Influencia de la ruta Hedgehog-Gli en tumores gliales

Introducción Los astrocitomas de alto grado son los tumores intrínsecos más frecuentes en el cerebro adulto con una supervivencia media alrededor de 14,2 meses. Desde el aislamiento de las células madre tumorales (CMT) de glioblastomas (GBM) como población minoritaria implicada en el origen y mantenimiento de la masa tumoral, hay un interés creciente en el estudio de la ruta clásicamente implicada en desarrollo Hedgehog-Gli (Hh-Gli) con gran controversia en la literatura en cuanto a su papel. Hh-Gli se ha visto alterada en distintos tumores malignos y algunos trabajos apuntan a una reducción tumoral in vitro e in vivo en GBM con la aplicación de distintos inhibidores de esta ruta. En este trabajo se analiza el papel de intermediarios de la ruta Hh-Gli en una serie de tumores gliales y CMT procedentes de pacientes intervenidos en el Hospital Universitario La Fe de Valencia a partir de enero de 2008. Material y métodos Se estudiaron 43 tumores gliales (32 GBM, 7 astrocitomas anaplásicos, 4 gliomas de bajo grado) y 12 controles (4 de sustancia blanca, 4 de sustancia gris, 4 de hipocampo) procedentes de pacientes adultos con esclerosis mesial del lóbulo temporal a los que se les realizó lobectomía temporal y amigdalohipocampectomía. Tras comprobar la anatomía patológica tumoral se aislaron y crecieron CMT a partir de muestras frescas de GBM. Se confirmó que las características de estas células era consistente con la definición de CMT mediante ensayos de multipotencialidad y evaluación de la capacidad para formar tumores cerebrales en ratones nude. Se diseñaron primers de los intermediarios de la ruta Hh-Gli y se cuantificó la expresión de los mismos mediante Real Time PCR tanto en tumores y controles como en líneas de CMT y células madre neurales. Posteriormente se realizó un estudio estadístico sobre diferentes parámetros clínicos (demográficos, tumorales, pronósticos y de seguimiento) y se compararon con los análisis de expresión de intermediarios de la ruta Hh-Gli. Resultados 26 de 43 tumores mostraron disregulación Hh-Gli. Gli1, Gli2 y SMO se encuentran significativamente elevados en tumores. El análisis de las 4 líneas de CMT ha mostrado un incremento de los efectores de Hh-Gli con los sucesivos pases in vitro. Importantes características clínicas se han relacionado con Hh-Gli: Sufu, supresor tumoral, se encuentra sobreexpresado en tumores diseminados a través de los tractos de sustancia blanca al diagnóstico y Smo con un mayor tamaño tumoral, ambos factores implicados en el pronóstico. Conclusiones La ruta Hh-Gli está sobreexpresada en la mayoría de tumores gliales. Variables clínicas estudiadas relacionadas con la ruta y correlaciones entre los diferentes intermediarios, permiten establecer una nueva hipótesis de disregulación de la ruta que podría ayudar en el desarrollo de nuevas estrategias terapéuticas.Introduction Glioblastoma(GBM) is the most common primary malignant brain tumor in adults accounting for 12-15% of all intracranial neoplasms. Since the isolation of tumor stem cells(TSC) from GBM, numerous works have been focusing on this subpopulation of cells instead of the tumor bulk. Certain signals involved classically in embryonic development like Notch, BMP, Noggin, Eph/ephrins and Hedgehog-Gli(Hh-Gli) seem to be important in maintaining neural stem cell(NSC) niches and might play an important role in brain tumors. The aim of the present study is to analyze the expression of Hh-Gli intermediates in a series of human glioma and TSC derived from some of them. Materials and methods We studied 43 astrocytomas(39 high-grade and 4 low-grade) and 12 controls: 4 white matter, 4 grey matter and 4 hippocampus (from adult epileptic patients with mesial temporal sclerosis), one culture of NSC from WM and NSC from hippocampus. After the histological diagnosis, TSC were cultured. We designed primers of the intermediates of the Hh-Gli pathway: Patch1, Smoothened(Smo), Gli1, Gli2, Sufu and the stem cell marker CD133. The transcription of these genes in tumors, TSC and controls was quantified with Real-Time PCR. We demonstrated the multipotentiality of the TSC with differentiation assays in vitro and oncogenicity in athymic mice. Demographic, clinical and radiologic characteristics were obtained from the patient’s clinical record. All the data were statistically analyzed. Results 26 out of 43 tumours showed dysregulation of some of the intermediates of Hh-Gli. Gli1, Gli2 and Smo were significantly up-regulated in tumors compared to controls. The analysis of 4 lineages of TSC has shown an increase of effectors of Hh-Gli with serial passages in vitro. Several important clinical characteristics were related to Hh-Gli: Sufu, a tumor suppressor, was up-regulated in disseminated tumors across white matter fibers at diagnosis and Smo with an increased tumor size, both factors involved in patient’s prognosis. Conclusions An up-regulation in transcription of Hh-Gli intermediates was demonstrated in 60,46% of tumors. More studies in vitro and in vivo have to confirm if Sufu has a direct influence in tumor dissemination or growth. Data obtained from TSCs culture also reveal that Hh-Gli intermediates are not only dysregulated in tumor bulk, which supports the hypothesis of the influence of developmental pathways in TSC. These data open an interesting investigation line towards drug discovery with Hh-Gli inhibitors

Combined endoscopic endonasal transpterygoid and sublabial transmaxillary approaches for a large infratemporal fossa trigeminal schwannoma

Background Trigeminal schwannomas (TSs) with solitary extracranial location are rare, and surgical excision is challenging. In recent years, the endoscopic endonasal transmaxillary transpterygoid approach (EETPA) has been advocated as an effective strategy for TSs in the infratemporal fossa (ITF). Method We describe the steps of the EETPA combined with the sublabial transmaxillary approach for the surgical excision of a giant mandibular schwannoma of the ITF. Indications, advantages, and approach-specific complications are also discussed. The main surgical steps are shown in an operative video. Conclusion A combined EETPA and sublabial transmaxillary approach represents a safe and effective option for the surgical excision of extracranial TSs

Trigeminal Nerve Schwannoma of the Cerebellopontine Angle.

Introduction  Large and even moderate sized, extra-axial cerebellopontine angle (CPA) tumors may fill this restricted space and distort the regional anatomy. It may be difficult to determine even with high resolution magnetic resonance imaging (MRI) if the tumor is dural-based, or what the nerve of origin is if a schwannoma. While clinical history and exam are helpful, they are not unequivocal, particularly since many patients present with a myriad of symptoms, or conversely an incidental finding. We present an atypical appearing, asymptomatic CPA tumor, ultimately identified at surgery to be a trigeminal schwannoma. Case History  A 40-year-old man presented with new-onset seizure. MRI identified an incidental heterogeneously contrast-enhancing CPA lesion ( Fig. 1A - D ). The tumor was centered on the internal auditory canal (IAC) with no tumor extension into Meckel's cave, IAC or jugular foramen. Audiometry demonstrated 10db of relative left-sided hearing loss with 100% word recognition. Physical examination was negative for focal neurologic deficits. A retrosigmoid craniotomy was performed and an extra-axial, yellow-hued mass was encountered and resected, which was ultimately confirmed to originate from the trigeminal nerve ( Video 1 ). Gross total resection was achieved, and the patient recovered from surgery with partial ipsilateral trigeminal sensory loss and no other new neurologic deficits. Conclusion  Pure CPA trigeminal schwannomas are rare, but should be considered in the differential for enhancing CPA lesions. Although, Meckel's cave involvement is frequently observed, it is not universal, and pure CPA schwannomas of all cranial nerves IV-XII have been reported in the literature. The link to the video can be found at: https://youtu.be/AlodYCu70F8

The precuneal interhemispheric, trans-tentorial corridor to the pineal region and brainstem, surgical anatomy, and case illustration

