The role of systemic therapy in advanced skull base chordomas: overview of the current state and the MD Anderson protocol.

The role of systemic therapy in primary or advanced and metastatic chordoma has been traditionally limited because of the inherent resistance to cytotoxic therapies and lack of specific or effective therapeutic targets. Despite resection and adjuvant radiation therapy, local recurrence rates in clival chordoma remain high and the risk of systemic metastases is not trivial, leading to significant morbidity and mortality. Recently, molecular targeted therapies (MTTs) and immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic avenues in chordoma. In recent years, preclinical studies have identified potential targets based on intrinsic genetic dependencies, epigenetic modulators, or newly identified tumor-associated cell populations driving treatment resistance and recurrence. Nonetheless, the role of systemic therapies in the neoadjuvant or adjuvant setting for primary, locally progressive, and distant metastatic chordomas is still being investigated. Herein, an overview of current and emerging systemic treatment strategies in advanced clival chordoma is provided. Furthermore, several molecular biomarkers have been recently uncovered as potential predictors of the response to specific molecular therapeutics. The authors describe the recently discovered role of 1p36 and 9p21 deletions as biomarkers capable of guiding drug selection. Then they discuss completed and ongoing clinical trials of MTTs, including several tyrosine kinase inhibitors used as monotherapy or in combination, such as imatinib, sorafenib, dasatinib, and lapatinib, among others, as well as mammalian target of rapamycin inhibitors such as everolimus and rapamycin. They present their experience and other recent studies demonstrating vast benefits in advanced chordoma from ICIs. Additionally, they provide a brief overview of novel systemic strategies such as adoptive cell transfer (CAR-T and NK cells), oncolytic viruses, epigenetic targeting (KDM6, HDAC, and EZH2 inhibitors), and several promising preclinical studies with high translational potential. Finally, the authors present their institutional multidisciplinary protocol for the incorporation of systemic therapy for both newly diagnosed and recurrent chordomas based on molecular studies including upfront enrollment in MTT trials in patients with epidermal growth factor receptor upregulation or INI-1 deficiency or enrollment in ICI clinical trials for patients with high tumor mutational burden or high PD-L1 expression on tumor cells or in the tumor microenvironment.

Is endoscopic resection a useful technique for a cavernous sinus sellar cavernoma? A case report and literature review.

BACKGROUND: Cavernous sinus cavernous malformations (CSCMs) is a vascular malformation of the cavernous sinus. Nowadays, there is an increasing preference to withhold using the terms cavernoma or cavernous hemangioma in order to stop considering these lesions as vascular neoplasms. These lesions are highly vascularized making surgical resection a challenge, mainly in endoscopic approaches. We present a case of this tumor treated in our institution with an endoscopic endonasal approach and incomplete resection. Because of the strenuous resection through this approach, we systematically reviewed the reported endoscopic cases of CSCMs to determine their intraoperative complications, results and tumor features. METHODS: Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, one database (PubMed) and crossed references were queried for CSCMs from 1948 to 2020. Data regarding demographic features, clinical presentation, MRI features, surgical results and overall pathology features extracted. RESULTS: Eighteen patients were selected (including our case). The mean age was 50.4 ± 14 years. Pituitary dysfunction and cavernous sinus nerve compression were the most reported symptoms. Only five cases (27%) reported a gross total resection (GTR) through endoscopic endonasal approach. Intraoperative bleeding was the most frequent intraoperative complication. CONCLUSION: We present a comprehensive analysis of every reported CSCM treated through endoscopic approach. Partial or subtotal resection are the most used techniques because of the intraoperative bleeding and the adherence to surrounding structures. Radiotherapy is a very good option for patients with incomplete resections.

Granular cell tumors of the sellar region: what should be done after subtotal resection? A systematic review.

