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Biomolecular characterization of metastatic medulloblastoma and study of telomere lengthening control
Full text linkMedulloblastoma (MDB) is a malignant embryonic brain tumor and occurs typically in pediatric patients. Medulloblastoma cells can disseminate through the cerebrospinal fluid in the leptomeningeal space; approximately 30% of children present metastasis at the onset and no gold standard treatment has been defined for these patients. Genetic, epigenetic and molecular analyses identified four molecular subgroups (WNT, SHH, group 3 and group 4), associated with prognostic stratification of patients; however, previous works in literature included only small amount of metastatic cases, not analyzed independently from the non-metastatic counterpart. Furthermore, recent studies evidenced that mechanisms of telomeres elongation can be activated in pediatric brain tumours and telomeres maintenance was enriched in SHH and group 3 non-metastatic MDB; however, elongation of telomeres was not previously investigated in metastatic medulloblastomas.
Therefore, our aim is to characterize a series of 39 pediatric MDB, selected from a cohort of 60, with leptomeningeal dissemination at the onset, studying molecular features involved in malignancy, metastasis, telomeres elongation and senescence escape. We analyzed several biomarkers and we correlated results to outcome of patients, evaluating the prognostic relevance of molecular biomarkers and subgroups. Furthermore, we analyzed the activation of mechanisms involved in control of telomeres lengthening, in order to figure out if telomeres elongation could have a role in metastatic medulloblastomas.
We show that distribution of metastatic MDB into four molecular subgroups is highly similar to the distribution of non-metastatic cases, reflecting a high molecular heterogeneity; interestingly, our molecular subgrouping system defines high-risk (group SHH, 3 and 4) and standard-risk (group WNT and Not Classifiable) patients. Furthermore, we evidence that FSTL5 over-expression is associated exclusively with groups 3/4 and with poor outcome of patients, highlighting that FSTL5 can be used to better define molecular subgroups, prognosis and risk stratification of metastatic medulloblastomas.
In addition, we analyzed H3.3 and ATRX mutations, involved in activation of the Alternative Lengthening of Telomeres (ALT) pathway, and the mutation and methylation status of TERT promoter, involved in telomerase reactivation. We evidence that metastatic MDB activate elongation of telomeres both via telomerase (14%) and via ALT mechanism (27%), triggered by ATRX mutations; interestingly, ALT pathway is highly activated in our cohort compared to MDB previously analysed in literature (<5%), highlighting the differences between metastatic and non-metastatic tumors in control of telomeres elongation and senescence escape. Furthermore, metastatic MDB show a higher reactivation of telomerase compared to pHGG (0%), triggered by TERT promoter mutations in combination with hyper-methylation. Our findings suggest that immortalization of tumor cells in metastatic MDB is a common process to escape from senescence and characterizes all molecular subgroups.
In conclusion, our results contribute to improve the current characterization of pediatric patients with metastatic medulloblastoma; however, further studies will be necessary to increase the number of cases and to analyze, with statistical significance, the molecular subgroups, FSTL5 expression, and telomeres elongation, which could be used to “personalize” treatments or develop targeted therapies, reducing the side effects of the current therapeutic protocols
Distribution and prognostic impact of molecular subgroups in a homogeneously treated series of metastatic medulloblastoma
No full textMedulloblastoma (MDB) is the most common malignant paediatric brain
tumor. Prognostic system based on clinical parameters and histopathological
variants is commonly used in clinical practice. Four different molecular subgroups
are recognized: WNT and SHH, having specific homonymous
pathwayalterations;Cand D, havingseveral genetic alterationsand associated
to a worse outcome, but the system has not been prospectively validated in
metastatic cohorts. Purpose of this studywasto evaluate distribution andprognostic
impact of the four molecular subgroups in 47 MDB metastatic at the
onset, homogenously treated in a single institution (Gandola et al, JCO
2009). Subgroup biomarkers were investigated by IHC, RT-PCR, mRNA sequencing,
FISH; results were correlated with patient outcomes by
Kaplan-Meier. We identify 11% WNT with nuclear b-catenin, 19% SHH,
26%groupCand15%group D;29%were unclassifiable (NC) having heterogeneous
biomarkers. MYC amplification was more frequent (32.5%) compared
to MYCN (2.7%). WNT and NC groups showed longer (not
significant) OSand PFS compared to SHH,Cand D. Furthermore, low expression
of FSTL5 was associated with good prognosis (OS rate 90%, PFS rate
