MicroRNA in Human Gliomas

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Malignant gliomas: Current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods

Malignant gliomas consist of glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, and some less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas. Malignant gliomas have high morbidity and mortality. Even with optimal treatment, median survival is only 12-15 months for glioblastomas and 2-5 years for anaplastic gliomas. However, recent advances in imaging and quantitative analysis of image data have led to earlier diagnosis of tumors and tumor response to therapy, providing oncologists with a greater time window for therapy management. In addition, improved understanding of tumor biology, genetics, and resistance mechanisms has enhanced surgical techniques, chemotherapy methods, and radiotherapy administration. After proper diagnosis and institution of appropriate therapy, there is now a vital need for quantitative methods that can sensitively detect malignant glioma response to therapy at early follow-up times, when changes in management of nonresponders can have its greatest effect. Currently, response is largely evaluated by measuring magnetic resonance contrast and size change, but this approach does not take into account the key biologic steps that precede tumor size reduction. Molecular imaging is ideally suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered early in treatment. We expect that successful integration of quantitative imaging biomarker assessment into the early phase of clinical trials could provide a novel approach for testing new therapies, and importantly, for facilitating patient management, sparing patients from weeks or months of toxicity and ineffective treatment. This review will present an overview of epidemiology, molecular pathogenesis and current advances in diagnoses, and management of malignant gliomas. © 2014 Ahmed et al

Towards personalized diagnosis of Glioblastoma in Fluid-attenuated inversion recovery (FLAIR) by topological interpretable machine learning

Glioblastoma multiforme (GBM) is a fast-growing and highly invasive brain tumour, it tends to occur in adults between the ages of 45 and 70 and it accounts for 52 percent of all primary brain tumours. Usually, GBMs are detected by magnetic resonance images (MRI). Among MRI, Fluid-attenuated inversion recovery (FLAIR) sequence produces high quality digital tumour representation. Fast detection and segmentation techniques are needed for overcoming subjective medical doctors (MDs) judgment. In the present investigation, we intend to demonstrate by means of numerical experiments that topological features combined with textural features can be enrolled for GBM analysis and morphological characterization on FLAIR. To this extent, we have performed three numerical experiments. In the first experiment, Topological Data Analysis (TDA) of a simplified 2D tumour growth mathematical model had allowed to understand the bio-chemical conditions that facilitate tumour growth: the higher the concentration of chemical nutrients the more virulent the process. In the second experiment topological data analysis was used for evaluating GBM temporal progression on FLAIR recorded within 90 days following treatment (e.g., chemo-radiation therapy - CRT) completion and at progression. The experiment had confirmed that persistent entropy is a viable statistics for monitoring GBM evolution during the follow-up period. In the third experiment we had developed a novel methodology based on topological and textural features and automatic interpretable machine learning for automatic GBM classification on FLAIR. The algorithm reached a classification accuracy up to the 97%.Comment: 22 pages; 16 figure

Novel Therapeutic Concepts in Targeting Glioma

Novel Therapeutic Concepts for Targeting Glioma offers a comprehensive collection of current information and the upcoming possibilities for designing new therapies for Glioma by an array of experts ranging from Cell Biologists to Oncologists and Neurosurgeons. A variety of topics cover therapeutic strategies based on Cell Signaling, Gene Therapy, Drug Therapy and Surgical methods providing the reader with a unique opportunity to expand and advance his knowledge of the field

Molecular Targets of CNS Tumors

Molecular Targets of CNS Tumors is a selected review of Central Nervous System (CNS) tumors with particular emphasis on signaling pathway of the most common CNS tumor types. To develop drugs which specifically attack the cancer cells requires an understanding of the distinct characteristics of those cells. Additional detailed information is provided on selected signal pathways in CNS tumors

Astrocytes in glioblastoma : enhancers of tumor growth, predictors of patient survival and potential therapeutic targets

The tumor microenvironment plays an important role in glioblastoma, the most malignant primary brain tumor in adults. Astrocytes are a major component of the glioblastoma tumor microenvironment; therefore, their influence on glioblastoma biology needs to be clarified. In this thesis, the role of astrocytes was explored with regard to glioblastoma growth, patient survival and their potential as a therapeutic target through a set of in vitro and in vivo studies and analyses of clinical samples. Co-culture experiments identified astrocytes as enhancers of glioblastoma cell growth in cell lines and in a patient-derived culture. Furthermore, orthotopic co-injection of astrocytes with glioblastoma cells reduced survival of NOD scid mice, compared to mice that received mono- injection of glioblastoma cells. A gene signature reflecting glioblastoma-activated astrocytes was associated with poor prognosis in two glioblastoma datasets. Through this set of experiments, astrocytes were thus shown to enhance glioblastoma growth. In a glioblastoma tissue collection, a subset of peritumoral astrocytes co-expressing PDGFRα and GFAP was examined for biomarker significance; experiments showed that such astrocytes did not carry tumor markers, supporting their non-malignant nature. Inter-case variability was observed, both with regard to the presence of such a subset and the general astrocyte density. High density in the peritumoral areas of the PDGFRα and GFAP co- expressing astrocytes, but not total astrocyte density, was identified as an independent poor prognostic factor. This observation suggests the presence of differentially functional astrocyte subsets in glioblastoma holding clinical relevance. A high-throughput screening assay was designed to screen a library of compounds in a novel glioblastoma/astrocyte co-culture system. The assay was implemented to identify compounds that specifically blocked the astrocyte-driven enhancement of glioblastoma growth. Three such compounds were identified and one of them was further validated in an additional cell line. Results from the high-throughput screen suggested the crosstalk between glioblastoma cells and astrocytes as a potential therapeutic target. In conclusion, these studies suggest clinically and biologically relevant roles of astrocytes, as validated in patient datasets and peritumoral tissue. Co-culture specific drug response implies the crosstalk between malignant cells and astrocytes as a candidate target for novel therapies. Further studies will lead to better characterization of the mechanisms behind the glioblastoma-astrocyte crosstalk, while the clinical association of the novel PDGFRα+/GFAP+ peritumoral astrocyte subset should be further investigated and validated in larger cohorts

Convection enhanced delivery in the setting of high‐grade gliomas

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood–brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas