Artificial intelligence innovations in neurosurgical oncology: a narrative review.

PURPOSE: Artificial Intelligence (AI) has become increasingly integrated clinically within neurosurgical oncology. This report reviews the cutting-edge technologies impacting tumor treatment and outcomes. METHODS: A rigorous literature search was performed with the aid of a research librarian to identify key articles referencing AI and related topics (machine learning (ML), computer vision (CV), augmented reality (AR), virtual reality (VR), etc.) for neurosurgical care of brain or spinal tumors. RESULTS: Treatment of central nervous system (CNS) tumors is being improved through advances across AI-such as AL, CV, and AR/VR. AI aided diagnostic and prognostication tools can influence pre-operative patient experience, while automated tumor segmentation and total resection predictions aid surgical planning. Novel intra-operative tools can rapidly provide histopathologic tumor classification to streamline treatment strategies. Post-operative video analysis, paired with rich surgical simulations, can enhance training feedback and regimens. CONCLUSION: While limited generalizability, bias, and patient data security are current concerns, the advent of federated learning, along with growing data consortiums, provides an avenue for increasingly safe, powerful, and effective AI platforms in the future.

Development and prospective validation of an artificial intelligence-based smartphone app for rapid intraoperative pituitary adenoma identification.

BACKGROUND: Intraoperative pathology consultation plays a crucial role in tumor surgery. The ability to accurately and rapidly distinguish tumor from normal tissue can greatly impact intraoperative surgical oncology management. However, this is dependent on the availability of a specialized pathologist for a reliable diagnosis. We developed and prospectively validated an artificial intelligence-based smartphone app capable of differentiating between pituitary adenoma and normal pituitary gland using stimulated Raman histology, almost instantly. METHODS: The study consisted of three parts. After data collection (part 1) and development of a deep learning-based smartphone app (part 2), we conducted a prospective study that included 40 consecutive patients with 194 samples to evaluate the app in real-time in a surgical setting (part 3). The smartphone app's sensitivity, specificity, positive predictive value, and negative predictive value were evaluated by comparing the diagnosis rendered by the app to the ground-truth diagnosis set by a neuropathologist. RESULTS: The app exhibits a sensitivity of 96.1% (95% CI: 89.9-99.0%), specificity of 92.7% (95% CI: 74-99.3%), positive predictive value of 98% (95% CI: 92.2-99.8%), and negative predictive value of 86.4% (95% CI: 66.2-96.8%). An external validation of the smartphone app on 40 different adenoma tumors and a total of 191 scanned SRH specimens from a public database shows a sensitivity of 93.7% (95% CI: 89.3-96.7%). CONCLUSIONS: The app can be readily expanded and repurposed to work on different types of tumors and optical images. Rapid recognition of normal versus tumor tissue during surgery may contribute to improved intraoperative surgical management and oncologic outcomes. In addition to the accelerated pathological assessments during surgery, this platform can be of great benefit in community hospitals and developing countries, where immediate access to a specialized pathologist during surgery is limited.

In tumor surgery, precise identification of abnormal tissue during surgical removal of the tumor is paramount. Traditional methods rely on the availability of specialized pathologists for a reliable diagnosis, which could be a limitation in many hospitals. Our study introduces a user-friendly smartphone app that quickly and precisely diagnoses pituitary tumors, powered by artificial intelligence (AI), which is the simulation of human intelligence in machines for tasks like learning, reasoning, problem-solving, and decision-making. Through data collection, app development, and validation, our findings demonstrate that the app can rapidly and accurately identify tumors in real-time. External validation further confirmed its effectiveness in detecting tumor tissue collected from a different source. This AI-driven app could contribute to elevating surgical precision, particularly in settings lacking immediate access to specialized pathologists.

Automated Preoperative and Postoperative Volume Estimates Risk of Retreatment in Chronic Subdural Hematoma: A Retrospective, Multicenter Study.

