Epigenetic landscape reorganization and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma.

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is however difficult and, apart from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. Experimental Design: RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n=138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. We used the DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) that is based on classification scores derived from a CNS-tumor classifier. We found that the CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with i) an upregulation of cell cycling genes; ii) a downregulation of glial differentiation genes; iii) an upregulation of embryonic development genes (e.g. HOX, PAX and TBX) and iv) an upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes.

The role of adjuvant chemotherapy in patients with H3K27 altered diffuse midline gliomas: a multicentric retrospective study.

PURPOSE: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. METHODS: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. RESULTS: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1-68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05-0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03-0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1-0.65, p = 0.004). CONCLUSION: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed.

Management of patients with rare adult solid cancers: objectives and evaluation of European reference networks (ERN) EURACAN.

About 500,000 patients with rare adult solid cancers (RASC) are diagnosed yearly in Europe. Delays and unequal quality of management impact negatively their survival. Since 2017, European reference networks (ERN) aim to improve the quality of care of patients with rare disease. The steering committee of EURACAN, including physicians, researchers and patients review here the previous actions, present objectives of the ERN EURACAN dedicated to RASC. EURACAN promoted management in reference centres, and equal implementation of excellence and innovation in Europe and developed 22 clinical practice guidelines (CPGs). Additionally, fourteen information brochures translated in 24 EU languages were developed in collaboration with patient advocacy groups (ePAGs) and seventeen training session were organized. Nevertheless, connections to national networks in the 26 participating countries (106 centres), simplification of cross-border healthcare, international multidisciplinary tumour boards, registries and monitoring of the quality of care are still required. In this Health Policy, evaluation criteria of the performances of the network and of health care providers are proposed.

Connectome-Based Neurosurgery in Primary Intra-Axial Neoplasms: Beyond the Traditional Modular Conception of Brain Architecture for the Preservation of Major Neurological Domains and Higher-Order Cognitive Functions.

Despite the therapeutical advancements in the surgical treatment of primary intra-axial neoplasms, which determined both a significative improvement in OS and QoL and a reduction in the incidence of surgery-induced major neurological deficits, nowadays patients continue to manifest subtle post-operative neurocognitive impairments, preventing them from a full reintegration back into social life and into the workforce. The birth of connectomics paved the way for a profound reappraisal of the traditional conception of brain architecture, in favour of a model based on large-scale structural and functional interactions of a complex mosaic of cortical areas organized in a fluid network interconnected by subcortical bundles. Thanks to these advancements, neurosurgery is facing a new era of connectome-based resections, in which the core principle is still represented by the achievement of an ideal onco-functional balance, but with a closer eye on whole-brain circuitry, which constitutes the foundations of both major neurological functions, to be intended as motricity; language and visuospatial function; and higher-order cognitive functions such as cognition, conation, emotion and adaptive behaviour. Indeed, the achievement of an ideal balance between the radicality of tumoral resection and the preservation, as far as possible, of the integrity of local and global brain networks stands as a mandatory goal to be fulfilled to allow patients to resume their previous life and to make neurosurgery tailored and gentler to their individual needs.

H3 K27M-altered glioma and diffuse intrinsic pontine glioma: Semi-systematic review of treatment landscape and future directions.

H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on www.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least 1 treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen receptor T-cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.

Spinal ependymoma in adults: from molecular advances to new treatment perspectives.

Ependymomas are rare glial tumors with clinical and biological heterogeneity, categorized into supratentorial ependymoma, posterior fossa ependymoma, and spinal cord ependymoma, according to anatomical localization. Spinal ependymoma comprises four different types: spinal ependymoma, spinal ependymoma MYCN-amplified, myxopapillary ependymoma, and subependymoma. The clinical onset largely depends on the spinal location of the tumor. Both non-specific and specific sensory and/or motor symptoms can be present. Owing to diverse features and the low incidence of spinal ependymomas, most of the current clinical management is derived from small retrospective studies, particularly in adults. Treatment involves primarily surgical resection, aiming at maximal safe resection. The use of radiotherapy remains controversial and the optimal dose has not been established; it is usually considered after subtotal resection for WHO grade 2 ependymoma and for WHO grade 3 ependymoma regardless of the extent of resection. There are limited systemic treatments available, with limited durable results and modest improvement in progression-free survival. Thus, chemotherapy is usually reserved for recurrent cases where resection and/or radiation is not feasible. Recently, a combination of temozolomide and lapatinib has shown modest results with a median progression-free survival (PFS) of 7.8 months in recurrent spinal ependymomas. Other studies have explored the use of temozolomide, platinum compounds, etoposide, and bevacizumab, but standard treatment options have not yet been defined. New treatment options with targeted treatments and immunotherapy are being investigated. Neurological and supportive care are crucial, even in the early stages. Post-surgical rehabilitation can improve the consequences of surgery and maintain a good quality of life, especially in young patients with long life expectancy. Here, we focus on the diagnosis and treatment recommendations for adults with spinal ependymoma, and discuss recent molecular advances and new treatment perspectives.

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.

Phospholipases in Gliomas: Current Knowledge and Future Perspectives from Bench to Bedside.

Phospholipases are essential intermediaries that work as hydrolyzing enzymes of phospholipids (PLs), which represent the most abundant species contributing to the biological membranes of nervous cells of the healthy human brain. They generate different lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid, representing key elements of intra- and inter-cellular signaling and being involved in the regulation of several cellular mechanisms that can promote tumor progression and aggressiveness. In this review, it is summarized the current knowledge about the role of phospholipases in brain tumor progression, focusing on low- and high-grade gliomas, representing promising prognostic or therapeutic targets in cancer therapies due to their influential roles in cell proliferation, migration, growth, and survival. A deeper understanding of the phospholipases-related signaling pathways could be necessary to pave the way for new targeted therapeutic strategies.

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.

Glioblastoma treatment slowly moves toward change: novel druggable targets and translational horizons in 2022.

INTRODUCTION: Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches. AREAS COVERED: This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations. EXPERT OPINION: GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific 'off-the-shelf' CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.

How to treat histone 3 altered gliomas: molecular landscape and therapeutic developments.

INTRODUCTION: Diffuse midline gliomas (DMG) and diffuse hemispheric glioma (DHG) are both rare tumors characterized and recognized for specific alterations of histone 3 including H3K27 (DMG) and H3G34 (DHG). Despite these tumors arising from alterations of the same gene their clinical, radiological, and molecular behaviors strongly diverge, requiring a personalized therapeutic approach. AREAS COVERED: We performed a review on Medline/PudMed aiming to search papers relative to prospective trials, retrospective studies, case series, and case reports of interest in order to investigate current knowledge toward the main clinical and molecular characteristics, radiology, and diagnosis, loco-regional and systemic treatments of these tumors. Moreover, we also evaluated the novel treatments under investigation. EXPERT OPINION: Thanks to an increased knowledge of the genomic landscape of these rare tumors, there are novels promising therapeutic targets for these malignancies. However, the majority of available trials allowed enrollment only in DMG, while few studies are focused on or allow the inclusion of DHG patients.

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.

Beyond Imaging and Genetic Signature in Glioblastoma: Radiogenomic Holistic Approach in Neuro-Oncology.

Glioblastoma (GBM) is a malignant brain tumor exhibiting rapid and infiltrative growth, with less than 10% of patients surviving over 5 years, despite aggressive and multimodal treatments. The poor prognosis and the lack of effective pharmacological treatments are imputable to a remarkable histological and molecular heterogeneity of GBM, which has led, to date, to the failure of precision oncology and targeted therapies. Identification of molecular biomarkers is a paradigm for comprehensive and tailored treatments; nevertheless, biopsy sampling has proved to be invasive and limited. Radiogenomics is an emerging translational field of research aiming to study the correlation between radiographic signature and underlying gene expression. Although a research field still under development, not yet incorporated into routine clinical practice, it promises to be a useful non-invasive tool for future personalized/adaptive neuro-oncology. This review provides an up-to-date summary of the recent advancements in the use of magnetic resonance imaging (MRI) radiogenomics for the assessment of molecular markers of interest in GBM regarding prognosis and response to treatments, for monitoring recurrence, also providing insights into the potential efficacy of such an approach for survival prognostication. Despite a high sensitivity and specificity in almost all studies, accuracy, reproducibility and clinical value of radiomic features are the Achilles heel of this newborn tool. Looking into the future, investigators' efforts should be directed towards standardization and a disciplined approach to data collection, algorithms, and statistical analysis.