1,721,109 research outputs found
MULTIGENE MUTATIONAL PROFILING OF CHOLANGIOCARCINOMAS IDENTIFIES ACTIONABLE MOLECULAR SUBGROUPS
No full text153 tumori delle vie biliari, di cui 70 colangiocarcinomi intraepatici (ICC), 57 colangiocarcinomi extraepatici (ECC) e 26 carcinomi della colecisti (GBC) sono stati valutati per le mutazioni in 56 geni utilizzando sequenziamento multigenico di ultima generazione. L'espressione di EGFR e geni coinvolti nella pathway di mTOR sono stati studiati mediante immunoistochimica. Almeno un gene mutato è stato osservato in 118/153 (77%) tumori. I geni più frequentemente coinvolti sono KRAS (28%), TP53 (18%), ARID1A (12%), IDH1 / 2 (9%), PBRM1 (9%), BAP1 (7%), e PIK3CA (7%) . Le mutazioni in IDH1 / 2 (p = 0,0005) e BAP1 (p = 0,0097) sono caratteristiche degli ICC, mentre KRAS (p = 0,0019) e TP53 (p = 0,0019) sono più frequenti in ECC e GBC. L'analisi multivariata ha identificato lo stadio del tumore e le mutazioni in TP53 come predittori indipendenti di sopravvivenza. I geni coinvolti nel rimodellamento della cromatina (ARID1A, BAP1, PBRM1, SMARCB1) sono stati osservati nel 31% dei casi. Mutazioni in geni bersaglio di farmaci anti-tumorali sono stati osservati in 104/153 (68%) dei tumori: i) Mutazioni in KRAS / NRAS / BRAF sono state osservate nel 34% dei casi; ii) l'attivazione di mTOR è stata documentata attraverso immunoistochimica nel 51% dei casi e da mutazioni nei geni della pathway di mTOR nel 19% dei casi; iii) La segnalazione TGF-ß / Smad è stata trovata alterata nel 10.5% dei tumori; iv) Mutazioni nei recettori tirosin-chinasici sono state trovate nel 9% dei casi. Il nostro studio ha identificato sottogruppi molecolari di colangiocarcinoma che possono essere esplorati per il targeting farmaco specifico in studi clinici.One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials
Techniques and New Diagnostic Technologies (Limitations, Applications)
No full textTechniques and New Diagnostic Technologies (Limitations, Applications
Pathology of Biliary Tract Cancers
No full textBiliary tract cancers are highly malignant tumors that comprise bile duct cancers (so called cholangiocarcinoma, CCA) and gallbladder carcinomas. Based on their anatomical location, bile duct cancers fall into two main categories: intrahepatic and extrahepatic cholangiocarcinomas. Each type displays peculiar clinic-pathologic and molecular features. Intrahepatic cholangiocarcinoma (iCCA) is further subvided in small duct and large duct iCCA. Small duct iCCA usually involves septal and interlobar bile ducts, produces mass-forming lesions, has a better prognosis than large-duct iCCA and has no known precursor lesions. Large duct iCCA usually involves the first to third branches of hepatic bile ducts, shows a periductal-infiltrating pattern of invasion, has a poorer prognosis than the small duct counterpart and can derive from two types of precursor lesions: biliary intraepithelial neoplasia and intraductal papillary neoplasms. Extrahepatic cholangiocarcinomas (eCCA) includes perihilar eCCA (so-called Klatskin tumors) and distal eCCA. Histologically, eCCA display the morphology of a classic pancreatico-biliary adenocarcinoma. Gallbladder carcinomas (GBC) are malignant tumors mostly involving the gallbladder fundus (70% of cases), with the typical histology of a pancreatico-biliary adenocarcinoma. From the molecular point of view, mutations affecting the driver genes KRAS and TP53 can be found in all CCA subtypes. Of note, mutations affecting IDH1 and IDH2 genes and the chromatin-remodelers ARID1A, BAP1 and PBRM1 are typically enriched in iCCA, whereas ELF3 and ARID1B are more common in eCCA. In GBC, amplification of ERBB2 is more typical and also represent a therapeutic target
Undifferentiated Sarcomatoid Carcinoma of the Pancreas: From Histology and Molecular Pathology to Precision Oncology
No full textUndifferentiated sarcomatoid carcinoma of the pancreas (SCP) is a rare and aggressive subtype of pancreatic cancer. Histologically, SCP is a poorly differentiated tumor characterized by the lack of glandular differentiation and the presence of mesenchymal-like, spindle-shaped tumor cells. Due to its rarity, only sporadic cases have been reported, while its molecular characterization has not been sufficiently described. Surgical resection with curative intent is the gold-standard of SCP management, but this strategy is possible only in a small proportion of cases due to SCP early metastasization. Although SCP is generally associated with a poor prognosis, some clinical cases amenable to surgical resection and followed by adjuvant chemotherapy have demonstrated a remarkably long survival. Preliminary molecular insights on the SCP molecular landscape have demonstrated the recurrent presence of KRAS and TP53 mutations, highlighting genetic similarities with conventional pancreatic ductal adenocarcinoma (PDAC). Although the use of immunotherapy in PDAC remains an unmet challenge, recent insights indicated a potentially significant role of the PD-L1/Notch3 axis in SCP, opening new horizons for immunotherapy in this cancer subtype. In this review, we described the most important clinic-pathologic features of SCP, with a specific focus on their molecular landscape and the potential targets for precision oncology
New genomic landscapes and therapeutic targets for biliary tract cancers
No full textBiliary tract cancers (BTCs) are a heterogeneous group of neoplasms characterized by a dismal prognosis. At variance with most solid tumors, no effective molecular targeted agent has been currently approved for BTCs treatment and their molecular landscape has only been recently investigated. Comprehensive mutational profiling studies identified IDH1/2 and BAP1 as characteristic of intrahepatic cholangiocarcinomas, while extrahepatic cholangiocarcinomas and gallbladder carcinomas were characterized by frequent KRAS and TP53 alterations. Moreover, targeted next-generation sequencing has uncovered alterations in several key cellular pathways. BTC-specific alterations include disorders of major regulators of cell cycle and chromatin remodeling processes, as well as deregulation of the mTOR-, TGF-beta/Smad- and receptor tyrosine kinases signaling. The next step will be the correlation of these findings with clinical trials to identify predictive biomarkers for the development of personalized therapies. This will permit early access for BTC patients to innovative drugs
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
Pro-inflammatory factors secreted by pancreatic cancers with evasive resistance to anti-VEGF treatment contribute to malignant progression by inducing EMT
No full textPro-inflammatory factors secreted by pancreatic cancers with evasive resistance to anti-VEGF treatment contribute to malignant progression by inducing EM
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