For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too.

SUMMARY Disregarding the widely used division of skull base into anterior and lateral, since the skull base should be conceived as a single anatomic structure, it was to our convenience to group all those approaches that run from the antero-lateral, pure lateral and postero-lateral side of the skull base as “Surgery of the lateral skull base”. “50 years of endeavour” points to the great effort which has been made over the last decades, when more and more difficult surgeries were performed by reducing morbidity. The principle of lateral skull base surgery, “remove skull base bone to approach the base itself and the adjacent sites of the endo-esocranium”, was then combined with function preservation and with tailoring surgery to the pathology. The concept that histology dictates the extent of resection, balancing the intrinsic morbidity of each approach was the object of the first section of the present report. The main surgical approaches were described in the second section and were conceived not as a step-by-step description of technique, but as the highlighthening of the surgical principles. The third section was centered on open issues related to the tumor and its treatment. The topic of vestibular schwannoma was investigated with the current debate on observation, hearing preservation surgery, hearing rehabilitation, radiotherapy and the recent efforts to detect biological markers able to predict tumor growth. Jugular foramen paragangliomas were treated in the frame of radical or partial surgery, radiotherapy, partial “tailored” surgery and observation. Surgery on meningioma was debated from the point of view of the neurosurgeon and of the otologist. Endolymphatic sac tumors and malignant tumors of the external auditory canal were also treated, as well as chordomas, chondrosarcomas and petrous bone cholesteatomas. Finally, the fourth section focused on free-choice topics which were assigned to aknowledged experts. The aim of this work was attempting to report the state of the art of the lateral skull base surgery after 50 years of hard work and, above all, to raise questions on those issues which still need an answer, as to allow progress in knowledge through sharing of various experiences. At the end of the reading, if more doubts remain rather than certainties, the aim of this work will probably be achieved.

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The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies.The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS.In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases.