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I. INTRODUZIONE.- 2. LA CATTURA DELLA SANTA CATARINA.- 3. IL GIUDIZIO DELLA SANTA CATARINA.- 4. ANTECEDENTI STORICI E DOTTRINALI- 5. LE OPERE DI GROZIO E FREITAS: I. I fondamenti della libertà di navigazione per Grozio; II. I poteri del pontefice per Grozio; III. La libertà di commercio per Grozio. IV. Freitas e la libertà di navigazione. V. I poteri del pontefice per Freitas.- 6. CONCLUSIONE

Pancreatic ductal adenocarcinoma (PADC) represents a highly lethal cancer with a very dismal prognosis. Absence of early symptoms, advanced stage at diagnosis, aggressive biological behaviour and lack of effective systemic treatment are the most important factors, explaining its elevated mortality rate and its low overall five-year survival (< 5%). Until now, the causes of this malignancy remain still largely unknown and further efforts are underway to reach a better knowledge of PADC aetiology and to improve our understanding of mechanisms involved in carcinogenesis of this organ. In the last years it has progressively emerged that viruses play a key role in human carcinogenesis. Unfortunately, some host and viral factors have contributed to make the study of the pancreas extremely difficult and to hamper the identification of pathogenetic processes involved in cancer development, including its retroperitoneal localization as well as the small size of precursor cancer lesions. However, in the past and more recently, some histological investigations suggested that both antigens and genome of hepatitis B (HBV) and hepatitis C (HCV) viruses, two pathogens with well-known high liver tropism and pro-oncogenic properties may be detected also in extra-hepatic tissues, such as pancreas. In addition, some epidemiological articles have suggested that HBV and HCV might be involved even in pancreatic carcinogenesis. Here we review the results of available reports, evaluating the possible association between HBV or/HCV infections and risk of pancreatic cancer development as well as to discuss the limiting factors of these researches.

Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these “inconclusive” specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.

Squamous cell carcinoma (SCC) is the most common malignancy of the nail unit. Pathogenetic mechanisms are yet to be determined, and a deeper molecular characterization of this disease is still necessary. The aim was to obtain a molecular characterization of NU SCC samples using an NGS approach to identify the genetic drivers involved in this tumor. The presence of HPV infection was also assessed. Furthermore, the mutational status was correlated with specific clinical-pathological features for a better insight into the carcinogenesis of this uncommon tumor. We analysed twenty paraffin-embedded nail unit SCC samples from patients diagnosed with primary SCC of the nail unit by next genome sequencing. In the 20 tested samples, the neoplastic cells enrichment ranged from 10% to 50% (mean value: 25.7%). In 14/20 cases (70.0%), at least one mutation was detected; whereas in the other six cases (30.0%), no alterations were observed (‘wild-type/WT cases’). Overall, a total of 23 mutations were identified in the 20 specimens. TP53 was the most mutated gene (6/20 cases, 30.0%), while cKit, GNAS, EGFR, DICER1 and CTNNB1 were observed in one sample each (5.0%). No clinical-pathological parameters (age, sex, depth of invasion-DOI, histological subtype, grading and HPV) were significantly associated with the mutational status. The nail unit SCC mutational landscape appeared to be heterogeneous, favouring the hypothesis of a complex pathogenesis and an interaction of multiple elements, including HPV infections. This wealth of information undoubtedly improves our understanding of SCC biology.

Introduction: Different models have been proposed for the prediction of the risk/benefit ratio of surgery in patients with carotid atheromasic disease, mainly based on clinical patients’ characteristics and risk factors, but no definite biological markers predictive of plaque instability and disease evolution have emerged so far, able to help the surgeon in the choice and timing of treatment. The main purpose of the present study was to assess the role of the polymorphism for genes commonly implicated in cell proliferation and neoangiogenesis in the clinical and histopathological carotid plaque vulnerability. Materials and methods: We retrospectively studied 29 consecutive patients who underwent carotid endarterectomy in 6 months. All histological variables were collected, as well as patients’ cardiovascular risk factors, clinical presentation, and brain computed tomography (CT) for the presence of ischemic lesions. Next-Generation Sequencing (NGS) was performed on 10-µm FFPE sections by means of a multi-gene panel used for sequencing 343 amplicons in 28 genes. Results: Among the gene variants observed, the polymorphism p.(Gln787=) in the EGFR gene was inversely correlated with intraplaque hemorrhage (p = 0.014), but also with the presence of ischemic brain lesions at CT (p = 0.001). Also p.(Gly105=) polymorphism in the IDH1 gene was inversely correlated with the presence of ischemic brain lesions (p = 0.038). Conclusions: The variant p.(Gln787=) in the EGFR gene seems to play a role in plaque stability in patients with carotid atheromasic disease, on both histopathological and clinical grounds, probably acting on plaque matrix remodeling. This can open new scenarios on the pre-surgical management of these patients.

