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

New neuroanatomy learning paradigms for the next generation of trainees: A novel literature-based 3D methodology

Background: An appreciation for complex three-dimensional relationships in neuroanatomy forms a fundamental tenet of neurosurgical education. The value of experience in the cadaver lab is indisputable; however, it is expensive and often inaccessible. The wide availability of 3D technologies has opened new possibilities, although scientific inaccuracy has hitherto limited their use. Objective: In the present study, we aim to describe a novel, literature-based process of scientific 3D modeling for the creation of neuroanatomical models adapted for mobile technology. Methods: A systematic literature review regarding current resources in neuroanatomy education was performed according to PRISMA guidelines. The composition of the team and the workflow behind the 3D Head Atlas app are also described. Results: A total of 101 manuscripts were reviewed, and 24 included. Cadaveric dissections improve the learning process, although high costs limit their availability. Digital advancements have partially overcome the limitations of dissection, and have been associated with improved knowledge retention. Nevertheless, 3D models are often inaccurate, poorly adapted to mobile hardware, and expensive. Recent technological advances provide a new way to widely disseminate complex 3D models, with a revolutionary impact on learning. The approach behind the 3D Head Atlas app, based on the synergistic work of scientific and development teams, facilitates the creation of interactive 3D scientific material with high accuracy and wide accessibility. Conclusion: The study of neuroanatomy is intimately related to the evolution of digital technology. Traditional methods (i.e. cadaveric dissections) have undisputed value but high costs. High-fidelity 3D scenarios and mobile devices may revolutionize learning if based on a sound evidence-based approach

Pituitary Adenomas and Invasiveness from Anatomo-Surgical, Radiological, and Histological Perspectives: A Systematic Literature Review

Invasiveness in pituitary adenomas has been defined and investigated from multiple perspectives, with varying results when its predictive value is considered. A systematic literature review, following PRISMA guidelines, was performed, searching PubMed and Scopus databases with terms that included molecular markers, histological, radiological, anatomical and surgical data on invasiveness of pituitary adenomas. The results showed that differing views are still present for anatomical aspects of the sellar region that are relevant to the concept of invasiveness; radiological and histological diagnoses are still limited, but might improve in the future, especially if they are related to surgical findings, which have become more accurate thanks to the introduction of the endoscope. The aim is to achieve a correct distinction between truly invasive pituitary adenomas from those that, in contrast, present with extension in the parasellar area through natural pathways. At present, diagnosis of invasiveness should be based on a comprehensive analysis of radiological, intra-operative and histological findings

Aero packs in good shape with advanced mesh morphing

Increasing environmental awareness has led to changes in motorsport regulations that limit the quantity of traditional and computationally intensive optimizations that can be used and encourages the use of numerical methods to improve the vehicles. This article describes a new method of aerodynamic design, the result of a collaboration between Dallara Automobili and RBF Morph, that uses adjoint methods and mesh morphing to create an innovative solution to accelerate the optimization process, reducing both time and costs

Lactotroph PitNET/adenoma associated to granulomatous hypophysitis in a patient with Crohn's disease: A case report

Granulomatous hypophysitis is a rare and poorly understood condition. Although certain cases are treated as primary pituitary autoimmune disorders, rare cases may be associated with pituitary neuroendocrine tumours (PitNETs) and systemic inflammatory diseases. Here, we report a case of a 47-year-old man that underwent endoscopic trans-sphenoidal excision of a pituitary mass diagnosed as PitNET. On histologic evaluation, the neoplasm showed an admixture of granulomas with extensive inflammatory infiltrate and lactotroph PitNET/adenoma. Careful anamnestic examination revealed a diagnosis of Crohn's disease 20 years prior. Although rarely done, both PitNET and Crohn's disease may be associated with granulomatous hypophysitis, and our patient had both conditions. During the 6-year follow-up, PitNETs and hypophysitis did not recur, while Crohn's disease was only partially controlled by medical therapy. To our knowledge, this is the first description of association of granulomatous hypophysitis, PitNET and Crohn's disease

3D Printed Affordable Nose Model: a Reliable Start in Endoscopic Training For Young Neurosurgeons

Background: Training neurosurgical skills is one of the most important tasks of a residency program. Techniques' complexity and pathology rarity define a long learning curve for mastering different surgical skills for which simulation on anatomical samples is extremely important. For this purpose, cadaver laboratory training is the most reliable tool. However, since access to cadaveric specimens is limited, due to costs and availability, surgical skills could be developed using inanimate models. This work aimed to develop a printable 3D model of the nasal cavity and sellar floor using an open-source downloadable file, to give residents the opportunity to improve their endoscopic surgical skills in a low-risk atmosphere with little cost. Methods: The 3D model was realized taking as a sample a real-case CT scan imaging from which the sellar floor was removed. A quail egg was placed underneath the printed model covering the sellar floor opening. Under endoscopic visualization, the "sellar floor" was drilled by each participant with the goal of sparing the egg's inner membrane. Once the task was achieved, surgeons were asked to participate in a satisfaction survey. Results: Total cost for printing was 6,31€. The satisfaction survey showed technical improvement (90%), increased confidence (80%), bringing learned skills in the O.R. (70%), leading to a 100% agreement in introducing this project into residency programs. Conclusion: Training on affordable anatomical models represents a useful tool in technical skills improvement. We believe this model could help residents bring their technical capabilities to more sophisticated levels

Surgical Anatomy and Approaches of the Anterior Cranial Fossa from a Transcranial and Endonasal Perspective

The anterior cranial fossa (ACF) is a complex anatomical region that can be affected by a broad spectrum of pathology. For the surgical treatment of these lesions, many approaches have been described, each of them with different scope and potential surgical complications, often associated with significant morbidity. Traditionally, tumors involving the ACF have been operated by transcranial approaches; however, in the last two decades, endoscopic endonasal approaches (EEAs) have been gaining popularity. In this work, the authors review and describe the anatomical aspects of the ACF and the technical nuances of transcranial and endoscopic approaches for tumors located in this region. Four approaches were performed in embalmed cadaveric specimens and the key steps were documented. Four illustrative cases of ACF tumors were selected to demonstrate the clinical application of anatomical and technical knowledge, which are essential in the preoperative decision-making process

Surgical Anatomy of the Microscopic and Endoscopic Transorbital Approach to the Middle Fossa and Cavernous Sinus: Anatomo-Radiological Study with Clinical Applications

Background: The transorbital approaches (TOAs) have acquired growing notoriety, thanks to their ability to offer alternative corridors to the skull base. However, the limited access and the unfamiliarity with this surgical perspective make recognition of key landmarks difficult, especially for less experienced surgeons. The study wants to offer a detailed description of the anatomy to comprehend the potential and limitations of TOAs. Methods: Measurements of the orbit region and the surrounding areas were performed on two hundred high-resolution CT scans and thirty-nine dry skulls. Five specimens were dissected to illustrate the TOA, and one was used to perform the extradural clinoidectomy. Three clinical cases highlighted the surgical applications. Results: A step-by-step description of the key steps of the TOA was proposed and a comparison with the transcranial anterior clinoidectomy was discussed. The mean work distance was 6.1 ± 0.4 cm, and the lateral working angle increased 20 ± 5.4° after removing the lateral orbital rim. Conclusions: TOAs are indicated in selected cases when tumor involves the lateral portion of the cavernous sinus or the middle skull base, obtaining a direct decompression of the optic nerve and avoiding excessive manipulation of the neurovascular structures. Comprehension of surgical anatomy of the orbit and its surrounding structures is essential to safely perform these approaches

Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain