Multimodal Use of Contact Endoscopy in Neurosurgery: Case Series with Technical Note and Literature Review.

BACKGROUND: Originally adopted for the cytological screening of cervical and uterine cancer, contact endoscopy (CE) is now widely used in several fields of oncological surgery. The CE method, with magnification power up to 150x, was designed to enhance visualization and identify microscopic changes indicative of precancerous and cancerous lesions at early stages. In this pilot study, we evaluated the multimodal applications of CE during different endoscopic intracranial neurosurgical procedures. METHODS: Twenty patients with skull base lesions underwent surgery using different minimally invasive endoscopic approaches (endonasal, transorbital, and supraorbital). CE was used to distinguish the pathology from the surrounding healthy tissue by positioning the endoscope either in proximity or directly onto the target tissue. Special attention was given to the visualization of the margins of the lesion to differentiate compression/displacement from infiltration of the normal surrounding tissue. RESULTS: With its unprecedented range of magnification, CE could clearly identify the microvascular pattern and cytological architecture of a tissue not detectable by simple white light endoscopy, with no reported damage due to heat transmission or iatrogenic injuries. All the lesions diagnosed as "presumed neoplastic tissue" by CE were confirmed by histopathology. The most promising results were observed in surgeries for meningioma and pituitary adenoma, as these lesions exhibit distinctive microvascular networks. CONCLUSIONS: CE represents a new and effective technique for the in vivo identification of pathological microvascular and tissue features, allowing preservation of normal tissue during different endoscopic approaches. The use of CE could improve diagnostic accuracy and assist in intraoperative decision-making, becoming a key tool in various applications in neurosurgical field.

Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth.

Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.

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.

MGMT and Whole-Genome DNA Methylation Impacts on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme.

Epigenetic changes in DNA methylation contribute to the development of many diseases, including cancer. In glioblastoma multiforme, the most prevalent primary brain cancer and an incurable tumor with a median survival time of 15 months, a single epigenetic modification, the methylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene, is a valid biomarker for predicting response to therapy with alkylating agents and also, independently, prognosis. More recently, the progress from single gene to whole-genome analysis of DNA methylation has allowed a better subclassification of glioblastomas. Here, we review the clinically relevant information that can be obtained by studying MGMT gene and whole-genome DNA methylation changes in glioblastomas, also highlighting benefits, including those of liquid biopsy, and pitfalls of the different detection methods. Finally, we discuss how changes in DNA methylation, especially in glioblastomas bearing mutations in the Isocitrate Dehydrogenase (IDH) 1 and 2 genes, can be exploited as targets for tailoring therapy.

Three-Dimensional versus 2-Dimensional Endoscopic Third Ventriculostomy: Surgical Results of a Preliminary Comparative Study.

BACKGROUND: Three-dimensional (3-D) endoscopes have been widely used for a large variety of approaches in neurosurgical practice. However, in the last decade, 3-D scopes were barely used for ventricular surgery. In this study, we illustrated our preliminary experience with a 3-D endoscope for third ventriculostomy using new dedicated endoscopic equipment. METHODS: Over a 12-month period, a high-definition 3-D endoscopic third ventriculostomy (ETV) was performed in 14 patients with obstructive hydrocephalus. Patients were followed prospectively and compared retrospectively with a matched group of 16 similar patients who underwent ETV with a standard 2-dimensional (2-D) endoscope. Surgical outcome and intra- and postoperative course were retrospectively reviewed. RESULTS: 3-D ETV provided excellent surgical results, and no significant difference was shown in terms of outcome, complication, and length of hospitalization between the 2 groups. Moreover, operative time (minutes) was significantly shorter in the 3-D group than the 2-D ETV group (19.9 ± 4.8 vs. 22.9 ± 1.4, respectively; P < 0.05), and the use of the 3-D endoscope provided subjective improvements of depth perception, hand-eye coordination, and surgeon comfort. CONCLUSIONS: Our preliminary study clearly demonstrated the effectiveness of 3-D ETV and provided a significant reduction of operative time. Depth information from the 3-D scope appears to facilitate rapid and stable ETV maneuvers, representing a critical development that may become a valuable tool for neuroendoscopy.

