Telomerase inhibition in malignant gliomas: a systematic review.

Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18 months. Thus, new therapeutic strategies are urgently needed. However, the identification of cancer-specific targets is particularly challenging in GBM, due to the high heterogeneity of this tumour in terms of histopathological, molecular, genetic and epigenetic features. Telomerase reactivation is a hallmark of malignant glioma. An activating mutation of the hTERT gene, encoding for the active subunit of telomerase, is one of the molecular criteria to establish a diagnosis of GBM, IDH-wildtype, in the 2021 WHO classification of central nervous system tumours. Telomerase inhibition therefore represents, at least theoretically, a promising strategy for GBM therapy: pharmacological compounds, as well as direct gene expression modulation therapies, have been successfully employed in in vitro and in vivo settings. Unfortunately, the clinical applications of telomerase inhibition in GBM are currently scarce. The aim of the present systematic review is to provide an up-to-date report on the studies investigating telomerase inhibition as a therapeutic strategy for malignant glioma in order to foster the future translational and clinical research on this topic.

Resection versus biopsy for management of primary central nervous system lymphoma: a meta-analysis.

The role of surgery in the management of primary central nervous system lymphomas (PCNSL) is currently confined to diagnosis. However, over recent years, an increasing number of papers have suggested a possible positive prognostic impact of surgery in selected cases. The present work aims to perform a meta-analysis of the available literature evidence. A meta-analysis with meta-regression on the role of surgical resection compared to biopsy in the management of PCNSL was conducted according to the PRISMA statement, searching MEDLINE via PubMed and Embase. The random effect model was used. The quality of evidence was assessed using the GRADE framework. After screening 1395 records, we included 11 papers in our analysis. Patients who underwent surgical resection harbored superficial and single-lesion tumors. At 1-, 2-, and 5-year follow-up, progression-free survival did not differ between the two groups, while overall survival favored resection, even if in a non-significant fashion. Meta-regression analysis showed that the overall survival rate at 2 years, but not at 1 or 5 years, was significantly influenced by tumor location. There were no differences in terms of age, sex, Karnofsky performance status, adjuvant therapy, or procedure-related complications. Overall, the quality of evidence is low. The results of the present meta-analysis do not change the current standard of care for PCNSL. However, surgery could be non-inferior to biopsy with an acceptable risk profile in selected patients harboring single and superficial lesions. The low quality of evidence prompts future randomized studies.

Atlas invagination through the foramen magnum: expanding the spectrum of craniovertebral junction malformations.

PURPOSE: Malformations of the craniovertebral junction (CVJ) range from mild, asymptomatic conditions to severe forms of instability with basilar invagination. Rarely, there have been accounts of forms of so-called paramedian basilar invagination, with abnormal bone masses invading the lateral portion of the foramen magnum. All these entities have been comprehensively classified both from an anatomical and embryological standpoint. METHODS: Here, we report a case of a unique CVJ malformation which is not included in any existing classification framework and could represent a novel pathologic entity. We also provide an overview of the pertinent literature. RESULTS: The patient was a 14-year-old boy with a recent onset of spastic tetraparesis. Radiological studies documented a malformation of the atlas which invaginated through the foramen magnum, causing anterolateral medullary incarceration. Surgical treatment involved posterior decompression with resection of the abnormal bone and occipito-cervical fusion. CONCLUSION: Our report enriches the panorama of CVJ malformations, showing how anatomical knowledge and embryological insights constitute the basis for the correct assessment and treatment of these complex entities.

The anterolateral triangle as window on the foramen lacerum from transorbital corridor: anatomical study and technical nuances.

OBJECTIVE: Neurosurgical indications for the superior eyelid transorbital endoscopic approach (SETOA) are rapidly expanding over the last years. Nevertheless, as any new technique, a detailed knowledge of the anatomy of the surgical target area, the operative corridor, and the specific surgical landmark from this different perspective is required for a safest and successful surgery. Therefore, the aim of this study is to provide, through anatomical dissections, a detailed investigation of the surgical anatomy revealed by SETOA via anterolateral triangle of the middle cranial fossa. We also sought to define the relevant surgical landmarks of this operative corridor. METHODS: Eight embalmed and injected adult cadaveric specimens (16 sides) underwent dissection and exposure of the cavernous sinus and middle cranial fossa via superior eyelid endoscopic transorbital approach. The anterolateral triangle was opened and its content exposed. An extended endoscopic endonasal trans-clival approach (EEEA) with exposure of the cavernous sinus content and skeletonization of the paraclival and parasellar segments of the internal carotid artery (ICA) was also performed, and the anterolateral triangle was exposed. Measurements of the surface area of this triangle from both surgical corridors were calculated in three head specimens using coordinates of its borders under image-guide navigation. RESULTS: The drilling of the anterolateral triangle via SETOA unfolds a space that can be divided by the course of the vidian nerve into two windows, a wider "supravidian" and a narrower "infravidian," which reveal different anatomical corridors: a "medial supravidian" and a "lateral supravidian," divided by the lacerum segment of the ICA, leading to the lower clivus, and to the medial aspect of the Meckel's cave and terminal part of the horizontal petrous ICA, respectively. The infravidian corridor leads medially into the sphenoid sinus. The arithmetic means of the accessible surface area of the anterolateral triangle were 45.48 ± 3.31 and 42.32 ± 2.17 mm2 through transorbital approach and endonasal approach, respectively. CONCLUSION: SETOA can be considered a minimally invasive route complementary to the extended endoscopic endonasal approach to the anteromedial aspect of the Meckel's cave and the foramen lacerum. The lateral loop of the trigeminal nerve represents a reliable surgical landmark to localize the lacerum segment of the ICA from this corridor. Nevertheless, as any new technique, a learning curve is needed, and the clinical feasibility should be proven.

Comparison of combined anterior-posterior and posterior-only approaches for lumbosacral chordomas: a systematic review and meta-analysis of surgical and clinical outcomes.

Lumbosacral chordoma is a slow-growing but locally aggressive tumor, resistant to adjuvant treatments and endowed with dismal prognosis. Surgery is the mainstay of treatment but the choice of surgical approach (the posterior-only approach or the combined anterior-posterior approach) remains an open question due to the need of both pursuing a surgical radicality and preserving the neurologic function. The aim of the study was to compare the surgical and clinical outcomes of these approaches in the management of lumbosacral chordomas. A systematic review and meta-analysis in agreement with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines of papers comparing the outcomes of the two approaches was performed. Ten papers met the inclusion criteria. The combined anterior-posterior approach was more frequently performed for tumors with an upper level beyond S2 (p = 0.012). The 5-year progression-free survival was significantly higher in posterior-only approach compared with the combined anterior-posterior approach (44.7% vs 27.1%, p = 0.049). Adjuvant radiotherapy was added more frequently after a posterior-only approach (p = 0.036) and the rate of complications was significantly lower after a posterior-only approach (p = 0.040). No significant differences in sex, age, tumor diameter, entity of resection, and overall survival were observed. Posterior-only surgical approach may be a reasonable option for lumbosacral chordoma, being associated with comparable entity of surgical resection, reduced complication rate and increased 5-year progression-free survival rate as compared with combined anterior-posterior approach.

Posterior vault "free-floating" bone flap: indications, technique, advantages, and drawbacks.

BACKGROUND: The enlargement of the posterior cranial fossa volume is considered one of the main steps of the surgical management of children with multiple sutures craniosynostosis. Different management options have been proposed including fixed expansive craniotomy, free bone flap craniotomy, and distraction osteogenesis. OBJECTIVES: To review indications to "free bone flap" craniotomy for the posterior fossa expansion, detailing advantages, disadvantages, and complications related to the technique. RESULTS AND CONCLUSIONS: A review of the literature shows that "free bone flap" posterior expansion cranioplasty still has a role, particularly in infants with thin and "honeycomb" structure of the bone, allowing to gain adequate intracranial volume increases and to postpone to a more adequate time surgery aimed at anterior cranial fossa expansion.