BACKGROUND AND OBJECTIVES: Several neurosurgical pathologies, ranging from glioblastoma to hemorrhagic stroke, use volume thresholds to guide treatment decisions. For chronic subdural hematoma (cSDH), with a risk of retreatment of 10%-30%, the relationship between preoperative and postoperative cSDH volume and retreatment is not well understood. We investigated the potential link between preoperative and postoperative cSDH volumes and retreatment. METHODS: We performed a retrospective chart review of patients operated for unilateral cSDH from 4 level 1 trauma centers, February 2009-August 2021. We used a 3-dimensional deep learning, automated segmentation pipeline to calculate preoperative and postoperative cSDH volumes. To identify volume thresholds, we constructed a receiver operating curve with preoperative and postoperative volumes to predict cSDH retreatment rates and selected the threshold with the highest Youden index. Then, we developed a light gradient boosting machine to predict the risk of cSDH recurrence. RESULTS: We identified 538 patients with unilateral cSDH, of whom 62 (12%) underwent surgical retreatment within 6 months of the index surgery. cSDH retreatment was associated with higher preoperative (122 vs 103 mL; P < .001) and postoperative (62 vs 35 mL; P < .001) volumes. Patients with >140 mL preoperative volume had nearly triple the risk of cSDH recurrence compared with those below 140 mL, while a postoperative volume >46 mL led to an increased risk for retreatment (22% vs 6%; P < .001). On multivariate modeling, our model had an area under the receiver operating curve of 0.76 (95% CI: 0.60-0.93) for predicting retreatment. The most important features were preoperative and postoperative volume, platelet count, and age. CONCLUSION: Larger preoperative and postoperative cSDH volumes increase the risk of retreatment. Volume thresholds may allow identification of patients at high risk of cSDH retreatment who would benefit from adjunct treatments. Machine learning algorithm can quickly provide accurate estimates of preoperative and postoperative volumes.

Interaction of admission platelet count with current medications and the risk for chronic subdural recurrence.

OBJECTIVE: Chronic subdural hematoma (cSDH) has a reported 10%-24% rate of recurrence after surgery, and prognostic models for recurrence have produced equivocal results. The objective of this study was to leverage a data mining algorithm, chi-square automatic interaction detection (CHAID), which can incorporate continuous, nominal, and binary data into a decision tree, to identify the most robust predictors of repeat surgery for cSDH patients. METHODS: This was a retrospective cohort study of all patients with SDH from two level 1 trauma centers at a single institution. All patients underwent cSDH evacuation performed by 15 neurosurgeons between 2011 and 2020. The primary outcome was the rate of repeat surgery for recurrent cSDH following the initial evacuation. The authors used CHAID to identify relevant predictors of repeat surgery, including age, sex, comorbidities, postsurgical complications, platelet count prior to the first procedure, midline shift prior to the first procedure, hematoma volume, and preoperative use of anticoagulants, antiplatelets, or statins. RESULTS: Sixty (13.8%) of 435 study-eligible patients (average age 74.0 years) had a cSDH recurrence. These patients had 2.0 times greater odds of having used anticoagulants. The final CHAID model had an overall accuracy of 87.4% and an area under the curve of 0.76. According to the model, the predictor with the strongest association with cSDH recurrence was admission platelet count. Approximately 26% of patients (n = 23/87) with an admission platelet count < 157 × 109/L had a cSDH recurrence, whereas none of the 44 patients with admission platelets > 313 × 109/L had a recurrence. Approximately 17% of patients in the 157-313 × 109/L platelet group who had used preoperative statins required a second procedure, which was associated with a 2.3 times increased risk for repeat surgery compared to those who had not used statins preoperatively. Among those who had not used preoperative statins, a platelet count ≤ 179 × 109/L on admission for the first procedure was the strongest differentiator for a second surgery (n = 5/22 [23%]), which increased the risk of recurrence by 4.5 times. Among the patients using preoperative statins, the use of anticoagulants was the strongest differentiator for requiring repeat surgery (n = 11/33 [33%]). CONCLUSIONS: The described model identified platelet count on admission as the most important predictor of repeat cSDH surgery, followed by preoperative statin use and anticoagulant use. Critical cutoffs for platelet count were identified, which future studies should evaluate to determine if they are modifiable or reflective of underlying disease states.

Outcomes and Treatment Algorithm in Glioblastoma Patients 80 Years and Older.