Review of the main surgical and angiographic-oriented classifications of the course of the internal carotid artery through a novel interactive 3D model.

The course of the internal carotid artery (ICA) and its segment classifications were reviewed by means of a new and freely available 3D interactive model of the artery and the skull base, based on human neuroimages, that can be freely downloaded at the Public Repository of the University of Barcelona (http://diposit.ub.edu/dspace/handle/2445/112442) and runs under Acrobat Reader in Mac and Windows computers and Windows 10 tablets. The 3D-PDF allows zoom, rotation, selective visualization of structures, and a predefined sequence view. Illustrative images of the different classifications were obtained. Fischer (Zentralbl Neurochir 3:300-313, 1938) described five segments in the opposite direction to the blood flow. Gibo-Rothon (J Neurosurg 55:560-574, 1981) follow the blood flow, incorporated the cervical and petrous portions, and divided the subarachnoid course-supraclinoid-in ophthalmic, communicating, and choroidal segments, enhancing transcranial microscopic approaches. Bouthillier (Neurosurgery 38:425-433, 1996) divided the petrous portion describing the lacerum segment (exposed in transfacial procedures and exploration of Meckel's cave) and added the clinoid segment between the proximal and distal dural rings, of interest in cavernous sinus surgery. The Kassam's group (2014), with an endoscopic endonasal perspective, introduces the "paraclival segment," including the "lacerum segment" and part of the intracavernous ICA, and details surgical landmarks to minimize the risk of injury. Other classifications are also analyzed. This review through an interactive 3D tool provides virtual views of the ICA and becomes an innovative perspective to the segment classifications and neuroanatomy of the ICA and surrounding structures.

Pure Endoscopic Lateral Orbitotomy Approach to the Cavernous Sinus, Posterior, and Infratemporal Fossae: Anatomic Study.

Objective The aim of this anatomic study is to describe a fully endoscopic lateral orbitotomy extradural approach to the cavernous sinus, posterior, and infratemporal fossae. Material and Methods Three prefixed latex-injected head specimens (six orbital exposures) were used in the study. Before and after dissection, a computed tomography scan was performed on each cadaver head and a neuronavigation system was used to guide the approach. The extent of bone removal and the area of exposure of the targeted corridor were evaluated with the aid of OsiriX software (Pixmeo, Bernex, Switzerland). Results The lateral orbital approach offers four main endoscopic extradural routes: the anteromedial, posteromedial, posterior, and inferior. The anteromedial route allows a direct route to the optic canal by removal of the anterior clinoid process, whereas the posteromedial route allows for exposure of the lateral wall of the cavernous sinus. The posterior route is targeted to Meckel's cave and provides access to the posterior cranial fossa by exposure and drilling of the petrous apex, whereas the inferior route gives access to the pterygopalatine and infratemporal fossae by drilling the floor of the middle cranial fossa and the bone between the second and third branches of the trigeminal nerve. Conclusion The lateral orbitotomy endoscopic approach provides direct access to the cavernous sinus, posterior, and infratemporal fossae. Advantages of the approach include a favorable angle of attack, minimal brain retraction, and the possibility of dissection within the two dural layers of the cavernous sinus without entering its neurovascular compartment.

Fluorescein-assisted stereotactic needle biopsy of brain tumors: a single-center experience and systematic review.

Over the last years, fluorescence-based technology has begun an emergent intraoperative method for diagnostic confirmation of brain tumor tissue in stereotactic needle biopsy. However, the actual level of evidence is quite low, especially about fluorescein sodium (FL) application. This method needs to be further validated and better analyzed about its impact in clinical practice. Retrospective analysis of 11 cases with contrast-enhancing brain tumors, underwent awake stereotactic needle biopsy with intraoperative FL assistance (group 1), was verified under the operative microscope filter. This group was matched with a control group of 18 patients (group 2). In addition, a systematic literature review was performed in PubMed/Medline database according to PRISMA statement. All studies concerning FL or 5-ALA application in stereotactic biopsy as intraoperative confirmation of brain tumor tissue were included. The primary endpoint was the evaluation of diagnostic accuracy. In group 1, all fluorescent specimens were diagnostic. The number of samplings was the useful minimum and non-use of intraoperative neuropathological examination allowed to significantly reduce procedure time (42.09 vs 69.72 min of group 2). No complications occurred, and the average hospitalization time after procedure was 1.09 days (vs 2.33 of group 2). Literature analysis supports the usefulness of photodiagnosis and its high diagnostic yield especially at the core of high-grade/contrast-enhancing tumors. FL assistance during stereotactic biopsy of contrast-enhancing brain tumors may give a real-time confirmation of tumor tissue, maximizing the diagnostic yield, and reducing time of procedure, morbidity, and hospitalization.

Endoscopic Endonasal Transclival Approach to the Ventral Brainstem: Anatomic Study of the Safe Entry Zones Combining Fiber Dissection Technique with 7 Tesla Magnetic Resonance Guided Neuronavigation.

BACKGROUND: Treatment of intrinsic lesions of the ventral brainstem is a surgical challenge that requires complex skull base antero- and posterolateral approaches. More recently, endoscopic endonasal transclival approach (EETA) has been reported in the treatment of selected ventral brainstem lesions. OBJECTIVE: In this study we explored the endoscopic ventral brainstem anatomy with the aim to describe the degree of exposure of the ventral safe entry zones. In addition, we used a newly developed method combining traditional white matter dissection with high-resolution 7T magnetic resonance imaging (MRI) of the same specimen coregistered using a neuronavigation system. METHODS: Eight fresh-frozen latex-injected cadaver heads underwent EETA. Additional 8 formalin-fixed brainstems were dissected using Klingler technique guided by ultra-high resolution MRI. RESULTS: The EETA allows a wide exposure of different safe entry zones located on the ventral brainstem: the exposure of perioculomotor zone requires pituitary transposition and can be hindered by superior cerebellar artery. The peritrigeminal zone was barely visible and its exposure required an extradural anterior petrosectomy. The anterolateral sulcus of the medulla was visible in most of specimens, although its close relationship with the corticospinal tract makes it suboptimal as an entry point for intrinsic lesions. In all cases, the use of 7T-MRI allowed the identification of tiny fiber bundles, improving the quality of the dissection. CONCLUSION: Exposure of the ventral brainstem with EETA requires mastering surgical maneuvers, including pituitary transposition and extradural petrosectomy. The correlation of fiber dissection with 7T-MRI neuronavigation significantly improves the understanding of the brainstem anatomy.

A Survey on Pituitary Surgery in Italy.

BACKGROUND: Pituitary tumors are a heterogeneous group of lesions that are usually benign. Therefore, a proper understanding of the anatomy, physiology, and pathology is mandatory to achieve favorable outcomes. Accordingly, diagnostic tests and treatment guidelines should be determined and implemented. Thus, we decided to perform a multicenter study among Italian neurosurgical centers performing pituitary surgery to provide an actual depiction from the neurosurgical standpoint. METHODS: On behalf of the SINch (Società Italiana di Neurochirurgia), a survey was undertaken with the participants to explore the activities in the field of pituitary surgery within 41 public institutions. RESULTS: Of the 41 centers, 37 participated in the present study. The total number of neurosurgical procedures performed in 2016 was 1479. Most of the procedures were performed using the transsphenoidal approach (1320 transsphenoidal [1204 endoscopic, 53 microscopic, 53 endoscope-assisted microscopic] vs. 159 transcranial). A multidisciplinary tumor board is convened regularly in 32 of 37 centers, and a research laboratory is present in 18 centers. CONCLUSIONS: Diagnosing pituitary/hypothalamus disorders and treating them is the result of teamwork, composed of several diverse experts. Regarding neurosurgery, our findings have confirmed the central role of the transsphenoidal approach, with preference toward the endoscopic technique. Better outcomes can be expected at centers with a multidisciplinary team and a full, or part of a, residency program, with a greater surgical caseload.

Palatal Position of Patient Tracker for Magnetic Neuronavigation System: Technical Note.