Personalized Medicine in Brain Tumors.

Personalizing clinical, diagnostic and therapeutic approaches in neuro-oncology is a huge challenge [...].

A New Perspective on the Cavernous Sinus as Seen through Multiple Surgical Corridors: Anatomical Study Comparing the Transorbital, Endonasal, and Transcranial Routes and the Relative Coterminous Spatial Regions.

Background: The cavernous sinus (CS) is a highly vulnerable anatomical space, mainly due to the neurovascular structures that it contains; therefore, a detailed knowledge of its anatomy is mandatory for surgical unlocking. In this study, we compared the anatomy of this region from different endoscopic and microsurgical operative corridors, further focusing on the corresponding anatomic landmarks encountered along these routes. Furthermore, we tried to define the safe entry zones to this venous space from these three different operative corridors, and to provide indications regarding the optimal approach according to the lesion's location. Methods: Five embalmed and injected adult cadaveric specimens (10 sides) separately underwent dissection and exposure of the CS via superior eyelid endoscopic transorbital (SETOA), extended endoscopic endonasal transsphenoidal-transethmoidal (EEEA), and microsurgical transcranial fronto-temporo-orbito-zygomatic (FTOZ) approaches. The anatomical landmarks and the content of this venous space were described and compared from these surgical perspectives. Results: The oculomotor triangle can be clearly exposed only by the FTOZ approach. Unlike EEEA, for the exposure of the clinoid triangle content, the anterior clinoid process removal is required for FTOZ and SETOA. The supra- and infratrochlear as well as the anteromedial and anterolateral triangles can be exposed by all three corridors. The most recently introduced SETOA allowed for the exposure of the entire lateral wall of the CS without entering its neurovascular structures and part of the posterior wall; furthermore, thanks to its anteroposterior trajectory, it allowed for the disclosure of the posterior ascending segment of the cavernous ICA with the related sympathetic plexus through the Mullan's triangle, in a minimally invasive fashion. Through the anterolateral triangle, the transorbital corridor allowed us to expose the lateral 180 degrees of the Vidian nerve and artery in the homonymous canal, the anterolateral aspect of the lacerum segment of the ICA at the transition zone from the petrous horizontal to the ascending posterior cavernous segment, surrounded by the carotid sympathetic plexus, and the medial Meckel's cave. Conclusions: Different regions of the cavernous sinus are better exposed by different surgical corridors. The relationship of the tumor with cranial nerves in the lateral wall guides the selection of the approach to cavernous sinus lesions. The transorbital endoscopic approach can be considered to be a safe and minimally invasive complementary surgical corridor to the well-established transcranial and endoscopic endonasal routes for the exposure of selected lesions of the cavernous sinus. Nevertheless, peer knowledge of the anatomy and a surgical learning curve are required.

Molecular Analysis in a Glioblastoma Cohort-Results of a Prospective Analysis.

The prognostic role of epidermal growth factor receptor variant III (EGFRvIII), a constitutively activated oncogenic receptor, in glioblastoma is controversial. We performed a prospective study enrolling 355 patients operated on for de novo glioblastoma at a large academic center. The molecular profile, including EGFRvIII status, MGMT promoter methylation, and VEGF expression, was assessed. Standard parameters (age, clinical status and extent of surgical resection) were confirmed to hold prognostic value. MGMT promoter methylation portended a slightly improved survival. In the whole series, confirming previous results, EGFRvIII was not associated with worsened prognosis. Interestingly, female sex was associated with a better outcome. Such findings are of interest for the design of future trials.