Background The pineal region and dorsal midbrain are among the most challenging surgical targets. To approach lesions in this region that harbor a superior to inferior long axis, we describe the basic steps of the precuneal, interhemispheric, trans-tentorial approach and illustrate anatomical landmarks of this established, but not so popular, surgical trajectory.Method To study the anatomical landmarks and safety of this approach, the neurovascular anatomy was studied on 22 sides of 11 formalin-fixed latex-injected anatomical specimens. A step-by-step dissection of the precuneal interhemispheric trans-tentorial approach and study of the key anatomical landmarks was performed. An illustrative clinical case of a pontomesencephalic cavernous malformation (CM) resected through this approach is also detailed.Results The mean distance from the transverse sinus to the most posterior cortical vein draining into the superior sagittal sinus was 6.4 cm. The mean distance from the calcarine sulcus to the most posterior cortical vein was 5.3 cm. Key steps of the dissection are as follows: craniotomy exposing the posterior aspect of the superior sagittal sinus (SSS), durotomy and gentle retraction of the SSS edge, dissection of the interhemispheric fissure, linear incision of the tentorium that extends anteriorly to the incisura and lateral reflection of the tentorium, and arachnoidal dissection and exposure of the cerebellomesencephalic fissure.Conclusion The precuneal, interhemispheric, trans-tentorial approach affords excellent access to the falcotentorial junction, splenium, pineal region, quadrigeminal cistern, and dorsal pons once the cerebellomesencephalic fissure has been dissected

Endoscopic endonasal surgical anatomy through the prechiasmatic sulcus: the key window to suprachiasmatic and infrachiasmatic corridors

Background Classically, the transtuberculum and transplanum approaches have been utilized to reach the suprachiasmatic and infrachiasmatic corridors. The aim of this study was to provide a better understanding of the key endoscopic endonasal anatomy of the suprachiasmatic and infrachiasmatic corridors provided through selective removal of the prechiasmatic sulcus (SRPS).Method A SRPS was performed in 16 sides of 8 alcohol-fixed head specimens. Twenty anatomical measurements were collected on the suprachiasmatic and infrachiasmatic corridors. The transplanum and transtuberculum approaches were also performed.Results In the suprachiasmatic corridor, the SRPS exposed the anterior communicating artery (AComm) and the post-communicating segment of the anterior cerebral arteries in all the cases, while the pre-communicating segment of the anterior cerebral arteries, recurrent arteries of Heubner, and fronto-orbital arteries were visualized in 75% (12/16), 31% (5/16), and 69% (11/16) of cases, respectively. In the infrachiasmatic corridor, the ophthalmic segment of the internal carotid artery and superior hypophyseal arteries were always visible through the SRPS. The mean width and height of the prechiasmatic sulcus were 13.2 mm and 9.6 mm, respectively. The mean distances from the midpoint of the AComm to the anterior margin of the optic chiasm (OCh) was 5.3 mm. The mean width of the infrachiasmatic corridor was 12 3 mm at the level of the proximal margin of the ophthalmic segment of the internal carotid artery. The mean distances from the posterior superior limit of the pituitary stalk to the basilar tip and oculomotor nerve were 9.7 mm and 12.3 mm, respectively.Conclusions The SRPS provides access to the main neurovascular and cisternal surgical landmarks of the suprachiasmatic and infrachiasmatic corridors. This anatomical area constitutes the key part of the approach to the suprasellar area. To afford adequate surgical maneuverability, the transplanum or transtuberculum approaches are usually a necessary extension

Endoscopic endonasal surgical anatomy of the optic canal: key anatomical relationships between the optic nerve and ophthalmic artery

Purpose A detailed understanding of the neurovascular relationships between the optic nerve (ON) and the ophthalmic artery (OA) in the optic canal (OC) is paramount for safe surgery. We focused on the neurovascular anatomy of this area from both an endoscopic endonasal and transcranial trajectories to compare the surgical exposures and perspectives offered by these different views and provide recommendations to increase the intraoperative safety. Methods Twenty sides of ten formalin-fixed, latex-injected head specimens were utilized. The surgical anatomy and anatomical relationships of the OA in relationship to the ON along their intracranial and intracanalicular segments was studied from endoscopic endonasal and transcranial perspectives. Results Three types of OA-ON relationships at the origin of the OA were identified: inferomedial (type 1, 35%), inferior (type 2, 55%), and inferolateral (type 3, 10%). The endoscopic endonasal trajectory offers an inferomedial perspective of the ON-OA neurovascular complex, in which the OA, especially when located inferomedially, is first encountered. When comparing with the transcranial view, all OA were covered by the nerve, type 1 was located below the medial third, type 2 below the middle third, and type 3 below the lateral third of the OC. The mean extension of the intracanalicular portion of both OA and ON was 8.9 mm, while the intracranial portion of the OA and ON were 9.3 mm and 12.4 mm, respectively. The OA, endoscopically, is located within the inferior half of the OC, and occupies 39%, 43%, and 42% of the OC height at its origin, mid, and end points, respectively. The mean distance between the superior margin of the OC at its origin and superior margin of the OA is 1.4 mm. Conclusions Detailed anatomical understanding of the OC, and the ON and OA at their intracranial and intracanalicular segments is paramount to safe surgery. When opening the OC dura endoscopically, our results suggest that a medial incision along the superior third of the OC with a proximal to distal direction is recommended to avoid injury of the OA

Infraorbital nerve transposition to expand the endoscopic transnasal maxillectomy

Background: The infraorbital nerve (ION) is a terminal branch of the maxillary nerve (V2) providing sensory innervation to the malar skin. It is sometimes necessary to sacrifice the ION and its branches to obtain adequate maxillary sinus exposure for radical resection of sinonasal tumors. Consequently, patients suffer temporary or permanent paresthesia, hypoestesthia, and neuralgia of the face. We describe an innovative technique used for preservation of the ION while removing the anterior, superior, and lateral walls of the maxillary sinus through a medial endoscopic transnasal maxillectomy. Methods: All patients who underwent transnasal endoscopic maxillectomy with ION transposition in our institute were retrospectively reviewed. Results: Two patients were identified who had been treated for sinonasal cancers using this approach. No major complications were observed. Transient loss of ION function was observed with complete recovery of skin sensory perception within 6 months of surgery. One patient referred to a mild permanent anesthesia of the upper incisors. No diplopia or enophthalmos were encountered in any of the patients. Conclusion: The ION transposition is useful for selected cases of benign and malignant sinonasal tumors that do not infiltrate the ION itself but involve the surrounding portion of the maxillary sinus. Anatomic preservation of the ION seems to be beneficial to the postoperative quality of life of such patients

Anatomical Step-by-Step Dissection of Complex Skull Base Approaches for Trainees: Surgical Anatomy of the Endoscopic Endonasal and Endoscopic-Assisted Transmaxillary Transpterygoid Approaches

Introduction The endoscopic endonasal transpterygoid approach (EETPA) with or without the addition of the endoscopic-assisted sublabial anterior transmaxillary approach (ESTA) has become increasingly utilized for lesions posterior to the pterygopalatine fossa (PPF), including infratemporal fossa (ITF), lateral recess of the sphenoid sinus, Meckel's cave, petrous apex, and parapharyngeal space. The main goal of this study is to develop an educational resource to learn the steps of the EETPA for trainees. Methods EETPA and ESTA were performed in 12 specimens by neurosurgery trainees, under supervision from the senior authors. One EETPA and one ESTA were performed on each specimen on opposite sides. Dissections were supplemented with representative cases. Results After a wide unilateral sphenoidotomy, ethmoidectomy, and partial medial maxillectomy, the anteromedial bone limits of the PPF were identified and drilled out. The pterygoid progress was modularly removed. By enlarging the opening of the posterior and lateral walls of the maxillary sinus through EETPA and ESTA, respectively, the neurovascular and muscular compartments of the PPF and ITF were better identified. The EETPA opens direct corridors to the PPF, medial ITF, middle cranial fossa, cavernous sinus, Meckel's cave, petrous apex, and internal carotid artery. If a more lateral exposure of the ITF is needed, the ESTA is an appropriate addition. Conclusion Despite the steep learning curve of the EETPA, granular knowledge of its surgical anatomy and basic surgical steps are vital for those advancing their learning in complex endoscopic approaches to the ventral skull base when expanding the approach laterally in the coronal plane