OBJECTIVE: Recently, the neuronavigation system (NS) has become an essential intraoperative tool for many neurosurgical procedures, allowing for precise lesion localization. It is particularly important to avoid errors during the navigation process. Here we report a novel technique using palatal positioning of the patient tracker to ensure optimal accuracy during magnetic navigation in various neurosurgical procedures. METHODS: This retrospective study included a total of 34 patients treated in our institution between June 2017 and January 2018. The patients were split into 2 groups who underwent surgery under general anesthesia: a microscopic transcranial group and an endoscopic endonasal group. Preoperative and postoperative navigation accuracy was assessed by 2 neurosurgeons. RESULTS: After our surgical planning navigation protocol was applied, both transcranial and endonasal procedures were successfully performed under navigation guidance in all but 1 patient. There were no intraoperative or postoperative complications related to the tracker mounted under the hard palate. In 33 cases a maximal tracking view and optimal navigation accuracy was achieved, for a success rate of 97%. CONCLUSIONS: The positioning of the patient tracker under the hard palate proved safe, accurate, and feasible in 97% of our patients. In our case series, it met the main goal of avoiding device displacement without a sense of invasiveness and postoperative patient discomfort.

Cerebrovascular disorders and Fahr's disease: Report of two cases and literature review.

Fahr's disease is a rare idiopathic nosological entity, characterized by calcification of the basal ganglia and dentate nuclei of the cerebellum. Sometimes it may be associated to other diseases like cerebrovascular disorders. However, this link remains unclear and it needs to be further validated. We report two cases of patients with cerebrovascular disorders and Fahr's disease. In the first case, a 69-years-old woman with right internal capsule-basal ganglia haemorrhage. In the second case, a 72-years-old woman with ischemic stroke and pericallosal artery aneurysm. The physiopathology is discussed and concerning literature is reviewed.

Frontolateral Approach Combined with Endoscopic Endonasal Extradural Posterior Clinoidectomy to the Upper Clival Region: Anatomic and Feasibility Study.

BACKGROUND: Surgical management of lesions located in the upper clival region is challenging. Complex open transcranial approaches have been used to reach surgical targets in these areas. The frontotemporozygomatic approach combined with an intradural posterior clinoidectomy has been proposed as the most reliable route to manage such lesions. We investigated combining a minimally invasive endoscopic endonasal extradural posterior clinoidectomy (EPC) with a standard frontolateral approach to expand the working area within the upper clival region. METHODS: Investigators dissected 10 human cadaveric heads at the Laboratory of Surgical NeuroAnatomy of the University of Barcelona. The heads were positioned to simulate a supine position, enabling the simultaneous use of both endonasal and frontolateral routes. The dissections were divided into 3 steps-standard frontolateral approach, EPC, and re-evaluation of the frontolateral route-aiming to compare the surgical exposure before and after EPC. RESULTS: After EPC, through the frontolateral pathway it was possible to improve visualization and working angles to the interpeduncular fossa and retrosellar and upper clival regions. Increase in extension of the carotid-oculomotor window was 7 mm and 10 mm before and after the posterior clinoidectomy, respectively. CONCLUSIONS: EPC provided extra working space for the frontolateral approach to the upper clival area with 42.8% expansion of the carotid-oculomotor triangle. Surgical series are needed to demonstrate clinical advantages and disadvantages of this novel combined approach.

Multimodal use of indocyanine green endoscopy in neurosurgery: a single-center experience and review of the literature.

During the last 10 years, microscope-integrated indocyanine green fluorescence (m-ICG) has been widely used for assessing real-time blood flow during aneurysm surgery. More recently, an endoscope-integrated indocyanine green fluorescence (e-ICG) has been adopted as a versatile tool during different endoscopic neurosurgical procedures. The purpose of the present report is to evaluate multimodal applications of e-ICG during different endonasal, intraventricular, aneurysm and brain tumor surgeries and provide technical nuances. In addition, we reviewed the literature and identified and compare several overlapping case series of patients treated via an endoscopic integrated indocyanine green fluorescence technique. A total of 40 patients were retrospectively evaluated. Patients were divided into four main groups: (1) endoscopic endonasal approaches (n = 14); (2) ventricular endoscopic approach including patients undergoing third ventriculostomy (n = 8) and tumor biopsy (n = 1); (3) aneurysms surgery (n = 9); and (4) brain parenchymal tumors (n = 8). All patients were successfully treated using the e-ICG dynamic endoscopic visualization, and there were no perioperative complications. Such unique features open up a promising field of applications beyond the use of m-ICG in different surgical field due to the longer duration of e-ICG fluorescence up to 35 ± 7 min. E-ICG represents a new and effective technique for longer real-time visualization of vascular structures preserving normal tissues and functions during different transcranial and endonasal approaches. As the technology and e-ICG resolution improves, the technique has the potential to become a critical tool for different applications in neurosurgery.