PURPOSE: Granular cell tumors (GCT) are highly vascularized and adherent to adjacent structures, and so, complete resection represents a challenge. Adjuvant therapy decisions for residual GCTs currently relies on individual clinician decisions due to a paucity of systematic literature data. We present a comprehensive analysis about the impact of adjuvant therapy in reported cases of patients with incomplete GCT resection. METHODS: One database (PubMed) and crossed references were queried for GCT with incomplete resection or biopsy from 1962 to 2020. Literature review was performed according to the PRISMA guidelines. Also, two patients with residual GCT from our institutions are added to the analysis. Data regarding clinical presentation, surgical approach, use of adjuvant therapy, Ki-67 labeling, and follow up assessments were extracted and analyzed from selected publications. RESULTS: Thirty-three studies met the predetermined inclusion criteria and 53 patients were selected (including our two reported cases). The median of age was 49 [IQR, 39-60 years], with a slight male predominance (1.2:1). Among the surgical procedures, seven (13%) were biopsies alone. Adjuvant therapy was used in 18 patients (radiotherapy, 94.5%; chemotherapy, 5.5%) but there is no statistical correlation with adjuvant therapy and the progression of the remnant tumor (p = 0.33). Our institutions' patients did not receive adjuvant therapy and did not show tumor progression on MRI. CONCLUSION: Our systematic literature review suggests there is a limited role for chemo and/or radiotherapy in the management of incomplete GCT resection. It may be reasonable recommending close clinical follow up in patients with incomplete resection.

Impact of salvage surgery with or without reirradiation for skull base meningiomas recurring after prior radiotherapy.

OBJECTIVE: Long-term follow-up of meningiomas has demonstrated recurrence rates ranging from 2.5% to 48% after 10 years, depending on histology grade. There are limited data available to guide the management of recurrent and previously irradiated skull base meningiomas, and challenges related to salvage surgery, reirradiation, and lack of clear systemic therapy strategies remain. In this study, the authors analyzed data from their experience with recurrent and previously irradiated meningiomas to assess the impact of salvage surgery and reirradiation on progression-free survival (PFS). METHODS: A retrospective cohort study of 48 patients with recurrent and previously irradiated meningiomas who were treated between 1995 and 2021 was conducted. Data were extracted from medical records and included clinical, radiological, and pathologic reports. Patients were clustered according to WHO grades. The authors analyzed the complications related to reirradiation and salvage surgery and the impact of different treatment modalities on PFS using Cox proportional hazard ratios. RESULTS: Forty-eight patients (33 with WHO grade I, 11 with WHO grade II, and 4 with WHO grade III meningiomas) were treated for 143 recurrences after their first radiation treatment. For WHO grade I meningiomas, there was no change in tumor control rates with adjuvant repeat radiotherapy (HR 0.784, 95% CI 0.349-1.759; p = 0.55), and in terms of extent of resection (EOR), subtotal resection (STR) alone was associated with an increased risk of recurrence when compared with gross-total resection (GTR) (HR 3.38, 95% CI 1.268-9.036; p = 0.0189). For WHO grade II meningiomas, GTR did not significantly confer improved tumor control relative to STR (HR 0.42, 95% CI 0.17-1.037; p = 0.055), but adjuvant repeat radiotherapy after STR was associated with improved outcomes (HR 0.316, 95% CI 0.13-0.768; p = 0.0029). Finally, for WHO grade III meningiomas, EOR did not correlate with outcomes (HR 0.75, 95% CI 0.22-2.482; p = 0.588), but repeat radiotherapy alone was associated with a decreased odds of progression (HR 0.276, 95% CI 0.078-0.97; p = 0.0028). CONCLUSIONS: This study examined the impact of retreatment on PFS in a large cohort of patients with recurrent meningiomas that had been previously irradiated. At the time of recurrence, WHO grade I meningiomas exhibited improved PFS with GTR, subtotally resected WHO grade II meningiomas appeared to have improved PFS when reirradiated, and reirradiation in WHO grade III meningiomas showed improved PFS.

Synchronous Posterior and Anterior Pituitary Tumors: A Case Report of a Hypothetic Paracrine Relationship.

Tumors of the posterior pituitary are a distinct group of low-grade sellar neoplasms. Furthermore, the coexistence with an anterior pituitary tumor is extremely unlikely and could not be a mere coincidence and could be a paracrine relationship. Here, we present a case of 41-year-old woman with Cushing syndrome and two pituitary masses on magnetic resonance imaging. Histologic examination shows two distinct lesions. The first consisted of a pituitary adenoma with intense adrenocorticotropic hormone immunostaining and the second lesion consisted of a proliferation of pituicytes arranged in vague fascicles or pituicytoma. After a narrative review of the literature, we found that synchronous pituitary adenoma and a thyroid transcription factor 1 (TTF-1) pituitary tumor were only reported eight times in the past. These patients included two granular cell tumors and six pituicytomas and all of them coexisted with pituitary adenomas, seven functioning and one nonfunctioning. We analyze the hypothesis of a possible paracrine relationship for this concomitance, but this exceedingly rare situation is still a matter of debate. To the best of our knowledge, our case represents the ninth case of a TTF-1 pituitary tumor coexisting with a pituitary adenoma.

Lateral ventricle subependymoma resected with a transcallosal approach: illustrative case.

BACKGROUND: Subependymomas are World Health Organization grade I tumors, and 30% occur in the lateral ventricles. Surgery is the mainstay of treatment, and the transcallosal or transcortical/transsulcal approaches are preferred for those tumors occurring near the foramen of Monro or atrium. Visualization, proximity to the fornix and basal ganglia, hydrocephalus, and brain retraction during surgery make these operations challenging. The authors present the case of a 65-year-old male with a subependymoma located in the left lateral ventricle. The tumor was completely resected using an interhemispheric/transcallosal approach. OBSERVATIONS: The authors analyze the anatomopathological features of subependymoma, along with the clinical behavior and therapeutic options. The authors discuss in detail the advantages and disadvantages of the interhemispheric/transcallosal approach for resection of these tumors. LESSONS: Subependymomas are slow-growing lesions with an indolent yet complicated course making surgical removal challenging yet feasible using the correct techniques. The interhemispheric transcallosal approach offers an excellent route for the resection of large subependymomas, but there is still a significant risk for postoperative complications.

Robotic guidance platform for laser interstitial thermal ablation and stereotactic needle biopsies: a single center experience.

While laser ablation has become an increasingly important tool in the neurosurgical oncologist's armamentarium, deep seated lesions, and those located near critical structures require utmost accuracy during stereotactic laser catheter placement. Robotic devices have evolved significantly over the past two decades becoming an accurate and safe tool for stereotactic neurosurgery. Here, we present our single center experience with the MedTech ROSA ONE Brain robot for robotic guidance in laser interstitial thermal therapy (LITT) and stereotactic biopsies. We retrospectively analyzed the first 70 consecutive patients treated with ROSA device at a single academic medical center. Forty-three patients received needle biopsy immediately followed by LITT with the catheter placed with robotic guidance and 27 received stereotactic needle biopsy alone. All the procedures were performed frameless with skull bone fiducials for registration. We report data regarding intraoperative details, mortality and morbidity, diagnostic yield and lesion characteristics on MRI. Also, we describe the surgical workflow for both procedures. The mean age was 60.3 ± 15 years. The diagnostic yield was positive in 98.5% (n = 69). Sixty-three biopsies (90%) were supratentorial and seven (10%) were infratentorial. Gliomas represented 54.3% of the patients (n = 38). There were two postoperative deaths (2.8%). No permanent morbidity related to surgery were observed. We did not find intraoperative technical problems with the device. There was no need to reposition the needle after the initial placement. Stereotactic robotic guided placement of laser ablation catheters and biopsy needles is safe, accurate, and can be implemented into a neurosurgical workflow.

Prognostic molecular biomarkers in chordomas: A systematic review and identification of clinically usable biomarker panels.

Introduction and objective: Despite the improvements in management and treatment of chordomas over time, the risk of disease recurrence remains high. Consequently, there is a push to develop effective systemic therapeutics for newly diagnosed and recurrent disease. In order to tailor treatment for individual chordoma patients and develop effective surveillance strategies, suitable clinical biomarkers need to be identified. The objective of this study was to systematically review all prognostic biomarkers for chordomas reported to date in order to classify them according to localization, study design and statistical analysis. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed published studies reporting biomarkers that correlated with clinical outcomes. We included time-to-event studies that evaluated biomarkers in skull base or spine chordomas. To be included in our review, the study must have analyzed the outcomes with univariate and/or multivariate methods (log-rank test or a Cox-regression model). Results: We included 68 studies, of which only 5 were prospective studies. Overall, 103 biomarkers were analyzed in 3183 patients. According to FDA classification, 85 were molecular biomarkers (82.5%) mainly located in nucleus and cytoplasm (48% and 27%, respectively). Thirty-four studies analyzed biomarkers with Cox-regression model. Within these studies, 32 biomarkers (31%) and 22 biomarkers (21%) were independent prognostic factors for PFS and OS, respectively. Conclusion: Our analysis identified a list of 13 biomarkers correlating with tumor control rates and survival. The future point will be gathering all these results to guide the clinical validation for a chordoma biomarker panel. Our identified biomarkers have strengths and weaknesses according to FDA's guidelines, some are affordable, have a low-invasive collection method and can be easily measured in any health care setting (RDW and D-dimer), but others molecular biomarkers need specialized assay techniques (microRNAs, PD-1 pathway markers, CDKs and somatic chromosome deletions were more chordoma-specific). A focused list of biomarkers that correlate with local recurrence, metastatic spread and survival might be a cornerstone to determine the need of adjuvant therapies.

When "Peripheral" Becomes "Central": Primary and Secondary Malignant Intracerebral Nerve Sheath Tumor: A Case Report and a Systematic Review.

BACKGROUND: The intracerebral occurrence of malignant peripheral nerve sheath tumors (MPNSTs) is exceedingly rare, and despite aggressive treatments, local recurrence and poor prognosis are very frequent. Like other brain tumors, these tumors could be primary or secondary, making the term "peripheral" an imprecise term for a primary brain tumor. OBJECTIVE: To analyze the reported cases of primary and secondary cerebral MPSNTs in terms of diagnosis, treatment, and overall survival. Additionally, we present a case of malignant intracerebral nerve sheath tumor (MINST) treated with radical surgery and radiotherapy. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, one database (PubMed) and crossed references were queried for MPNST with brain metastasis and primary MINSTs from 1971 to 2020. Data regarding demographic features, primary tumor site, risk factors, brain location of the lesion, treatment applied, and overall survival were extracted. RESULTS: A total of 55 patients were selected (including the reported case): 29 patients were secondary brain MPNST and 26 patients were primary MINST. The mean age was 41.8 ± 22 and 31.2 ± 23 yr, respectively. All brain metastases of MPNST (100%) had a primary tumor elsewhere in the body at the time of diagnosis. The overall survival was significantly shorter in patients with a secondary brain MPNST compared to MINST (P = .002). CONCLUSION: We present a comprehensive analysis of every reported primary and secondary intracerebral MPNST. The prognosis in terms of survival is worst in the last one despite aggressive treatment. The lack of a primary MPNST in screening tests is sufficient to confirm a MINST at time of diagnosis.

Clivus Hemangioma in a Pediatric Patient: Case Report.

BACKGROUND: Hemangiomas are benign blood vessels tumors that represent less than 1% of all the bone neoplasms. Calvarial hemangiomas are mainly solitary lesions commonly located in the frontal and parietal bone; however, they may occur in any skull region. These tumors increase in size over a period of months to years before they start showing their first symptoms such as headache, bone deformity, and pathological fractures. Differential diagnosis with osteosarcoma should be considered. Surgical resection with a safety margin is a standard treatment of the cranial hemangioma. Furthermore, radiotherapy has proven to stop the tumor's growth but not its size. CASE DESCRIPTION: We treated an 11-year-old male who had a rare case of a capillary hemangioma located in the clivus bone. The patient underwent 2 endoscopic endonasal resection because of tumor recurrence. Surgical safety margins are highly recommended, but this procedure could not be performed because of the tumor's location. After the second relapse, the oncology team decided to initiate radiotherapy. At 6-month follow-up, the tumor reduced its size and remained unchanged. CONCLUSIONS: Surgical safety margins are highly important to prevent recurrence in this type of bone tumors. Skull base hemangiomas are a big challenge when you want to achieve these safety margins. We believe that a combined treatment of surgery and radiotherapy should be considered as the main treatment.

[Purely endoscopic supracerebellar infratentorial approach for epidermoid cyst in third ventricle]. / Abordaje Puramente Endoscópico Supracerebeloso Infratentorial para Quiste Epidermoide en Tercer Ventrículo.

BACKGROUND: The epidermoid cyst as a pineal region tumor is an infrequent pathology and with few descriptions in literature. Its prevalence in the third ventricle is 0,0042% of all intracranial tumors. To achieve a complete exéresis we used an endoscopic supracerebellar-infratentorial approach, surgical technique for pineal region approach. OBJECTIVES: The purpose of this work is to show the surgical technique of this novel approach for the treatment of a very infrequent disease. METHODS: 16 years old male patient with history of diabetes insipidus and chronic headaches (m-RS 1). Brain MRI showed a lesion with hyperintensity in T2WI and hypointensity in T1WI. It presents peripheral enhancement with gadolinium and restricted diffusion pattern in DWI. The pituitary stalk also showed enhancement with contrast. Germ cell tumor was a possible diagnosis but tumor cell markers were negative in CSF samples. We decided to make the purely endoscopic approach to the region to make a biopsy and a possible resection. Intraoperative pathology result informed an epidermoid tumor, so we continued with the complete exeresis of the tumor. RESULTS: We achieved a complete resection of a third ventricle epidermoid cyst with a purely endoscopic supracerebellar-infratentorial approach and a skull base rigid endoscope in a 16 years old male patient. The patient has recovered without any sequelae, headaches free but persistence of diabetes insipidus (m-RS 1).Conclusion: The purely endoscopic supracerebellar-infratentorial approach is a safe option to the surgical management of third ventricle pathologies, in this case, an epydermoid cyst.

Craneofaringioma: resección paso a paso en un paciente pediátrico / Craniopharyngioma: Step-by-Step Resection in a Pediatric Patient

Introducción: Describir detalladamente paso a paso la resección de un craneofaringioma por vía endoscópica endonasal en un paciente pediátrico, con el fin de guiar a neurocirujanos en formación. Materiales y métodos: Se describe detalladamente la técnica endoscópica endonasal transesfenoidal para la resección de un tumor de estirpe craneofaringioma adamantinomatoso en un paciente masculino de 3 años de edad con la variante de seno esfenoidal tipo conchal. Resultados: Se logró resección total de un craneofaringioma en paciente pediátrico mediante abordaje endoscópico endonasal. Se respetaron las estructuras vasculares circundantes y se pudo prevenir la fístula de líquido cefalorraquídeo con la utilización del flap nasoseptal. Conclusión: El abordaje endoscópico endonasal transesfenoidal ofrece una exposición amplia de la región selar y supraselar permitiendo una excelente resección de los craneofaringiomas en pacientes pediátricos. Consideramos de importancia la curva de aprendizaje para lograr una resección máxima sin agregar comorbilidades al paciente.

Objective: To give a detailed description, step by step, of endoscopic endonasal resection for craniopharyngioma in a pediatric patient. This manuscript was made to teach neurosurgeons in their former years. Methods: Detailed description with intraoperative images from a complete resection of adamantinomatous craniopharyngioma in a 3 years-old patient with a conchal variant sphenoid sinus. Results: We achieved a gross total resection of a craniopharyngioma in a pediatric patient by endoscopic endonasal approach. We preserve the surrounding vascular structures with no comorbidities. Cerebrospinal leak was prevented by using the nasoseptal flap covering the sphenoid defect. Conclusion: The endoscopic endonasal approach offers a wide exposure of the selar and supraselar región. This allowed us a great possibility for complete resection in selar and supraselar craniopharyngiomas in pediatric population. We consider that maximal resection should be balanced with a good learning curve to avoid comorbidities.

Clipado microquirúrgico de aneurisma asistido por endoscopia / Microsurgical clipping of aneurysm assisted by endoscopy

Introducción: Las complicaciones postoperatorias secundarias al compromiso inadvertido de una arteria normal durante el clipado de aneurismas son situaciones que pueden resultar catastróficas tanto para el paciente como para el neurocirujano tratante. El terreno de la neurocirugía vascular continúa siendo un desafío para la neuroendoscopia, sin embargo, al momento de realizar el control del clipado puede llegar a ser un elemento sumamente útil para evitar dichas complicaciones. Objetivos: El Objetivo del Trabajo es la presentación de un clipado de aneurisma coroideo anterior asistido mediante endoscopia. Materiales y métodos: Paciente femenina de 23 años que presenta hemorragia subaracnoidea (Fisher 2 y Hunt-Hess 2) secundaria a rotura de aneurisma comunicante anterior (ACA). En angiografía digital cerebral se evidencia a su vez aneurisma coroideo anterior derecho (ACoA). Mediante abordaje pterional derecho se realiza clipado microquirúrgico de ambos aneurismas. Para realizar revisión del clip en ACoA se utiliza endoscopio rígido de base de cráneo (0° y 45°). Se evidencia compromiso de arteria coroidea anterior por lo cual se realiza recolocación del mismo mediante guía endoscópica. Resultados: Se realizó clipado microquirúrgico asistido por endoscopia de ACA y ACoA. La paciente curso postoperatorio con vasoespasmo prolongado y tercer par derecho incompleto (ptosis y midriasis). Actualmente persiste solo la midriasis, resto del examen neurológico sin particularidades. Conclusión: El uso del endoscopio para control y asistencia durante el clipado microquirúrgico es una herramienta sumamente útil que permite realizar una revisión cercana y adecuada de la posición del clip.

Background: Surgical complications secondary to undetected clipping of a main or perforator artery next to an aneurysm can lead to a catastrophic event for both the patient and vascular neurosurgeon. Neuro-endoscopy is difficult during vascular neurosurgery; however, for surgeons desiring a multi-modality check of vessels to ensure the patency of important arteries, endoscopy could be a very useful tool. Objective: The aim of the present report is to describe our results with endoscopy-assisted anterior choroidal aneurysm clipping in a single patient. Results: A 23-year-old female presented with a subarachnoid hemorrhage (SAH, Fisher 2, Hunt-Hess 2) secondary to a ruptured anterior communicating aneurysm (ACA). Digital angiography revealed an unruptured right anterior choroidal aneurysm (AChA). Surgical clipping via a right pterional approach was accomplished for both aneurysms. Clip position in the AChA was evaluated with a rigid skull-base endoscope (0° and 45°). It revealed accidental compromise of the AChA, so the clip was replaced under endoscopic guidance. Post-operatively, the patient experienced late vasospasm and a partial right third nerve palsy, manifested as ptosis and mydriasis. Currently, only the right mydriasis persists. Conclusions: In one patient with a SAH caused by a ruptured anterior communicating aneurysm, successful endoscopic-assisted surgical clipping of both the ruptured aneurism and an unruptured right anterior choroidal aneurysm was achieved.