Novel insights toward diagnosis and treatment of glioneuronal and neuronal tumors in young adults.

Aim: Glioneuronal and neuronal tumors are rare primary central nervous system malignancies with heterogeneous features. Due to the rarity of these malignancies diagnosis and treatment remains a clinical challenge. Methods: Here we performed a narrative review aimed to investigate the principal issues concerning the diagnosis, pathology, and clinical management of glioneuronal tumors. Results: Diagnostic criteria have been recently overturned thanks to a better characterization on a histological and molecular biology level. The study of genomic alterations occurring within these tumors has allowed us to identify potential therapeutic targets including BRAF, FGFR, and PDGFRA. Conclusion: Techniques allowing molecular sequencing DNA methylation assessment of the disease are essential diagnostic tools. Targeting agents should be included in the therapeutic armamentarium after loco-regional treatment failure.

[Box: see text].

Olfactory neuroblastoma: diagnosis, management, and current treatment options.

Olfactory neuroblastoma (ONB) is a rare neoplasm originating from the olfactory neuroepithelium representing 3-6% of tumors of the sinonasal tract. ONB require multi-disciplinary care. Historically, the gold standard surgical procedure for ONB has been open craniofacial resection. In the last years, endoscopic endonasal approaches have been largely introduced with lower complication rates, shorter hospital stay, and similar clinical outcome. Radiotherapy plays an important role in the management of ONB, however there are not generally accepted recommendations for its application. Although there is agreement that multimodal therapy is needed, the optimal use of chemotherapy is still unknown. The rarity of the disease, makes difficult to draw definitive conclusions about the role of systemic treatment in induction and concomitant setting.

CAR-T cells neurotoxicity from consolidated practice in hematological malignancies to fledgling experience in CNS tumors: fill the gap.

Chimeric antigen receptor (CAR-T) therapy has marked a paradigm shift in the treatment of hematological malignancies and represent a promising growing field also in solid tumors. Neurotoxicity is a well-recognized common complication of CAR-T therapy and is at the forefront of concerns for CAR-based immunotherapy widespread adoption, as it necessitates a cautious approach. The non-specific targeting of the CAR-T cells against normal tissues (on-target off-tumor toxicities) can be life-threatening; likewise, immune-mediate neurological symptoms related to CAR-T cell induced inflammation in central nervous system (CNS) must be precociously identified and recognized and possibly distinguished from non-specific symptoms deriving from the tumor itself. The mechanisms leading to ICANS (Immune effector Cell-Associated Neurotoxicity Syndrome) remain largely unknown, even if blood-brain barrier (BBB) impairment, increased levels of cytokines, as well as endothelial activation are supposed to be involved in neurotoxicity development. Glucocorticoids, anti-IL-6, anti-IL-1 agents and supportive care are frequently used to manage patients with neurotoxicity, but clear therapeutic indications, supported by high-quality evidence do not yet exist. Since CAR-T cells are under investigation in CNS tumors, including glioblastoma (GBM), understanding of the full neurotoxicity profile in brain tumors and expanding strategies aimed at limiting adverse events become imperative. Education of physicians for assessing individualized risk and providing optimal management of neurotoxicity is crucial to make CAR-T therapies safer and adoptable in clinical practice also in brain tumors.

DCVax-L Vaccination in Patients with Glioblastoma: Real Promise or Negative Trial? The Debate Is Open.

The lack of significant improvement in the prognosis of patients with GB over the last decades highlights the need for innovative treatments aimed at fighting this malignancy and increasing survival outcomes. The results of the phase III clinical trial of DCVax-L (autologous tumor lysate-loaded dendritic cell vaccination), which has been shown to increase both median survival and long-term survival in newly diagnosed and relapsed glioblastoma, have been enthusiastically received by the scientific community. However, this study deserves some reflections regarding methodological issues related to the primary endpoint change, the long accrual period, and the suboptimal validity of the external control population used as the comparison arm.

Tumor Microenvironment in Gliomas: A Treatment Hurdle or an Opportunity to Grab?

Gliomas are the most frequent central nervous system (CNS) primary tumors. The prognosis and clinical outcomes of these malignancies strongly diverge according to their molecular alterations and range from a few months to decades. The tumor-associated microenvironment involves all cells and connective tissues surrounding tumor cells. The composition of the microenvironment as well as the interactions with associated neoplastic mass, are both variables assuming an increasing interest in these last years. This is mainly because the microenvironment can mediate progression, invasion, dedifferentiation, resistance to treatment, and relapse of primary gliomas. In particular, the tumor microenvironment strongly diverges from isocitrate dehydrogenase (IDH) mutated and wild-type (wt) tumors. Indeed, IDH mutated gliomas often show a lower infiltration of immune cells with reduced angiogenesis as compared to IDH wt gliomas. On the other hand, IDH wt tumors exhibit a strong immune infiltration mediated by several cytokines and chemokines, including CCL2, CCL7, GDNF, CSF-1, GM-CSF, etc. The presence of several factors, including Sox2, Oct4, PD-L1, FAS-L, and TGF ß2, also mediate an immune switch toward a regulatory inhibited immune system. Other important interactions are described between IDH wt glioblastoma cells and astrocytes, neurons, and stem cells, while these interactions are less elucidated in IDH-mutated tumors. The possibility of targeting the microenvironment is an intriguing perspective in terms of therapeutic drug development. In this review, we summarized available evidence related to the glioma microenvironment, focusing on differences within different glioma subtypes and on possible therapeutic development.

The Biological and Clinical Role of the Telomerase Reverse Transcriptase Gene in Glioblastoma: A Potential Therapeutic Target?

Glioblastoma IDH-wildtype represents the most lethal and frequent primary tumor of the central nervous system. Thanks to important scientific efforts, we can now investigate its deep genomic assessment, elucidating mutated genes and altered biological mechanisms in addition to its clinical aggressiveness. The telomerase reverse transcriptase gene (TERT) is the most frequently altered gene in solid tumors, including brain tumors and GBM IDH-wildtype. In particular, it can be observed in approximately 80-90% of GBM IDH-wildtype cases. Its clonal distribution on almost all cancer cells makes this gene an optimal target. However, the research of effective TERT inhibitors is complicated by several biological and clinical obstacles which can be only partially surmounted. Very recently, novel immunological approaches leading to TERT inhibition have been investigated, offering the potential to develop an effective target for this altered protein. Here, we perform a narrative review investigating the biological role of TERT alterations on glioblastoma and the principal obstacles associated with TERT inhibitions in this population. Moreover, we discuss possible combination treatment strategies to overcome these limitations.