5-Aminolevulinic Acid (5-ALA)-Induced Protoporphyrin IX Fluorescence by Glioma Cells-A Fluorescence Microscopy Clinical Study.

5-aminolevulinic acid (5-ALA)-induced PpIX fluorescence is used by neurosurgeons to identify the tumor cells of high-grade gliomas during operation. However, the issue of whether 5-ALA-induced PpIX fluorescence consistently stains all the tumor cells is still debated. Here, we assessed the cytoplasmatic signal of 5-ALA by fluorescence microscopy in a series of human gliomas. As tumor markers, we used antibodies against collapsin response-mediated protein 5 (CRMP5), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and anti-isocitrate dehydrogenase 1 (IDH1). In grade III-IV gliomas, the signal induced by 5-ALA was detected in 32.7-75.5 percent of CRMP5-expressing tumor cells. In low-grade gliomas (WHO grade II), the CRMP5-expressing tumor cells did not fluoresce following 5-ALA. Immunofluorescence with antibodies that stain various components of the blood-brain barrier (BBB) suggested that 5-ALA does not cross the un-breached BBB, in spite of its small dimension. To conclude, 5-ALA-induced PpIX fluorescence has an established role in high-grade glioma surgery, but it has limited usefulness in surgery for low-grade glioma, especially when the BBB is preserved.

Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma.

Predictive factors for response to regorafenib in recurrent glioblastoma, IDH-wildtype, are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform. We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a clinically available platform. Moreover, MGMT methylation and EGFRvIII expression analyses were performed. Six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months, in line with literature data. NGS analysis revealed a mutation in the EGFR pathway in 18% of cases and a mutation in the mitogen-activated protein-kinase (MAPK) pathway in 18% of cases. In the remaining cases, no mutations were detected. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p = 0.0061; for OS, 7 vs 9 months, p = 0.1076). Multivariate analysis confirmed that MAPK pathway mutations independently predicted a shorter PFS after regorafenib treatment (p = 0.0188). The negative prognostic role of MAPK pathway alteration was reinforced when we combined EGFR-mutated with EGFRvIII-positive cases. Recurrent glioblastoma tumors with an alteration in MAPK pathway could belong to the mesenchymal subtype and respond poorly to regorafenib treatment, while EGFR-altered cases have a better response to regorafenib. We thus provide a molecular selection criterion easy to implement in the clinical practice.

Old Perched Facet Joint Syndrome: "The Always-Anterior Strategy." Report of Two Cases and Review of the Literature.

BACKGROUND: Perched facet joint syndrome is a common post-traumatic condition encountered at the level of subaxial cervical spine in acute settings but more rarely found in a chronic manner. We define this dislocation as old subaxial cervical facet dislocation (OSCFD) when adequate treatment is not established within 3 weeks after initial trauma. It is a clinical entity, moreover, associated with significant impact on neurologic functions such as nerve root or spine compression. Many factors are attributed to explain delayed diagnosis, such as living in a developing country, misreading or inadequate imaging, the presence of multiple injuries, or an absence of symptoms at the time of trauma. CASE DESCRIPTION: We report 2 typical examples of long-lasting OSCFD (up to 6 months), treated both by an anterior cervical approach but with 2 different surgical strategies, associated with similar subsequent clinical restoration and neuroradiologic realignment. We also review the related literature regarding the mechanisms underlying this unusual observation and varied surgical strategies adopted, finally explaining the reasons for our choosing the always-anterior strategy. CONCLUSIONS: In OSCFD, performing a vertebral canal decompression and realignment of the cervical spine column is crucial. More options are purposed to treat this challenging condition, and more of them could be complicated by time-consuming resetting in the operating room, prolonged anesthesiologic procedures, and elevated risk of 360° instrumentation surgical maneuvers. The one-stage combined anterior-approach only (corpectomy or discectomy) is an effective, fast, and safe surgical strategy for treating OSCFD.