OBJECTIVE: The current standard of care for patients with glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy with concurrent temozolomide chemotherapy. Previous studies that identified this treatment regimen focused on younger patients with GBM. The proportion of patients with GBM over the age of 80 years is increasing. We investigate whether elderly patients benefit from the current standard of care with additional maximal safe resection. METHODS: Clinical, operative, radiographic, demographic, genetic, and outcomes data were retrospectively collected for patients treated for histologically confirmed World Health Organization grade 4 GBM at University of Pittsburgh Medical Center from 2009 to 2020. Only patients 80 years and older were included (n = 123). Statistically significant values were set at P < 0.05. RESULTS: A univariate Cox proportional hazards analysis of GBM patients aged >80 years identified the use of temozolomide, radiation, Karnofsky Performance Status (KPS) > 70, and methylguanine DNA methyltransferase methylation with increased overall survival (OS). Further multivariate Cox proportional hazards model analysis showed that the variables identified in the univariate analysis passed multicollinearity testing, and that use of temozolomide, KPS >70, and gross total resection were shown to significantly impact survival. Survival analysis showed that patients with biopsy alone had a shorter median OS compared with patients who received resection, temozolomide, and radiation (P < 0.0001, median OS 1.6 vs. 7.5 months). Additionally, patients who underwent biopsy and then received temozolomide and radiation had a shorter median OS when compared with patients who received resection, temozolomide, and radiation (P = 0.0047, median OS 3.6 vs. 7.5 months). CONCLUSIONS: For elderly patients with KPS >70, GTR followed by radiation and temozolomide is associated with maximum OS.

Advances in surgical approaches for refractory pituitary adenomas.

Refractory pituitary adenomas are difficult to control tumors that progress through optimal surgical, medical, and radiation management. Repeat surgery is a valuable tool to reduce tumor volume for more effective radiation and/or medical therapy, and to decompress critical neurovascular structures. Advances in surgical techniques and technologies, including minimally invasive cranial approaches, intraoperative MRI suites, and cranial nerve monitoring, have improved surgical outcomes and expanded indications. Today, repeat transsphenoidal surgery has similar complications rates to upfront surgery in historical cohorts. The decision to operate on refractory adenomas should be made with multidisciplinary teams, balancing the benefit of tumor reduction with the potential for complications, including cranial nerve injury, carotid injury, and cerebrospinal fluid leak.

Radiosurgery outcomes in infratentorial juvenile pilocytic astrocytomas.

PURPOSE: To assess survival and neurological outcomes for patients who underwent primary or salvage stereotactic radiosurgery (SRS) for infratentorial juvenile pilocytic astrocytomas (JPA). METHODS: Between 1987 and 2022, 44 patients underwent SRS for infratentorial JPA. Twelve patients underwent primary SRS and 32 patients underwent salvage SRS. The median patient age at SRS was 11.6 years (range, 2-84 years). Prior to SRS, 32 patients had symptomatic neurological deficits, with ataxia as the most common symptom in 16 patients. The median tumor volume was 3.22 cc (range, 0.16-26.6 cc) and the median margin dose was 14 Gy (range, 9.6-20 Gy). RESULTS: The median follow-up was 10.9 years (range, 0.42-26.58 years). Overall survival (OS) after SRS was 97.7% at 1-year, and 92.5% at 5- and 10-years. Progression free survival (PFS) after SRS was 95.4% at 1-year, 79.0% at 5-years, and 61.4% at 10-years. There is not a significant difference in PFS between primary and salvage SRS patients (p = 0.79). Younger age correlated with improved PFS (HR 0.28, 95% CI 0.063-1.29, p = 0.021). Sixteen patients (50%) had symptomatic improvements while 4 patients (15.6%) had delayed onset of new symptoms related to tumor progression (n = 2) or treatment related complications (n = 2). Tumor volumetric regression or disappearance after radiosurgery was found in 24 patients (54.4%). Twelve patients (27.3%) had delayed tumor progression after SRS. Additional management of tumor progression included repeat surgery, repeat SRS, and chemotherapy. CONCLUSIONS: SRS was a valuable alternative to initial or repeat resection for deep seated infratentorial JPA patients. We found no survival differences between patients who had primary and salvage SRS.

Mice lacking proSAAS display alterations in emotion, consummatory behavior and circadian entrainment.

ProSAAS is a neuroendocrine protein that is cleaved by neuropeptide-processing enzymes into more than a dozen products including the bigLEN and PEN peptides, which bind and activate the receptors GPR171 and GPR83, respectively. Previous studies have suggested that proSAAS-derived peptides are involved in physiological functions that include body weight regulation, circadian rhythms and anxiety-like behavior. In the present study, we find that proSAAS knockout mice display robust anxiety-like behaviors in the open field, light-dark emergence and elevated zero maze tests. These mutant mice also show a reduction in cued fear and an impairment in fear-potentiated startle, indicating an important role for proSAAS-derived peptides in emotional behaviors. ProSAAS knockout mice exhibit reduced water consumption and urine production relative to wild-type controls. No differences in food consumption and overall energy expenditure were observed between the genotypes. However, the respiratory exchange ratio was elevated in the mutants during the light portion of the light-dark cycle, indicating decreased fat metabolism during this period. While proSAAS knockout mice show normal circadian patterns of activity, even upon long-term exposure to constant darkness, they were unable to shift their circadian clock upon exposure to a light pulse. Taken together, these results show that proSAAS-derived peptides modulate a wide range of behaviors including emotion, metabolism and the regulation of the circadian clock.