100%), while FSTL5 higher expression correlate with worse outcome (OS
and PFS rate 66%); difference was statistically significant (p 1⁄4 0,05). We
have previously shown that histological variants maintain prognostic value
in metastatic MDB; on the opposite, molecular sub-grouping is inefficient to
allow a better risk stratification in our metastatic MDB cohort; furthermore,
FSTL5 gene expression might be used in metastatic MDB as prognostic
factor to better define patient outcome
Biomolecular Analysis of Pediatric Medulloblastoma and Prognostic Relevance of FSTL5 Expression: A Single-Center Study
No full textFSTL5 expression is a marker of Group C metastatic medulloblastomas
Full text linkINTRODUCTION: Medulloblastoma (MB) is the most commonmalignant
brain tumor in children. Four different molecular subgroups are recognized,
which differ in gene expression, genomic aberrations, histology, demographics
and survival:WNT and SHH groups, having specific mutations in the homonymous
pathway, and groups C and D having several genetic alternations
not specific to a single pathway. The gene for follistatin-like protein 5, FSTL5,
is overexpressed in nonSHH/nonWNT MBs poorly characterized. Highexpression
of FSTL5 is significantly associated with reduced event-free and
overall survival in non-WNT/non-SHHMBs. The major aim of this project is
to study the FSTL5 expression level in pediatric MBs with metastasis at the
onset. METHOD: We investigated the protein expression of biomarkers involved
in metastatic pathways by IHC and FSTL5 expression level by
RT-PCR in 26 metastatic MBs samples and correlated these data with the outcomes
by Kaplan-Meier statistic analysis. RESULTS: 83% of Group C MBs
showed high level of FSTL5 while none of these presented down-expression.
Low-expression level of FSTL5 was find in 60% of SHH MBs and none
showed over-expression. Kaplan-Meier test revealed that, in our cohort, highexpression
ofFSTL5didnot correlatewithworse outcomewhile lowexpression
of FSTL5 was associated with good prognosis and the co-presence of FSTL5
with other biomarkers correlated with poorer prognosis. CONCLUSION:
FSTL5 is a marker of Group C in medulloblastomas with metastasis at the
onset and the results highlighted decreased FSTL5 expression as a marker of
good prognosis. Group C MBs have characteristic molecular features that
confirm the poorest outcome also inMBs with metastasis at the onset
Brafv600e and Ctbn1 Mutational Study in Rathke's Cleft Cysts
Full text linkAim: Rathke's cleft cysts and craniopharyngiomas tipically involve sellar region and their histogenetic relationship
is still matter of debate. Clinical and histopathologic differentiation of cystic lesions from the sellar region, that is,
craniopharyngiomas (CPs) and Rathke cleft cysts (RCCs), is challenging and has great importance with respect to
variable clinical manifestation and adapted surgical treatment strategies in both entities. The recent acquisition that
adamantinomatous and papillary craniopharyngiomas bear distinct molecular alterations i.e., β-catenin (CTNNB1)
and BRAFv600 mutations respectively, has suggest to screen for such alteration a series of Rathke cyst to seek a
possible relation with one of the two craniopharyngioma type.
Methods: Seven Rathke's cleft cysts were analyzed for BRAF and CTNNB1 mutational status by sequencing and
immunohistochemistry. Radiological, clinical and histological features were performed.
Results: None of the 7 Rathke's cleft cysts harbor BRAFV600E mutation. No CTNNB1 mutation was found.
Radiological, clinical and histological re-evaluation of the cases confirmed the diagnosis of Rathke's cleft cysts.
Conclusion: BRAFV600E and CTNNB1 mutations appeared, as most reliable factor for the differentiation
between purely cystic CPs and RCCs, whereas tumor location, tumor size, and radiological parameter of the tumor
were less consistent parameters. This study again confirms that craniopharyngiomas (CPs) and Rathke cleft cysts
(RCCs), are associated with distinct pathogenic pathways
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
Solitary juvenile xanthogranuloma of the hypopharynx. Clinico-pathologic study in a child with β-thalassemia major and cutaneous mastocytosis
No full textJuvenile Xanthogranuloma (JXG), the most common pediatric non-Langerhans cell histiocytosis, may rarely occur in association with Neurofibromatosis (types 1 and 2), Juvenile Myelomonocytic Leukemia and Cutaneous Mastocytosis (CM) and, morphologically, mimics Erdheim-Chester Disease tissue lesions and ALK-positive histiocytosis. We describe a 4-year-old girl with Beta-Thalassemia Major who developed an hypopharyngeal BRAFV600E- and ALK-negative JXG and CM. JXG has been rarely reported in the aerodigestive tract and in association with CM. In this molecular era, knowledge of genetic heterogeneity of JXG and clinical scenarios in which it may develop is essential for the appropriate diagnosis and treatment of each individual patient
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