Deregulated expression and activity of Farnesyl Diphosphate Synthase (FDPS) in Glioblastoma.

Glioblastoma (GBM), the most aggressive brain cancer, is highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical for cell proliferation but the function and regulation of key intermediate enzymes like farnesyl-diphosphate synthase (FDPS), up to now, remained unknown. A deregulated expression and activity of FDPS was the central research idea of the present study. FDPS mRNA, protein and enzyme activity were analyzed in a cohort of stage III-IV glioma patients (N = 49) and primary derived cells. FDPS silencing helped to clarify its function in the maintenance of malignant phenotype. Interestingly, compared to tumor-free peripheral (TFB) brain and normal human astrocytes (NHA), FDPS protein expression and enzyme activity were detected at high degree in tumor mass where a correlation with canonical oncogenic signaling pathways such as STAT3, ERK and AKT was also documented. Further, FDPS knockdown in U87 and GBM primary cells but not in NHA, enhanced apoptosis. With the effort to develop a more refined map of the connectivity between signal transduction pathways and metabolic networks in cancer FDPS as a new candidate metabolic oncogene in glioblastoma, might suggest to further target MVA pathway as valid therapeutic tool.

Fluorescein-Guided Surgery for High-Grade Glioma Resection: An Intraoperative "Contrast-Enhancer".

BACKGROUND: Fluorescein sodium salt is widely used in medicine as fluorescein isothiocyanate and commonly named fluorescein (FL). This fluorophore has been used as a fluorescent tracer for many applications, especially in ophthalmic surgery. It was initially used in neuro-oncology in 1948 to control tumor resection margins. After a transient disuse, it has recently had a second spring with the development of dedicated filters for operating microscopes, although it is still under evaluation in clinical use. The aim of this study is to contribute to the investigation according to which FL-guided surgery for high-grade glioma (HGG) is related to better rates of gross total resection (GTR) and so to a better outcome. METHODS: We retrospectively analyzed 23 cases of patients with new diagnosis of HGG, operated on in our unit by intraoperative FL use with a filter system directly integrated into an operative microscope (group 1). Fluorescence was compared with histology by biopsies carried out both in the fluorescent areas and in the periphery of fluorescent areas. Group 1 was matched with a control group of 25 patients with HGG operated on in our unit during the last 2 years without FL guidance (group 2). RESULTS: No side effects occurred related to FL. Histology and intraoperative neuronavigation showed strong correspondence with fluorescent and nonfluorescent areas. GTR rate was significantly higher in group 1 (82.6%) than in group 2 (52%). CONCLUSIONS: Intraoperative fluorescein-guided surgery showed safety and feasibility. Our and other studies suggest an improvement of GTR rate in HGG than nonuse.

Endoscopic transorbital route to the cavernous sinus through the meningo-orbital band: a descriptive anatomical study.

OBJECTIVE Exposure of the cavernous sinus is technically challenging. The most common surgical approaches use well-known variations of the standard frontotemporal craniotomy. In this paper the authors describe a novel ventral route that enters the lateral wall of the cavernous sinus through an interdural corridor that includes the removal of the greater sphenoid wing via a purely endoscopic transorbital pathway. METHODS Five human cadaveric heads (10 sides) were dissected at the Laboratory of Surgical NeuroAnatomy of the University of Barcelona. To expose the lateral wall of the cavernous sinus, a superior eyelid endoscopic transorbital approach was performed and the anterior portion of the greater sphenoid wing was removed. The meningo-orbital band was exposed as the key starting point for revealing the cavernous sinus and its contents in a minimally invasive interdural fashion. RESULTS This endoscopic transorbital approach, with partial removal of the greater sphenoid wing followed by a "natural" ventral interdural dissection of the meningo-orbital band, allowed exposure of the entire lateral wall of the cavernous sinus up to the plexiform portion of the trigeminal root and the petrous bone posteriorly and the foramen spinosum, with the middle meningeal artery, laterally. CONCLUSIONS The purely endoscopic transorbital approach through the meningo-orbital band provides a direct view of the cavernous sinus through a simple and rapid means of access. Indeed, this interdural pathway lies in the same sagittal plane as the lateral wall of the cavernous sinus. Advantages include a favorable angle of attack, minimal brain retraction, and the possibility for dissection through the interdural space without entering the neurovascular compartment of the cavernous sinus. Surgical series are needed to demonstrate any clinical advantages and disadvantages of this novel route.