Successful management of an intraluminal superior sagittal sinus meningioma causing elevated intracranial pressure using gamma knife radiosurgery in subacute setting: A case report.

BACKGROUND: Gamma Knife stereotactic radiosurgery (GKRS) facilitates precisely focused radiation to an intracranial target while minimizing substantial off-target radiation in the surrounding normal tissue. Meningiomas attached to or invading the superior sagittal sinus may result in sinus occlusion and are often impossible to completely resect safely. The authors describe successful management of a patient with a meningioma located completely inside the posterior aspect of the superior sagittal sinus. CASE DESCRIPTION: A 46-year-old woman presented to the emergency department with progressive generalized headaches accompanied by worsening vision. The patient underwent a diagnostic brain magnetic resonance imaging which showed a solitary a 7 × 6 × 10 mm homogeneously contrast-enhancing lesion within the lumen of the posterior aspect of superior sagittal sinus without ventricular enlargement or peritumoral edema. The lesion was thought to be a meningioma radiographically. To evaluate the suspected increased intracranial pressure, a lumbar puncture was subsequently performed and demonstrated an opening pressure of 30 cm H2O. After drainage of 40 cc of CSF, the spinal closing pressure was 9 cm H2O. After failure of conservative management with acetazolamide, and determination of surgical inoperability due to the critical intraluminal location of the mass lesion, the patient underwent Gamma Knife radiosurgery. The 0.36 cc tumor was treated as an outpatient in the Perfexion® model Gamma Knife with a highly conformal and selective plan that enclosed the 3D geometry of the tumor with a minimal margin tumor dose of 14 gy at the 50% isodose. Three months after GKRS, the patient reported continued reduction in the frequency and severity of both her headaches and her visual disturbance. Ophthalmological consultation noted progressive resolution of her optic disc edema confirmed by formal optical coherence tomography. The patient is now 3 years out from GKRS with complete resolution of headache symptoms along with persistent reduction in tumor size (3 × 1 × 4 mm) on serial period imaging and resolution of papilledema. CONCLUSION: Tumors located in such critical anatomic regions, as in our patient, should be considered for primary GKRS when the risks of biopsy or removal are too high. GKRS was able to provide great radiographic and clinical result in an intricately located meningioma.

A contemporary update on glioblastoma: molecular biology, current management, and a vision towards bio-adaptable personalized care.

INTRODUCTION: Glioblastoma (GBM) is the most fatal brain tumor in adults. Current survival rates of GBM remain below 2 years due to GBM's aggressive cellular migration and genetically driven treatment escape pathways. Despite our rapidly increasing understanding of GBM biology, earlier diagnoses, and refined surgical techniques, only moderate survival benefits have been achieved. Nonetheless, the pressing need for better survival rates has brought forward a multitude of newer therapeutic approaches and opened the door for potential personalization of these modalities in the near future. METHODS: We reviewed the published literature discussing the current state of knowledge regarding GBM biology and therapy and summarized the information that may point toward future personalized therapeutic strategies. RESULTS: Several novel modalities such as oncolytic viruses, targeted immune, and molecular therapies, and tumor treating fields have been introduced. To date, there is no single treatment modality for GBM, but rather a wide spectrum of combined modalities that address intratumoral cellular and genetic variabilities. While the current state of GBM research and clinical trial landscape may hold promise, current literature lacks any fruitful progress towards personalized GBM therapy. CONCLUSION: In this review, we are discussing our recent knowledge of the GBM genetic biologic landscape and the current advances in therapy, as well as providing a blueprint for an envisioned GBM management paradigm that should be personalized and adaptable to accommodate each patient's diverse genetic variations and therapy response/escape patterns.

Associations of meningioma molecular subgroup and tumor recurrence.

BACKGROUND: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients. METHODS: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling. RESULTS: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence. CONCLUSION: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.

Long term results of primary radiosurgery for vestibular schwannomas.