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.

Tumorigenesis of biliopancreatic lesions is linked to specific alterations in key genes. Pancreatic neoplasms are well characterized at the genomic level. For example, exome and genome sequencing analyses revealed that pancreatic adenonocarcinomas are characterized by mutations manly in KRAS, TP53, CDKN2A/p16, and SMAD4 genes. Nevertheless, the pre-operative diagnosis and the management of patients with biliopancreatic lesion are still a clinical challenge, involving not only the endoscopic ultrasound-guided fine-needle aspiration procedure but also the appropriate biomolecular assessment of these lesions. The aim of the present chapter is to provide an overview of the current knowledge of the biology of biliopancreatic lesions as detected by molecular techniques.

BRAF exon 15 mutations are the most common molecular alterations found in papillary thyroid carcinoma (PTC). To date, there is no information regarding BRAF alterations in the thyroid parenchyma surrounding the tumor. To explore the early events associated with the development of PTC, we used massively parallel sequencing to investigate BRAF exon 15 in 30 PTCs and in 100 samples from the thyroid parenchyma surrounding the tumor. BRAF p.V600E was identified in 19/30 PTCs (63.3%). BRAF p.V600E mutations were identified in the tissue adjacent the PTC only in samples containing psammoma bodies. The other samples were either BRAF wild type (WT) or carried BRAF non p.V600E mutations. Specifically, BRAF p.G593D, -p.A598T, -p.V600M, -p.R603Q, -p.S607F, and -p.S607P were identified in 4 of 36 (11.1%) samples with follicular cell atypia, in 2 of 16 (12.5%) with follicular cell hyperplasia, and in 1 of 33 (3.0%) histologically normal samples&mdash, only in tissue surrounding BRAF p.V600E mutated PTCs. These mutations are predicted to affect protein function in silico but, in vitro, have kinase activity and BRAF phosphorylation levels similar to BRAF WT. No BRAF exon 15 mutations were identified in samples adjacent to PTCs that were BRAF WT. A mutagenic process affecting BRAF exon 15 occurs in a subset of thyroid glands that develop BRAF p.V600E mutated PTCs.

Context.—Integration of the analysis of genetic markers with endoscopic ultrasound–guided fine-needle aspiration and cytologic evaluation has increased the accuracy of the preoperative diagnosis of pancreatic lesions. The application of high-throughput gene panel analysis using next-generation sequencing platforms is now offering a great opportunity for further improvements.Objective.—To review the application of next-generation sequencing to the preoperative diagnosis of pancreatic lesions.Data Sources.—For data acquisition, a PubMed search using the terms next-generation sequencing, pancreas, pancreatic lesions, pancreatic tumors, and EUS-FNA was performed covering the years 2000–2017.Conclusions.—KRAS remains the gene most widely studied for preoperative single-gene tests. Next-generation sequencing reliably allows analysis of multiple gene markers starting from limited amounts of DNA. The study of multigene panels has become a very attractive option for the management and preoperative risk stratification of patients with pancreatic cancer.

Background Pancreatic adenocarcinoma (PDAC) is one of the deadliest human malignancies. Although surgery is currently the only effective treatment for PDAC, most patients survive less than 20 months after tumor resection. Objective The primary goal was to investigate alterations in KRAS, TP53, SMAD4 and CDKN2A/p16 in tumors from patients with exceptionally long survival after surgery. Methods Tumors from 15 patients with PDAC that survived more than 55 months after surgery ("LS") were analyzed for KRAS, TP53, IDH1, NRAS and BRAF using next-generation sequencing. SMAD4 and CDKN2A/p16 was tested using immunohistochemistry. MGMT promoter methylation was investigated. Results Tumors from "LS" have a lower prevalence of KRAS and TP53 mutations and had more frequently SMAD4 retained expression, if compared with that of patients died within 24 months from surgery. The survival of patients with wild-type KRAS and TP53 tumors was more than twice longer than that of patients bearing KRAS and TP53 mutations (90.2 vs. 41.1 months). Patients with KRAS wild-type tumors and that retained SMAD4 expression had a survival twice longer than cases with alterations in both genes (83.8 vs. 36.7 months). Eleven tumors (39.3%) showed MGMT methylation. Conclusions Our data indicate that absence of KRAS, TP53 and SMAD4 genetic alterations may identify a subset of pancreatic carcinomas with better outcome.