Antiglioma effects of N6-isopentenyladenosine, an endogenous isoprenoid end product, through the downregulation of epidermal growth factor receptor.

Malignant gliomas are highly dependent on the isoprenoid pathway for the synthesis of lipid moieties critical for cell proliferation. The isoprenoid derivative N6-isopentenyladenosine (iPA) displays pleiotropic biological effects, including a direct anti-tumor activity in several tumor models. The antiglioma effects of iPA was then explored in U87MG cells both in vitro and grafted in mice and the related molecular mechanism confirmed in primary derived patients' glioma cells. iPA powerfully inhibited tumor cell growth and induced caspase-dependent apoptosis through a mechanism involving a marked accumulation of the pro-apoptotic BIM protein and inhibition of EGFR. Indeed, activating AMPK following conversion into its iPAMP active form, iPA stimulated EGFR phosphorylation and ubiquitination along a proteasome-mediated pathway which was responsible for receptor degradation and its downstream signaling pathways inhibition, including the STAT3, ERK and AKT cascade. The inhibition of AMPK by compound C prevented iPA-mediated phosphorylation of EGFR, known to precede receptor loss. As expected the block of EGFR degradation, by exposure to the proteasome inhibitor MG132, significantly reduced iPA-induced cell death. Given the importance of receptor degradation in iPA-mediated cytotoxicity, we also documented that the EGFR expression levels in a panel of primary glioma cells confers them a high sensitivity to iPA treatment. In conclusion our study provides the first evidence of iPA antiglioma effect. Indeed, as glioma is driven by aberrant signaling of growth factor receptors, particularly the EGFR, iPA, alone or in association with EGFR targeted therapies, might be a promising therapeutic tool to achieve a potent anti-tumoral effect.

The use of a three-dimensional endoscope for different skull base tumors: results of a preliminary extended endonasal surgical series.

BACKGROUND: The evolution of skull base surgery over the past decade has been influenced by advancement in visualization technology. Recently, as a result of such improvements, three-dimensional (3-D) scopes have been widely used during endoscopic endonasal approaches. In the present study, we describe the use of 3-D stereoscopic endoscope for the treatment of a variety of skull base lesions. METHODS: From January 2010 to June 2015, a 3-D endoscopic endonasal approach (4 and 4.9 mm, 0°, and 30° rigid endoscopes) was performed in 70 patients with the following lesions: 42 large extrasellar pituitary macroadenomas, seven tuberculum sellae meningiomas, seven clivus chordomas, five craniopharyngiomas, three fibrous dysplasia of the clivus, three sinonasal malignancies, one orbital lymphangioma, one trigeminal neurinoma, one primary suprasellar lymphoma. RESULTS: Total tumor removal was obtained in 50 patients (71.4 %) while in 14 (20 %), subtotal removal was possible in six (8.6 %) only partial removal was achieved. Overall complications included diabetes insipidus in eight patients (11.4 %), hypopituitarism in seven patients (10 %), CSF leak in five patients (7.1 %), cranial nerve injury in two patients (2.8 %), panhypopituitarism in two patients (2.8 %), meningitis in one (1.4 %) and one postoperative central retinal artery occlusion (1.4 %). There was no mortality in the series. The mean follow-up time was 39 months (range, 6-72 months). CONCLUSIONS: In our experience, the 3-D endoscope represents a critical development in visualization, thus enabling improved hand-eye coordination and depth perception, which are mandatory for the management of complex intradural neurovascular structures during tumor removal surgery.

Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells.

Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-ß1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.