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BACKGROUND IDH-wildtype glioblastoma behaves differently from all other solid tumors. This is the reason why after decades of praiseworthy therapeutic efforts, the prognosis remains very poor. Many clues (radiological, clinical, surgical) and recent indirect experimental evidence converge to indicate that the entire brain parenchyma is micro-infiltrated from the very beginning by the founding clone before the primary bulk has started its growth. Therefore, only in IDH-wildtype glioblastoma the malignant (i.e. distantly infiltrating the organ of origin) and deadly (leading cause to patient’s death) phases coincide and overlap in one single phase. MATERIALS AND METHODS Appropriate sampling procedures must absolutely take into consideration both the tumor bulk and the micro-infiltrated brain parenchyma. They can be performed (with full respect for ethical issues) analyzing neoplastic and “healthy” material obtained from living patients (a), using animal models (b), studying post-mortem samples from rapid autopsies (c), comparing local and distant recurrences with the primary bulk (d). The study and analysis of the bulk tumor must be carried out by collecting multiple multiregional spatially separated samples throughout the whole tumor mass. The analysis of the micro-infiltrated brain parenchyma in living patients can be performed appropriately and ethically also from surgical patient tissue. RESULTS The phylogenetic tree of the tumor bulk must be inferred and reconstructed by the collection and analysis of multiple regionally separated samples. Additionally, driver and passenger events will be identified as well as the CSCs of samples. The procedures to ethically sample the micro-infiltrated brain parenchyma enable us to collect and identify the founder CSCs which lie quiescent in the perivascular parenchymal niches across the whole brain. Indeed, distant recurrences are due to their activation. CONCLUSION IDH-wildtype glioblastoma is the only brain tumor which arises from astrocyte-like cells of the SVZ ribbon layer and it is able to micro-infiltrate the whole supratentorial brain parenchyma before starting its growth. Its unique inverse paradigm explains the emergence of distant recurrences (sharing only truncal mutations with the primary bulk) and adds, in addition to the heterogeneity of the primary bulk and its residues, a second crucial cause of resistance to take into account (i.e. the founder CSCs which reside quiescent, in G0 state, in the perivascular parenchymal niches). Therefore, innovative therapies must identify and selectively target either CSCs unique properties related to their impaired asymmetrical division or stable driver lesions of the founder CSC (without alternative mutations and pathways) or exclusive markers used by the founder CSCs to settle dormant (involving mechanisms of adhesion, anchorage and cell cycle arrest) in their niches.

P14.19 The inverse paradigm of IDH-wildtype glioblastoma is fundamental to overcome the two causes of resistance and develop novel effective therapies