1,720,986 research outputs found
“MOLECULAR MARKERS IN DIFFUSE GLIOMAS: DIAGNOSTIC AND THERAPEUTIC TARGETS”
Full text linkDue to their capital diagnostic, prognostic and therapeutic implications, molecular markers have become essential for the management of patients with diffuse gliomas. Among them, IDH mutations have special importance, as they allow to classify diffuse gliomas, they are predictive of prolonged survival and increased sensitivity to alkylating agents and can be targeted by specific inhibitors. IDH-mutant diffuse gliomas deeply differ from IDH-wildtype diffuse gliomas in terms of molecular profile, prognosis and treatment, as different are the pathways of gliomagenesis and progression in the two groups.
In the first section of the thesis, we explored the association between 25 glioma risk loci and tumor genotype in a large cohort of glioma patients for whom we disposed of both germline and tumor DNA. Our study confirmed that IDH-mutant and IDH-wildtype gliomas are associated with different susceptibility loci and that certain germline risk loci associate with distinct molecular groups, suggesting a direct involvement in their pathogenesis.
In the second section of the thesis, we assessed the performance of two different techniques for the noninvasive detection of IDH mutations. The first technique is based on the identification of IDH1 mutations from the analysis of tumor-derived extracellular vesicles circulating in plasma, a procedure generally referred to as “liquid biopsy”. The second technique is based on the detection of 2-hydroxyglutarate, a metabolite that reflects the presence of IDH mutations, using in vivo magnetic resonance spectroscopy. While the experiments of liquid biopsy posed major challenges due to the limited amount of tumor-derived material circulating in plasma, magnetic resonance spectroscopy proved an overly sensitive and specific technique for the diagnosis and follow-up of patients with IDH-mutant gliomas.
In the third section of the thesis, we focused on three rare subsets of IDH-wildtype gliomas with the aim to better characterize their genetic profile, define their prognosis, and assess the prevalence of actionable alterations. We identified different mutational and immunological signatures in high- and low-grade gliomas associated with type 1 neurofibromatosis, we identified recurrent FGFR1 mutations in midline gliomas and frequent FGFR3-TACC3 fusions in low-grade astrocytomas lacking IDH mutations, observations that pave the way to the experimentation of novel therapeutic approaches for these rare tumor types.
In the fourth and last section of the thesis, we analyzed the response to targeted treatment in a cohort of adult patients with recurrent or disseminated BRAF-mutant gliomas. The substantial response rate observed in our study encourages the use of RAF/MEK inhibitors in BRAF-mutant gliomas and emphasizes the importance of screening for this rare but actionable alteration
CAR-T Cells for the Treatment of Central Nervous System Tumours: Known and Emerging Neurotoxicities
No full textThe advent of chimeric antigen receptor (CAR)-T cells has recently changed the prognosis of relapsing/refractory diffuse large B-cell lymphomas, showing response rates as high as 60 to 80%. Common toxicities reported in the pivotal clinical trials include the cytokine release syndrome (CRS) and the Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a stereotyped encephalopathy related to myeloid cell activation and blood–brain barrier dysfunction, presenting with a distinctive cascade of dysgraphia, aphasia, disorientation, attention deficits, vigilance impairment, motor symptoms, seizures, and diffuse brain oedema. The tremendous oncological efficacy of CAR-T cells observed in systemic B-cell malignancies is leading to their growing use in patients with primary or secondary central nervous system (CNS) lymphomas and in patients with solid tumours, including several CNS cancers. Early studies conducted in adult and paediatric patients with solid CNS tumours reported a distinct profile of neurotoxicity referred to as Tumour inflammation-associated neurotoxicity (TIAN), corresponding to local inflammation at the tumour site manifesting with focal neurological deficits or mechanical complications (e.g., obstructive hydrocephalus). The present review summarises available data on the efficacy and safety of CAR-T cells for solid and haematological CNS malignancies, emphasising known and emerging phenotypes, ongoing challenges, and future perspectives
Brain metastases from lung cancer: Is MET an actionable target?
Full text linkThe process of metastatic dissemination begins when malignant cells start to migrate and leave the primary mass. It is now known that neoplastic progression is associated with a combination of genetic and epigenetic events. Cancer is a genetic disease and this pathogenic concept is the basis for a new classification of tumours, based precisely on the presence of definite genetic lesions to which the clones are addicted. Regarding the scatter factor receptors MET and Recepteur d’Origin Nantais (RON), it is recognised that MET is an oncogene necessary for a narrow subset of tumours (MET-addicted) while it works as an adjuvant metastogene for many others. This notion highlights that the anti-MET therapy can be effective as the first line of intervention in only a few MET-addicted cases, while it is certainly more relevant to block MET in cases of advanced neoplasia that exploit the activation of the invasive growth program to promote dissemination in other body parts. Few data are instead related to the role played by RON, a receptor homologous to MET. We have already demonstrated an implication of MET and RON genes in brain metastases from lung cancer. On this basis, the aim of this work is to recapitulate and dissect the molecular basis of metastatic brain dissemination from lung cancer. The latter is among the big killers and frequently gives rise to brain metastases, most often discovered at diagnosis. Molecular mechanisms leading to tumour spread to the brain are mostly unknown and in turn these tragic cases are still lacking effective therapies. Based on previously published data from our group, we aim to summarise and analyse the pathogenic mechanisms leading to activation of the scatter factor receptor in brain metastatic lesions of lung primaries, from the point of view of replacing the currently used empirical treatment with a more targeted approach
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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