Validation of Myc-Associated Protein X (MAX) regulation in growth hormone secreting and nonfunctional pituitary adenoma.

INTRODUCTION: Many patients with growth hormone-secreting pituitary adenoma (GHPA) fail to achieve biochemical remission, warranting investigation into epigenetic and molecular signatures associated with tumorigenesis and hormonal secretion. Prior work exploring the DNA methylome showed Myc-Associated Protein X (MAX), a transcription factor involved in cell cycle regulation, was differentially methylated between GHPA and nonfunctional pituitary adenoma (NFPA). We aimed to validate the differential DNA methylation and related MAX protein expression profiles between NFPA and GHPA. METHODS: DNA methylation levels were measured in 52 surgically resected tumors (37 NFPA, 15 GHPA) at ~100,000 known MAX binding sites derived using ChIP-seq analysis from ENCODE. Findings were correlated with MAX protein expression using a constructed tissue microarray (TMA). Gene ontology analysis was performed to explore downstream genetic and signaling pathways regulated by MAX. RESULTS: GHPA had more hypomethylation events across all known MAX binding sites. Of binding sites defined using ChIP-seq analysis, 1,551 sites had significantly different methylation patterns between the two cohorts; 432 occurred near promoter regions potentially regulated by MAX, including promoters of TNF and MMP9. Gene ontology analysis suggested enrichment in genes involved in oxygen response, immune system regulation, and cell proliferation. Thirteen MAX binding sites were within coding regions of genes. GHPA demonstrated significantly increased expression of MAX protein compared to NFPA. CONCLUSION: GHPA have significantly different DNA methylation and downstream protein expression levels of MAX compared to NFPA. These differences may influence mechanisms involved with cellular proliferation, tumor invasion and hormonal secretion.

Endoscopic assisted craniotomy for resection of fourth ventricular lesions and confirmation of aqueductal patency via a suboccipital median aperture approach.

Adequate exposure to fourth ventricular (4V) lesions located adjacent to the cerebral aqueduct and superior medullary velum often mandates extensive telovelar dissection. We assessed the utility of endoscopic assistance via a median aperture approach during suboccipital resection of 4V lesions. We retrospectively reviewed a series of nine patients who underwent suboccipital resection of a 4V lesion via an endoscopic-assisted median aperture approach from 2011 to 2018. Our series included the following pathology: ependymoma (2), rosette-forming glioneuronal tumors (2), pilocytic astrocytoma (1), metastatic melanoma (1), epidermoid cyst (1), organized hematoma (1), and neurocysticercosis (1). Preoperative symptoms included headache (n = 8, 88.9%), nausea (n = 5, 55.6%), vomiting, dizziness, and gait disturbance (n = 4 each, 44.5%). In four cases, the endoscope was used for the majority of the resection or to resect additional tumor located rostrally in the 4V following maximal microscopic resection. In five patients, it was used to confirm extent of resection and patency of the cerebral aqueduct. Gross total resection was achieved in five patients (55.6%). No postoperative complications were attributed to use of the endoscope for additional resection. No patients required immediate CSF diversion, and one patient underwent ventriculoperitoneal (VP) shunt insertion over one year after initial biopsy/fenestration due to tumor progression. Our series is the first to demonstrate the utility of angled endoscopic assistance via a median aperture approach during microsurgical approaches for a variety of 4V lesions. Confirmation of patency of the cerebral aqueduct may help avoid requirements for CSF diversion.

Global neurosurgery: a scoping review detailing the current state of international neurosurgical outreach.

OBJECTIVE: Global neurosurgery is a rapidly emerging field that aims to address the worldwide shortages in neurosurgical care. Many published outreach efforts and initiatives exist to address the global disparity in neurosurgical care; however, there is no centralized report detailing these efforts. This scoping review aims to characterize the field of global neurosurgery by identifying partnerships between high-income countries (HICs) and low- and/or middle-income countries (LMICs) that seek to increase neurosurgical capacity. METHODS: A scoping review was conducted using the Arksey and O'Malley framework. A search was conducted in five electronic databases and the gray literature, defined as literature not published through traditional commercial or academic means, to identify studies describing global neurosurgery partnerships. Study selection and data extraction were performed by four independent reviewers, and any disagreements were settled by the team and ultimately the team lead. RESULTS: The original database search produced 2221 articles, which was reduced to 183 final articles after applying inclusion and exclusion criteria. These final articles, along with 9 additional gray literature references, captured 169 unique global neurosurgery collaborations between HICs and LMICs. Of this total, 103 (61%) collaborations involved surgical intervention, while local training of medical personnel, research, and education were done in 48%, 38%, and 30% of efforts, respectively. Many of the collaborations (100 [59%]) are ongoing, and 93 (55%) of them resulted in an increase in capacity within the LMIC involved. The largest proportion of efforts began between 2005-2009 (28%) and 2010-2014 (17%). The most frequently involved HICs were the United States, Canada, and France, whereas the most frequently involved LMICs were Uganda, Tanzania, and Kenya. CONCLUSIONS: This review provides a detailed overview of current global neurosurgery efforts, elucidates gaps in the existing literature, and identifies the LMICs that may benefit from further efforts to improve accessibility to essential neurosurgical care worldwide.

Development and clinical validation of a grading system for pituitary adenoma consistency.

OBJECTIVE: Pituitary adenoma (PA) consistency, or texture, is an important intraoperative characteristic that may dictate operative dissection techniques and/or instruments used for tumor removal during endoscopic endonasal approaches (EEAs). The impact of PA consistency on surgical outcomes has yet to be elucidated. METHODS: The authors developed an objective 5-point grading scale for PA consistency based on intraoperative characteristics, including ease of tumor debulking, manipulation, and instrument selection, ranging from cystic/hemorrhagic tumors (grade 1) to calcified tumors (grade 5). The proposed grading system was prospectively assessed in 306 consecutive patients who underwent an EEA for PAs, and who were subsequently analyzed for associations with surgical outcomes, including extent of resection (EOR) and complication profiles. RESULTS: Institutional database review identified 306 patients who underwent intraoperative assessment of PA consistency, of which 96% were macroadenomas, 70% had suprasellar extension, and 44% had cavernous sinus invasion (CSI). There were 214 (69.9%) nonfunctional PAs and 92 functional PAs (31.1%). Distribution of scores included 15 grade 1 tumors (4.9%), 112 grade 2 tumors (36.6%), 125 grade 3 tumors (40.8%), 52 grade 4 tumors (17%), and 2 grade 5 tumors (0.7%). Compared to grade 1/2 and grade 3 PAs, grade 4/5 PAs were significantly larger (22.5 vs 26.6 vs 27.4 mm, p < 0.01), more likely to exhibit CSI (39% vs 42% vs 59%, p < 0.05), and trended toward nonfunctionality (67% vs 68% vs 82%, p = 0.086). Although there was no association between PA consistency and preoperative headaches or visual dysfunction, grade 4/5 PAs trended toward preoperative (p = 0.058) and postoperative panhypopituitarism (p = 0.066). Patients with preoperative visual dysfunction experienced greater improvement if they had a grade 1/2 PA (p < 0.05). Intraoperative CSF leaks were noted in 32% of cases and were more common with higher-consistency-grade tumors (p = 0.048), although this difference did not translate to postoperative CSF leaks. Gross-total resection (%) was more likely with lower PA consistency score as follows: grade 1/2 (60%), grade 3 (50%), grade 4/5 (44%; p = 0.045). Extracapsular techniques were almost exclusively performed in grade 4/5 PAs. Assignment of scores showed low variance and high reproducibility, with an intraclass correlation coefficient of 0.905 (95% CI 0.815-0.958), indicating excellent interrater reliability. CONCLUSIONS: These findings demonstrate clinical validity of the proposed intraoperative grading scale with respect to PA subtype, neuroimaging features, EOR, and endocrine complications. Future studies will assess the relation of PA consistency to preoperative MRI findings to accurately predict consistency, thereby allowing the surgeon to tailor the exposure and prepare for varying resection strategies.

Differential Clinical Presentation, Intraoperative Management Strategies, and Surgical Outcomes After Endoscopic Endonasal Treatment of Cystic Sellar Masses.

BACKGROUND: Cystic sellar masses (CSMs) pose diagnostic and therapeutic challenges associated with subtotal cyst wall resection, cerebrospinal fluid (CSF) leak repair, and disease recurrence. Current magnetic resonance imaging (MRI) interpretation often cannot reliably differentiate CSMs, mandating adaptable intraoperative strategies. We reviewed our diagnostic and therapeutic experience after endoscopic endonasal approaches (EEAs) for CSMs. METHODS: A retrospective record review of patients with CSM managed via EEA at the University of Southern California from 2011 to 2018 was conducted. Patient demographics, preoperative characteristics, surgical details, pathologic findings, and postoperative outcomes were assessed. RESULTS: Analysis included 47 patients (mean age, 43.2 years); of these, 78.7% were women. Preoperative symptoms included headache (76.6%) and vision loss (42.6%). Histologically verified sellar pathology included 27 Rathke cleft cysts (RCCs) (57.4%), 17 cystic pituitary adenomas (CPAs) (36.2%), 2 arachnoid cysts (4.3%), and 1 xanthogranuloma (2.1%). Twelve patients (70.6%) with CPAs underwent complete resection and 5 (29.4%) underwent subtotal resection. All 27 patients with RCC and 2 patients with arachnoid cyst underwent complete fenestration and drainage. One xanthogranuloma was completely resected. There were 14 intraoperative (29.8%) and 4 postoperative CSF leaks (8.5%). Headaches, vision, and endocrinopathy improved in 69.2%, 80.0%, and 33.3% of patients with CPA and 73.9%, 71.4%, and 40.9% of patients with RCC, respectively. There were 2 RCC recurrences and 1 CPA recurrence over the follow-up period. CONCLUSIONS: Surgeons must prepare for versatile management strategies of CSMs based on pretest probability associated with MRI and intraoperative findings. Outcomes after EEA for CSMs show low complication profiles and excellent rates of headache and visual improvement, albeit lower rates of endocrine normalization.