Solitary fibrous tumors, which are characterized by their broad morphological spectrum and unpredictable behavior, are rare mesenchymal neoplasias that are currently divided into three main variants that have the NAB2-STAT6 gene fusion as their unifying molecular lesion: usual, malignant and dedifferentiated solitary fibrous tumors. The aims of this study were to validate molecular and immunohistochemical/biochemical approaches to diagnose the range of solitary fibrous tumors by focusing on the dedifferentiated variant, and to reveal the genetic events associated with dedifferentiation by integrating the findings of array comparative genomic hybridization. We studied 29 usual, malignant and dedifferentiated solitary fibrous tumors from 24 patients (including paired samples from five patients whose tumors progressed to the dedifferentiated form) by means of STAT6 immunohistochemistry and (when frozen material was available) reverse-transcriptase polymerase chain reaction and biochemistry. In addition, the array comparative genomic hybridization findings were used to profile 12 tumors from nine patients. The NAB2/STAT6 fusion was detected in all of the tumors, but immunohistochemistry and western blotting indicated that chimeric protein expression was atypical or absent in 9 out of 11 dedifferentiated tumors. The comparative genomic hybridization results revealed that the usual and malignant solitary fibrous tumors had a simple profile, whereas the genome of the dedifferentiated tumors was complex and unstable, and suggested that 13q and 17p deletions and TP53 mutations may be present in malignant lesions before the full expression of a dedifferentiated phenotype. Solitary fibrous tumor dedifferentiation is associated with the loss of chimeric oncoprotein expression, genomic instability, and cell decommitment and reprogramming. The assessment of dedifferentiated solitary fibrous tumors is based on the presence of the fusion transcripts and, in principle, negative STAT6 immunohistochemistry should not rule out a diagnosis of solitary fibrous tumor. Modern Pathology (2015Pathology ( ) 28, 1074Pathology ( -1083 doi:10.1038/modpathol.2015 published online 29 May 2015 Solitary fibrous tumors are rare mesenchymal tumors (incidence o 1 per million) that were originally described on the pleurae but have subsequently been recognized at virtually all body sites. 1 The current classification includes usual, malignant and the recently described dedifferentiated variants. [1][2][3] The morphobiological features distinguishing the malignant and usual variants are hypercellularity, cell pleomorphism, necrosis and a mitotic index of 44/10 high-power fields. However,
Background: To explore the activity of pazopanib in solitary fibrous tumour (SFT). Patients and methods: In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm 3 . Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure.
BACKGROUND AND PURPOSE Iron aggravates the cardiotoxicity of doxorubicin, a widely used anticancer anthracycline, and the iron chelator dexrazoxane is the only agent protecting against doxorubicin cardiotoxicity; however, the mechanisms underlying the role of iron in doxorubicin‐mediated cardiotoxicity and the protective role of dexrazoxane remain to be established. As iron is required for the degradation of hypoxia‐inducible factors (HIF), which control the expression of antiapoptotic and protective genes, we tested the hypothesis that dexrazoxane‐dependent HIF activation may mediate the cardioprotective effect of dexrazoxane. EXPERIMENTAL APPROACH Cell death, protein levels (by immunoblotting) and HIF‐mediated transcription (using reporter constructs) were evaluated in the rat H9c2 cardiomyocyte cell line exposed to low doses of doxorubicin with or without dexrazoxane pretreatment. HIF levels were genetically manipulated by transfecting dominant‐negative mutants or short hairpin RNA. KEY RESULTS Treatment with dexrazoxane induced HIF‐1α and HIF‐2α protein levels and transactivation capacity in H9c2 cells. It also prevented the induction of cell death and apoptosis by exposure of H9c2 cells to clinically relevant concentrations of doxorubicin. Suppression of HIF activity strongly reduced the protective effect of dexrazoxane. Conversely, HIF‐1α overexpression protected against doxorubicin‐mediated cell death and apoptosis also in cells not exposed to the chelator. Exposure to dexrazoxane increased the expression of the HIF‐regulated, antiapoptotic proteins survivin, Mcl1 and haem oxygenase. CONCLUSIONS AND IMPLICATIONS Our results showing HIF‐dependent prevention of doxorubicin toxicity in dexrazoxane‐treated H9c2 cardiomyocytes suggest that HIF activation may be a mechanism contributing to the protective effect of dexrazoxane against anthracycline cardiotoxicity.
Malignant peritoneal mesothelioma (MpM), arising in the setting of local inflammation, is a rare aggressive tumour with a poor prognosis and limited therapeutic options. The three major MpM histological variants, epithelioid (E-MpMs), biphasic, and sarcomatoid MpMs (S-MpMs), are characterised by an increased aggressiveness and enhanced levels of EZH2 expression. To investigate the MpM immune contexture along the spectrum of MpM histotypes, an extended in situ analysis was performed on a series of 14 cases. Tumour-infiltrating immune cells and their functionality were assessed by immunohistochemistry, immunofluorescence, qRT-PCR, and flow cytometry analysis. MpMs are featured by a complex immune landscape modulated along the spectrum of MpM variants. Tumour-infiltrating T cells and evidence for pre-existing antitumour immunity are mainly confined to E-MpMs. However, Th1-related immunological features are progressively impaired in the more aggressive forms of E-MpMs and completely lost in S-MpM. Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1. This study enriches the rising rationale for immunotherapy in MpM and points to the E-MpMs as the most immune-sensitive MpM histotypes, but it also suggests that synergistic interventions aimed at modifying the tumour microenvironment (TME) should be considered to make immunotherapy beneficial for these patients.
BackgroundIndirect 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.MethodsThe 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.ResultsBoth 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.ConclusionsOur 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 registrationEudraCT #2006–002859-33.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4910-8) contains supplementary material, which is available to authorized users.
Sunitinib improves the outcomes of patients with solitary fibrous tumours (SFTs). The aim of this study was to investigate and contextualise sunitinib-induced morpho-functional changes in order to gain insights into the drug's mechanism of action.To this end, four surgical specimens obtained from two sunitinib-responsive patients with malignant SFT, and one primary cell culture obtained from fresh tumoral tissue and its stabilised cell line, were studied by means of immunohistochemistry, bright field in situ hybridisation, immunofluorescence/confocal microscopy, and biochemistry.The post-sunitinib surgical samples were characterised by two biologically relevant morpho-functional changes: clear areas and necrotic foci. The first were associated with the attenuation/loss of PDGFRB expression and decreased mTOR signalling, and corresponded to a pathological response. The second were associated with the over-expression of PDGFRB and VEGFA, strong mTOR signalling activation, and the appearance of HIF1α expression, hallmarks of pathological progression. The analysis clearly showed that sunitinib reduces the vascular supply network and inhibits tumoral cells. It also either induces autophagy, thus favouring drug response, or impairs autophagy as a result of lysosome sequestration, thus favouring disease progression. These distinct autophagic events were associated with different myeloid immune contextures. Finally, we also found that PDGFRB is one of the components of a complex that includes Beclin 1 and VPS34.The results of these tissue-based analyses provide new insights into sunitinib's mechanism of action in SFT patients.
e14726 Background: CD205 is a type I transmembrane surface protein belonging to the mannose receptor family with propensity for antigen uptake/internalization. CD205 is expressed in different cancer histotypes and seems to have a role in migration and invasion. For these features CD205 is an ideal candidate to be exploited as an ADC target. MEN1309/OBT076 (herein as MEN1309) is a humanized IgG1 antibody against CD205, conjugated through a cleavable linker to DM4. It has shown impressive anti-tumor activity when tested in high/low CD205 expressing xenografts for solid tumours and NHL. MEN1309 is under assessment in Phase I trials in EU (NCT03403725) and as OBT076 in USA. Methods: A retrospective evaluation of CD205 expression in 103 triple negative breast carcinomas (TNBC), 50 pancreatic adenocarcinomas (PAC) and 100 bladder urothelial carcinomas (UC) was performed at INT in Milan, Italy. Immunohistochemistry was performed on one FFPE representative sample per case, using a commercial anti-CD205 antibody. A semiquantitative score was applied to measure CD205 expression. Absence of staining tumor cells was scored as negative. Positivity was scored based on the percentages of neoplastic cells (NCs), with intensity of cytoplasmic staining ranging from 1 (weak) to 3 (strong). Membrane staining in NCs, immunoreactivity of the intratumoral/peritumoral inflammatory component and of normal tissue were scored as absent or present. Results: TNBC: 85% were positive, 70% in > 5% of NCs; 14% showed 2+/3+ staining intensity in > 50% of NCs. 57% of cases showed a membrane positivity. PAC: 100% were positive in > 5% of NCs; 50% showed 2+/3+ staining intensity in > 50% of NCs. 98% of cases showed a membrane positivity. UC: 67% were positive, 60% in > 5% of NCs; 10% showed 2+/3+ staining intensity in > 50% of NCs. 29% of cases showed a membrane positivity. Inflammatory component and normal tissue were positive in almost all cases. Conclusions: CD205 is heterogeneously expressed in the majority of TNBC and UC and in all PAC cases. The results of this study support the clinical investigation of MEN1309 in these tumor types.
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