Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma.

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Hepatocellular carcinoma: a clinical and pathological overview

HCC incidence rates have been rising in the past 3 decades and by 2025 > 1 million individuals will be affected annually. High-throughput sequencing technologies led to the identification of several molecular HCC subclasses that can be broadly grouped into 2 major subgroups, each characterized by specific morphological and phenotypical features. It is likely that this increasing knowledge and a more appropriate characterization of HCC at the pathological level will impact HCC patient management

Multimodality imaging of adult rhabdomyosarcoma: the added value of hybrid imaging

Rhabdomyosarcoma (RMS) represents more than 50% of paediatric soft tissue tumours. Conversely, it is extremely rare among adults, where it shows peculiar biological and clinical features that are still poorly investigated. RMS patients should be referred to a Sarcoma Centre, where the contribution of experienced radiologists plays a relevant role in the diagnostic assessment of the disease, including precise localisation, staging, image-guided biopsy, response evaluation after treatment and follow-up. Besides CT and MRI, hybrid imaging including positron emission tomography (PET)/CT and PET/MRI are giving an increasing contribution to provide functional insights about tumour biology and to improve the diagnostic accuracy of the imaging work-up. This review paper provides a revision of the pathology, clinical and radiological features of adult RMS, with a particular focus on the growing role of hybrid PET-based imaging

Immune landscape and in vivo immunogenicity of NY-ESO-1 tumor antigen in advanced neuroblastoma patients

Abstract Background Indirect evidence suggesting the immunosensitivity/immunogenicity of neuroblastoma is accumulating. The aims of this study were to investigate the immune landscape of neuroblastoma and to evaluate the in vivo immunogenicity of the NY-ESO-1 tumor antigen in advanced neuroblastoma patients. Methods The immune infiltrating cells of the NY-ESO-1+ tumors from three HLA*A201 patients with metastatic neuroblastoma who relapsed after conventional treatments were evaluated by immunohistochemistry. The patients were vaccinated with the HLA-A*0201-restricted peptide NY-ESO-1157-165(V). The peptide was emulsified in Montanide ISA51 and given subcutaneously in a phase I pilot study. The immunogenicity of NY-ESO-1 antigen was evaluated by monitoring mononuclear cells in patient peripheral blood, pre- and post-vaccine, by short-term in vitro sensitization, HLA-multimer staining and IFN-γ ELISpot analysis. Results Both CD3 T cells and CD163 myeloid cells were present in pre-vaccine tumors and PD-1 and PD-L1 expression was mainly found in the immune infiltrate. Despite the advanced stage of the disease, the vaccination induced systemic NY-ESO-1 specific CD8 T cells releasing IFN-γ in response to activation with the NY-ESO-1 peptide and an HLA-A2 positive neuroblastoma cell line. Conclusions Our results indicate that vaccination with a tumor-associated peptide is able to boost NY-ESO-1-specific, functionally active T cells in advanced neuroblastoma patients with lymphocyte infiltration in their pre-vaccine tumors. Trial registration EudraCT #2006–002859-33

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma

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Identification of an actionable mutation of KIT in extraskeletal myxoid chondrosarcoma (EMC)

Background: EMC is an extremely rare soft tissue sarcoma, marked by a translocation involving NR4A3 gene. EMC are usually indolent and generally are moderately sensitive to anthracycline-based chemotherapy; we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. In addition, there is still the need to identify alternative therapeutic strategies. To better characterize the molecular background of this disease we performed whole transcriptome sequencing (WTS) in a small series of EMC identifying a case carrying an activating KIT mutation. Methods: Five EMC, positive for EWSR1-NR4A3 in FISH, were collected for WTS analysis. KIT phosphorylation was evaluated through Western Blot. KIT hotspot exons were sequenced through Sanger method in these cases and in an additional cohort of 15 EMC FFPE samples. Results: Presence of the chimeric EWSR1-NR4A3 mRNA was confirmed in all cases by WTS and no additional fusion event was identified. In concordance with previous reports, exon12/exon3 EWSR1-NR4A3 fusion was the most frequent breakpoint detected (sample #2, #3 and #5). While exon7/exon2 and exon13/exon3 were detected respectively in sample #1 and #4. Pathogenic SNV and INDEL were searched starting from WTS data. Peculiarly, in sample #1 an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. Sample #1 showed a marked high expression of KIT at mRNA level (9.8 fold greater than in the other 4 cases) and a mild phosphorylation of the receptor. KIT p.D579del is known to predict response to TKI treatment in GIST. However, Sanger sequencing of KIT in additional 15 FFPE EMC did not show any other mutated cases. Conclusions: Exon 11 KIT mutation has been detected in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in EMC and thus it could not explain the sensitivity of these tumors to sunitinib. Its role in the pathogenesis of EMC is left to be determined. No additional unknown fusion and/or mutation were detected

Identification of an Actionable Mutation of KIT in a Case of Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the NR4A3 gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. Moreover, there is still the need to identify alternative therapeutic strategies. To better characterize this disease, we performed whole transcriptome sequencing in five EMC cases. Peculiarly, in one sample, an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. This sample showed a marked high expression of KIT at the mRNA level and a mild phosphorylation of the receptor. Sanger sequencing of KIT in additional 15 Formalin Fixed Paraffin Embedded (FFPE) EMC did not show any other mutated cases. In conclusion, exon 11 KIT mutation was detected only in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in these tumors and cannot explain the EMC sensitivity to sunitinib, although it is an actionable mutation in the individual case in which it has been identified