Advancing Craniopharyngioma Management: A Systematic Review of Current Targeted Therapies and Future Perspectives

Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates genetic and immunological markers as potential targets for therapy in craniopharyngiomas, assessing their involvement in tumorigenesis, and their influence on prognosis and treatment strategies. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. Employing MeSH terms and Boolean operators, the search focused on craniopharyngiomas, targeted or molecular therapy, and clinical outcomes or adverse events. Inclusion criteria encompassed English language studies, clinical trials (randomized or non-randomized), and investigations into adamantinomatous or papillary craniopharyngiomas. Targeted therapies, either standalone or combined with chemotherapy and/or radiotherapy, were examined if they included clinical outcomes or adverse event analysis. Primary outcomes assessed disease response through follow-up MRI scans, categorizing responses as follows: complete response (CR), near-complete response (NCR), partial response, and stable or progressive disease based on lesion regression percentages. Secondary outcomes included treatment type and duration, as well as adverse events. A total of 891 papers were initially identified, of which 26 studies spanning from 2000 to 2023 were finally included in the review. Two tables highlighted adamantinomatous and papillary craniopharyngiomas, encompassing 7 and 19 studies, respectively. For adamantinomatous craniopharyngiomas, Interferon-2α was the predominant targeted therapy (29%), whereas dabrafenib took precedence (70%) for papillary craniopharyngiomas. Treatment durations varied, ranging from 1.7 to 28 months. Positive responses, including CR or NCR, were observed in both types of craniopharyngiomas (29% CR for adamantinomatous; 32% CR for papillary). Adverse events, such as constitutional symptoms and skin changes, were reported, emphasizing the need for vigilant monitoring and personalized management to enhance treatment tolerability. Overall, the data highlighted a diverse landscape of targeted therapies with encouraging responses and manageable adverse events, underscoring the importance of ongoing research and individualized patient care in the exploration of treatment options for craniopharyngiomas. In the realm of targeted therapies for craniopharyngiomas, tocilizumab and dabrafenib emerged as prominent choices for adamantinomatous and papillary cases, respectively. While adverse events were common, their manageable nature underscored the importance of vigilant monitoring and personalized management. Acknowledging limitations, future research should prioritize larger, well-designed clinical trials and standardized treatment protocols to enhance our understanding of the impact of targeted therapies on craniopharyngioma patients

Role of microenvironment in glioma invasion: What we learned from in vitro models

The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a crucial step. Since in vitro models represent an over-simplification of the in vivo system, in these years it has been attempted to increase the level of complexity of in vitro assays to create models that could better mimic the behaviour of the cells in vivo. These levels of complexity involved: 1. The dimension of the system, moving from two-dimensional to three-dimensional models; 2. The use of microfluidic systems; 3. The use of mixed cultures of tumour cells and cells of the tumour micro-environment in order to mimic the complex cross-talk between tumour cells and their micro-environment; 4. And the source of cells used in an attempt to move from commercial lines to patient-based models. In this review, we will summarize the evidence obtained exploring these different levels of complexity and highlighting advantages and limitations of each system used

A Systematic Review of the Metabolism of High-Grade Gliomas: Current Targeted Therapies and Future Perspectives

High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), and surgical resection. Despite the progress made in traditional treatments, the outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target for glioma therapies, a promising approach that harnesses the metabolism to target tumor cells. However, the efficacy of therapies targeting the metabolism of HGGs remains unclear, compelling a comprehensive review. This study aimed to assess the outcome of present trials on HGG therapies targeting metabolism. A comprehensive search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted until November 2023. The search method used pertinent Medical Subject Heading (MeSH) terminologies and keywords referring to "high-grade gliomas", "metabolism", "target therapies", "monoclonal antibodies", "overall survival", and "progression-free survival". The review analyzed studies that focused on therapies targeting the metabolism of HGGs in human subjects. These studies included both randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). Out of 284 articles identified, 23 trials met the inclusion criteria and were thoroughly analyzed. Phase II trials were the most numerous (62%). Targeted metabolic therapies were predominantly used for recurrent HGGs (67%). The most common targeted pathways were the vascular endothelial growth factor (VEGF, 43%), the human epidermal growth factor receptor (HER, 22%), the platelet-derived growth factor (PDGF, 17%), and the mammalian target of rapamycin (mTOR, 17%). In 39% of studies, the subject treatment was combined with CMT (22%), RT (4%), or both (13%). The median OS widely ranged from 4 to 26.3 months, while the median PFS ranged from 1.5 to 13 months. This systematic literature review offers a thorough exploration of the present state of metabolic therapies for HGGs. The multitude of targeted pathways underscores the intricate nature of addressing the metabolic aspects of these tumors. Despite existing challenges, these findings provide valuable insights, guiding future research endeavors. The results serve as a foundation for refining treatment strategies and enhancing patient outcomes within the complex landscape of HGGs

Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells

A major contributing factor to glioma development and progression is its ability to evade the immune system. Nano-meter sized vesicles, exosomes, secreted by glioma-stem cells (GSC) can act as mediators of intercellular communication to promote tumor immune escape. Here, we investigated the immunomodulatory properties of GCS-derived exosomes on different peripheral immune cell populations. Healthy donor peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3, anti-CD28 and IL-2, were treated with GSC-derived exosomes. Phenotypic characterization, cell proliferation, Th1/Th2 cytokine secretion and intracellular cytokine production were analysed by distinguishing among effector T cells, regulatory T cells and monocytes. In unfractionated PBMCs, GSC-derived exosomes inhibited T cell activation (CD25 and CD69 expression), proliferation and Th1 cytokine production, and did not affect cell viability or regulatory T-cell suppression ability. Furthermore, exosomes were able to enhance proliferation of purified CD4+ T cells. In PBMCs culture, glioma-derived exosomes directly promoted IL-10 and arginase-1 production and downregulation of HLA-DR by unstimulated CD14+ monocytic cells, that displayed an immunophenotype resembling that of monocytic myeloid-derived suppressor cells (Mo-MDSCs). Importantly, the removal of CD14+ monocytic cell fraction from PBMCs restored T-cell proliferation. The same results were observed with exosomes purified from plasma of glioblastoma patients. Our results indicate that glioma-derived exosomes suppress T-cell immune response by acting on monocyte maturation rather than on direct interaction with T cells. Selective targeting of Mo-MDSC to treat glioma should be considered with regard to how immune cells allow the acquirement of effector functions and therefore counteracting tumor progression

Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment

Exosomes are one of the most important mediators of the cross talk occurring between glioma stem cells (GSCs) and the surrounding microenvironment. We have previously shown that exosomes released by patient-derived glioma-associated stem cells (GASC) are able to increase, in vitro, the aggressiveness of both GSC and glioblastoma cell lines. To understand which molecules are responsible for this tumour-supporting function, we performed a descriptive proteomic analysis of GASC-exosomes and identified, among the others, Semaphorin7A (SEMA7A). SEMA7A was described as a promigratory cue in physiological and pathological conditions, and we hypothesised that it could modulate GSC migratory properties. Here, we described that SEMA7A is exposed on GASC-exosomes' surface and signals to GSC through Integrin \u3b21. This interaction activates focal adhesion kinase into GSC and increases their motility, in our patient-based in vitro model. Our findings suggest SEMA7A-\u3b21-integrin as a new target to disrupt the communication between GSCs and the supporting microenvironment

The impact of COVID-19 pandemic on surgical neuro-oncology: A survey from the Italian society of neurosurgery (SINch)

Background: The COVID-19 pandemic and its impact on hospitals' activity and organization has imposed a vast change in standard neurosurgical oncology practice to accommodate for shifting resources. Aims: This investigation aims to analyse the nationwide capability in reorganizing the surgical neuro-oncological activity during the COVID-19 pandemic to evaluate whether COVID-19-pandemic influenced the surgical management in these patients. Method: A web-based dataset model organized by the Italian Neurosurgical Society (SINCh) was sent to all the Italian neurosurgical departments in May 2021, requesting to report the types and numbers of surgical procedures performed in the pre-pandemic period (from March 9th 2019 to March 9th 2020) compared to the pandemic period (from March 10th 2020 to March 10th 2021). Results: This multicentre investigation included the surgical activity of 35 Italian Neurosurgical Departments in a pre-pandemic year versus a pandemic year. During the COVID period, 699 fewer neuro-oncological patients were operated on than in the pre-COVID period. We noted a slight increase in urgency and a more severe decrease in elective and benign pathology. None of these differences was statistically significant. Surgically treated patients who tested positive for SARS-CoV-2 were 36, of which 11 died. Death was found to be COVID-related only in 2 cases. Conclusion: The reorganization of the Italian Neurosurgical Departments was able to guarantee a redistribution of the CNS tumors during the inter-pandemic periods, demonstrating that patients even in the pandemic era could be treated without compromising the efficacy and safety of the surgical procedure

Glioma-associated stem cells: A novel class of tumor-supporting cells able to predict prognosis of human low-grade gliomas.

