAs and SEN, as well as cerebral cortical tubers. In addition, the occurrence of epileptic seizures was observed in TSC patients in the absence of cortical tubers.
Molecular Pathophysiology of TSC
Tuberous sclerosis complex (TSC) is a disease that affects approximately one in 6,000 people and is characterized by the formation of benign tumors and hamartomas (benign tumor-like growths consisting of normal mature cells in abnormal number and distribution) in many organs, mainly in the skin, brain, kidneys, lungs, heart and liver (Jozwiak et al., 2008). Seizures have been shown to originate mostly in the regions of nodules in the brain, therefore nodules are believed to serve as the epileptogenic focus.
Global Gene Expression Profiling and Analysis
Abbreviations: 4E-BP1, 4E-binding protein 1; Akt/PKB, protein kinase B; IRS, insulin receptor substrate; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Rheb, ras homolog enriched in brain; S6K1, S6 kinase 1; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2. Rapamycin has been used in clinical trials to treat SEGAs and significant tumor shrinkage has been observed (Lam et al., 2010).
Genes Up-regulated in SEGA are Linked to Progression or Inhibition
Its increased expression has been observed in glioblastoma multiforme, and GPNMB has been shown to promote breast cancer cell migration and invasiveness (Kuan et al., 2006; Rose et al., 2010). In addition, its downregulation was detected in prostate cancer (Shaheduzzaman et al., 2007; Zhou et al., 2008).
Down-Regulation of Identified Genes in SEGA May Be Associated with Neurologic
SEGA Exhibit a Mixed-Lineage Phenotype with Restricted Ability to
This hypothesis is supported by the data showing expression of doublecortin (DCX) in giant cells. The expression of DCX detected in giant cells may suggest their restricted differentiation (Jozwiak and Jozwiak, 2007).
Therefore, the cells were classified into neuron-like and indeterminate giant cells (Jozwiak and Jozwiak, 2007). Cellular markers detected in giant cells indicate their inability to differentiate terminally before migration to cortex.
Astrocytomas: Therapy
Time-Resolved Laser Induced Fluorescence Spectroscopy (TRLIFS): A Tool for Intra-operative Diagnosis of Brain
Background
This is especially true at the margins of tumor resection, where tumor infiltration into normal brain is difficult to determine by direct vision or MRI. In order to thus increase the surgeon's ability to achieve near-complete excision of brain tumors without sacrificing safety, newer technologies are being investigated to accurately distinguish between tumor and normal brain and to guide tumor resection in near real time.
Fluorescence Spectroscopy
Materials and Methods Clinical Methods
Baron AE (1991) Misclassification among methods used to discriminate multiple groups – effects of distributional properties. Bello AL (1992) Misclassification among methods used to discriminate multiple groups – effects of distributional properties.
Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Brain Tumors
Furthermore, advances in medical imaging modalities, particularly MRI, have enabled real-time control of LITT treatments. Several clinical trials have now been completed and have shown that LITT with real-time MRI can be used to treat deep-seated tumors with few side effects.
History of the Laser
To overcome this limitation and control the extent of the heated region, research was conducted to develop imaging techniques to more precisely control LITT procedures. Recently, a new technology used by Carpentier et al. 2008) allows for real-time temperature imaging and prediction of the extent of thermal damage, improving the safety and efficacy of LITT for the treatment of brain tumors.
Physical and Technical Parameters
Therefore, it is not suitable for wavelengths in the range of far-ultraviolet (excimer lasers), far-infrared (carbon dioxide lasers) or for very short pulses (nanoseconds). The effects on tissue of exposure to Nd-YAG lasers depend on the wavelength used and on the composition of the irradiated tissue (water, pigmentation.
Interactions Between Laser
In this zone of viable brain, microvacuolation of the neurophile is visible, as well as neuronal shrinkage and axonal swelling. To predict the induced thermal damage, the temperature increase in the irradiated volume is used to predict a probability of necrosis of the tissue.
MRI Imaging and LITT
This allows the preservation of adjacent normal tissue structures and further improves the safety of the procedure. The thin rim at the edge of the peripheral zone is hypointense with enhancement after gadolinium injection.
Clinical Studies
The procedures were still performed under general anesthesia, and location of the tumor was determined by MR imaging. The therapy was adjusted to the temperature of the lesion and the size of the tumor and its neighboring structures.
