Despite the multidisciplinary management in the treatment of glioblastomas, the average survival of GBM patients is still 15 months. In recent years, molecular biomarkers have gained more and more importance both in the diagnosis and therapy of glial tumors. At the same time, it has become clear that non neoplastic cells, which constitute about 30% of glioma mass, dramatically influence tumor growth, spread, and recurrence. This is the main reason why, in recent years, scientific research has been focused on understanding the function and the composition of tumor microenvironment and its role in gliomagenesis and recurrence. The aim of this review is to summarize the most recent discovery about resident microglia, tumor-associated macrophages, lymphocytes, and the role of extracellular vesicles and their bijective interaction with glioma cells. Moreover, we reported the most recent updates about new therapeutic strategies targeting immune system receptors and soluble factors. Understanding how glioma cells interact with non-neoplastic cells in tumor microenvironment is an essential step to comprehend mechanisms at the base of disease progression and to find new therapeutic strategies for GBM patients. However, no significant results have yet been obtained in studies targeting single molecules/pathways; considering the complex microenvironment, it is likely that only by using multiple therapeutic agents acting on multiple molecular targets can significant results be achieved.

Glioblastoma (GBM) is the most common and aggressive central nervous system tumor, requiring multimodal management. Due to its malignant behavior and infiltrative growth pattern, GBM is one of the most difficult tumors to treat and gross total resection is still considered to be the first crucial step. The deep understanding of GBM microenvironment and the possibility of manipulating the patient’s innate and adaptive immune system to fight the neoplasm represent the base of immunotherapeutic strategies that currently express the future for the fight against GBM. Despite the immunotherapeutic approach having been successfully adopted in several solid and haematologic neoplasms, immune resistance and the immunosuppressive environment make the use of these strategies challenging in GBM treatment. We describe the most recent updates regarding new therapeutic strategies that target the immune system, immune checkpoint inhibitors, chimeric antigen receptor T cell therapy, peptide and oncolytic vaccines, and the relevant mechanism of immune resistance. However, no significant results have yet been obtained in studies targeting single molecules/pathways. The future direction of GBM therapy will include a combined approach that, in contrast to the inescapable current treatment modality of maximal resection followed by chemo- and radiotherapy, may combine a multifaceted immunotherapy treatment with the dual goals of directly killing tumor cells and activating the innate and adaptive immune response.

Background Peripheral nerve injuries (PNIs) include several conditions in which one or more peripheral nerves are damaged. Trauma is one of the most common causes of PNIs and young people are particularly affected. They have a significant impact on patients’ quality of life and on the healthcare system, while timing and type of surgical treatment are of the utmost importance to guarantee the most favorable functional recovery. To date, several different classifications of PNIs have been proposed, most of them focusing on just one or few aspects of these complex conditions, such as type of injury, anatomic situation, or prognostic factors. Current classifications do not enable us to have a complete view of this pathology, which includes diagnosis, treatment choice, and possible outcomes. This fragmentation sometimes leads to an ambiguous definition of PNIs and the impossibility of exchanging crucial information between different physicians and healthcare structures, which can create confusion in the choice of therapeutic strategies and timing of surgery. Materials The authors retrospectively analyzed a group of 24 patients treated in their center and applied a new classification for PNI injuries. They chose (a) five injury-related factors, namely nerve involved, lesion site, nerve type (whether motor, sensory or mixed), surrounding tissues (whether soft tissues were involved or not), and lesion type—whether partial/in continuity or complete. An alphanumeric code was applied to each of these classes, and (b) four prognostic codes, related to age, timing, techniques, and comorbidities. Results An alphanumeric code was produced, similar to that used in the AO classification of fractures. Conclusions The authors propose this novel classification for PNIs, with the main advantage to allow physicians to easily understand the characteristics of nerve lesions, severity, possibility of spontaneous recovery, onset of early complications, need for surgical treatment, and the best surgical approach. Level of evidence: according to the Oxford 2011 level of evidence, level 2.

Background: Cerebral cavernous malformations (CCMs) are a major type of cerebrovascular lesions of proven genetic origin that occur in either sporadic (sCCM) or familial (fCCM) forms, the latter being inherited as an autosomal dominant condition linked to loss-of-function mutations in three known CCM genes. In contrast to fCCMs, sCCMs are rarely linked to mutations in CCM genes and are instead commonly and peculiarly associated with developmental venous anomalies (DVAs), suggesting distinct origins and common pathogenic mechanisms. Case report: A hemorrhagic sCCM in the right frontal lobe of the brain was surgically excised from a symptomatic 3 year old patient, preserving intact and pervious the associated DVA. MRI follow-up examination performed periodically up to 15 years after neurosurgery intervention demonstrated complete removal of the CCM lesion and no residual or relapse signs. However, 18 years after surgery, the patient experienced acute episodes of paresthesia due to a distant recurrence of a new hemorrhagic CCM lesion located within the same area as the previous one. A new surgical intervention was, therefore, necessary, which was again limited to the CCM without affecting the pre-existing DVA. Subsequent follow-up examination by contrast-enhanced MRI evidenced a persistent pattern of signal-intensity abnormalities in the bed of the DVA, including hyperintense gliotic areas, suggesting chronic inflammatory conditions. Conclusions: This case report highlights the possibility of long-term distant recurrence of hemorrhagic sCCMs associated with a DVA, suggesting that such recurrence is secondary to focal sterile inflammatory conditions generated by the DVA.

The association between multisutural craniosynostosis with Chiari malformation (CM), venous hypertension and hydrocephalus is widely described in the literature, especially in children with pediatric craniofacial syndromes. Some efforts have been done in the last years to understand the complex pathogenetic mechanisms underlying this association and several theories have been proposed. However, whatever the pathophysiological mechanism, it is still unclear what is the best management and treatment of CM and hydrocephalus in multisutural craniosynostosis patients. The aim of this study is to report our twenty-five years’experience in treating pediatric patients affected by these rare pathologies, in order to propose a simple and effective therapeutic flow-chart for their management. We collected data of each patient that underwent a cranial vault remodelling for a complex craniosynostosis in our institution in the last 25 years. We recorded data concerning type of craniosynostosis and craniofacial syndromes, presence of ventriculomegaly and Chiari Malformation (CM) at presentation and clinical and radiological follow-up. Therefore, we evaluated the final outcomes (improved, stable, deteriorated) of these patients and created a practical flow-chart that could help physicians to choose the best surgical treatment when different pathological conditions, as CM I or hydrocephalus, affect complex craniosynostosis children. Despite the proposed algorithm comes from a clinical experience on 85% successfully treated patients with multiple craniosynostosis, more extensive and deep studies are needed to better understand CM and hydrocephalus development in such conditions.