Background: Translational medicine aims at transferring advances in basic science research into new approaches for diagnosis and treatment of diseases. Low-grade gliomas (LGG) have a heterogeneous clinical behavior that can be only partially predicted employing current state-of-the-art markers, hindering the decision-making process. To deepen our comprehension on tumor heterogeneity, we dissected the mechanism of interaction between tumor cells and relevant components of the neoplastic environment, isolating, from LGG and high-grade gliomas (HGG), proliferating stem cell lines from both the glioma stroma and, where possible, the neoplasm. Methods and Findings: We isolated glioma-associated stem cells (GASC) from LGG (n=40) and HGG (n=73). GASC showed stem cell features, anchorage-independent growth, and supported the malignant properties of both A172 cells and human glioma-stem cells, mainly through the release of exosomes. Finally, starting from GASC obtained from HGG (n=13) and LGG (n=12) we defined a score, based on the expression of 9 GASC surface markers, whose prognostic value was assayed on 40 subsequent LGG-patients. At the multivariate Cox analysis, the GASC-based score was the only independent predictor of overall survival and malignant progression free-survival. Conclusions: The microenvironment of both LGG and HGG hosts non-tumorigenic multipotent stem cells that can increase in vitro the biological aggressiveness of glioma-initiating cells through the release of exosomes. The clinical importance of this finding is supported by the strong prognostic value associated with the characteristics of GASC. This patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor stroma

Surgical management of Glioma Grade 4: technical update from the neuro-oncology section of the Italian Society of Neurosurgery (SINch®): a systematic review

Purpose: The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal. Methods: A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients. Results: A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early postoperative MRI, with CE II and SR B. The EOR was defined the strongest independent risk factor for both OS and tumor recurrence with CE II and SR B. For intraoperative imaging only the use of 5-ALA reached a CE II and SR B. The estimation of EOR was established to be fundamental in planning postoperative adjuvant treatments with CE II and SR B and the stereotactic image-guided brain biopsy to be the procedure of choice when an extensive surgical resection is not feasible (CE II and SR B). Conclusions: A growing number of evidences evidence support the role of maximal safe resection as primary OS predictor in GG4 patients. The ongoing development of intraoperative techniques for a precise real-time identification of peritumoral functional pathways enables surgeons to maximize EOR minimizing the post-operative morbidity

Aspetti neuropsicologici in neuro-oncologia. Capire per aiutare

La paura generata da un tumore può inficiare l’efficacia della comunicazione medico-paziente. L’incapacità di trasmettere fiducia nelle cure rende ancora più fragili le famiglie e gli individui già profondamente colpita da una diagnosi spesso difficile da comprendere. Quest’opera nasce dal desiderio di aiutare i pazienti attraverso la spiegazione di ogni criticità che può insorgere nel percorso diagnostico-terapeutico di una neoplasia cerebrale. Oltre alla presentazione semplice e completa di ogni aspetto relativo al trattamento della malattia, la monografia fornisce consigli su alimentazione, stile di vita e sulla gestione dei possibili effetti collaterali delle terapie. La seconda parte dell’opera si concentra sugli aspetti neuropsicologici potenzialmente interessati dai tumori cerebrali e sulle strategie di supporto psicologico e psicoeducazione che possono essere messe in atto al fine di sostenere le esigenze delle famiglie e dei malati. Molteplici figure provenienti dal mondo della medicina, dello sport e della comunicazione hanno contribuito a realizzare un’opera che pone al centro dell’attenzione il recupero delle potenzialità dei pazienti, spesso travolte dal peso della diagnosi. Confidiamo che la monografia possa aiutare le persone colpite da neoplasie cerebrali trasformando le loro paure in coraggio per superare la malattia