Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. We comparatively investigated these unique complementary materials using morphofunctional, ultrastructural and flow cytometric assays accompanied by microRNA studies. We found that paragangliomas contain stem-like cells with hybrid mesenchymal/vasculoneural phenotype, stabilized and expanded in the derived cultures. The viability and growth of such cultures depended on the downregulation of the miR-200 and miR-34 families, which allowed high PDGFRA and ZEB1 protein expression levels. Both tumour tissue- and cell culture-derived xenografts recapitulated the vasculoneural paraganglioma structure and arose from mesenchymal-like cells through a fixed developmental sequence. First, vasculoangiogenesis organized the microenvironment, building a perivascular niche which in turn supported neurogenesis. Neuroepithelial differentiation was associated with severe mitochondrial dysfunction, not present in cultured paraganglioma cells, but acquired in vivo during xenograft formation. Vasculogenesis was the Achilles’ heel of xenograft development. In fact, imatinib, that targets endothelial-mural signalling, blocked paraganglioma xenograft formation (11 xenografts from 12 cell transplants in the control group versus 2 out of 10 in the treated group, P = 0.0015). Overall our key results were unaffected by the SDHx gene carrier status of the patient, characterized for 70 out of 77 cases. In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization.Electronic supplementary materialThe online version of this article (10.1007/s00401-017-1799-2) contains supplementary material, which is available to authorized users.

Purpose: Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged survival in 50 patients with glioblastoma. Here, we present an updated retrospective analysis that includes an additional 52 patients.Experimental Design: From December 2006 to November 2019, 102 patients with newly diagnosed glioblastoma received valganciclovir as an add-on to standard therapy. No additional toxicity was observed. Contemporary controls were 231 patients with glioblastoma who received similar baseline therapy.Results: Patients with newly diagnosed glioblastoma receiving valganciclovir had longer median overall survival (OS 24.1 vs. 13.3 months, P < 0.0001) and a 2-year survival rate (49.8% vs. 17.3%) than controls. Median time-to-tumor progression was also longer than in controls; 9.9 (0.7-67.5 months) versus 7.3 (1.2-49 months), P ¼ 0.0003. Valganciclovir improved survival in patients with radical or partial resection and an unmethylated or methylated MGMT promoter gene.Conclusions: Valganciclovir prolonged median OS of patients with newly diagnosed glioblastoma (with methylated or unmethylated MGMT promoter gene) and was safe to use.

Carotid body and vagal paragangliomas, although considered indolent tumors, represent a challenge for the treating physician. This is mainly because of their peculiar localization, in close proximity with important anatomical structures. In addition, there is no chemotherapy available for these