BACKGROUND: Stereotactic radiosurgery (SRS) has become a primary option for management for both newly diagnosed vestibular schwannomas (VS), as well as VS that enlarge after initial observation. METHODS: A retrospective review of our prospectively maintained data base found 871 patients who underwent Gamma knife® SRS as their initial (primary) management between 1987 and 2008. Follow-up ranged from 1-25 years (median = 5.2 years) Median tumor volume was 0.9 cc (0.02-36) and median margin dose was 13 Gy (12-25). RESULTS: Progression free survival (PFS) after SRS was 97% at 3 years, 95% at 5 years, and 94% at 10 years. Freedom from delayed surgical resection was found in 98.7% of patients. Smaller tumor volume was significantly associated with improved PFS. There were 326 patients with serviceable hearing (Gardner-Robertson 1 or 2) at the time of SRS with audiological follow-up of ≥ 1 year. Serviceable hearing preservation rates after SRS were 89.8% at 1 year, 76.9% at 3 years, 68.4% at 5 years, 62.5% at 7 years, and 51.4% at 10 years. Factors associated with improved serviceable hearing preservation included younger age, Gardner-Robertson grade 1 at SRS, and absence of subjective complaints of dysequilibrium or vertigo (vestibulopathy). Fifty-one patients (5.8%) developed trigeminal neuropathy. Fourteen (1.6%) developed a transient House-Brackmann grade 2 or 3 facial neuropathy. CONCLUSIONS: In this report with extended follow-up, primary SRS achieved tumor growth control in 94% of patients. Optimization of long- term cranial nerve outcomes remains an important achievement of this management strategy for VS.

Case Series: Pediatric Shunt Tunnel Catheter Infection.

Shunt infections are common pediatric neurosurgical cases with high morbidity that almost always requires surgical removal of the shunt, external ventricular drain placement, and delayed shunt replacement. Tunnel infections are well-described clinical entities occurring with indwelling catheters, whereby the indwelling tunnel portion of a line becomes externally infected with a sterile central lumen. These infections are typically treated with line replacement or antibiotics depending on clinical circumstances. We describe 2 cases of shunt tunnel infection. Both cases presented as erythema over the thoracic portion of the shunt without signs of CNS infection, with only a remote history of shunt surgery and no recent systemic illness. One case was treated with a course of antibiotics, and the other with surgical removal and eventual replacement. Both children made full recoveries. Our case series juxtaposes 2 alternative successful strategies for treating the rare entity of shunt tunnel infection.

Gamma Knife Radiosurgery for Trigeminal Neuralgia Caused by a Cavernous Malformation: Case Report and Literature Review.

OBJECTIVE: Trigeminal neuralgia (TN) related to a brainstem cavernous malformation (CM) is a rare entity. We present the first radiosurgical management of a patient with TN secondary to a CM. CLINICAL PRESENTATION: An 80-year-old female presented with a 33-year history of progressively severe TN refractory to medications. Imaging confirmed a solitary CM located at the pontine dorsal root entry zone of cranial nerve 5. TREATMENT: Stereotactic radiosurgery of the trigeminal nerve was performed using the Leksell gamma knife. A single 4-mm isocenter of radiation was focused on the trigeminal nerve and a maximum dose of 80 Gy (40 Gy at the 50% isodose line) was delivered to the nerve. RESULTS: At 1 year, the patient noted that the severe pain attacks had been reduced by 75%, although a background lingering discomfort persisted. Pain suppression medications had been significantly reduced to lamotrigine 100 mg twice daily. Her preoperative distribution of sensory dysfunction mildly increased. CONCLUSION: For medically refractory TN related to a CM, radiosurgery of the afferent nerve may ameliorate pain without a major decrease in sensation. The more than 30-year history of pain in our patient may have reduced the chance of more significant pain relief.

Supraorbital Versus Endoscopic Endonasal Approaches for Olfactory Groove Meningiomas: A Cost-Minimization Study.

OBJECTIVE: To perform a cost-minimization study comparing the supraorbital and endoscopic endonasal (EEA) approach with or without craniotomy for the resection of olfactory groove meningiomas (OGMs). METHODS: We built a decision tree using probabilities of gross total resection (GTR) and cerebrospinal fluid (CSF) leak rates with the supraorbital approach versus EEA with and without additional craniotomy. The cost (not charge or reimbursement) at each "stem" of this decision tree for both surgical options was obtained from our hospital's finance department. After a base case calculation, we applied plausible ranges to all parameters and carried out multiple 1-way sensitivity analyses. Probabilistic sensitivity analyses confirmed our results. RESULTS: The probabilities of GTR (0.8) and CSF leak (0.2) for the supraorbital craniotomy were obtained from our series of 5 patients who underwent a supraorbital approach for the resection of an OGM. The mean tumor volume was 54.6 cm3 (range, 17-94.2 cm3). Literature-reported rates of GTR (0.6) and CSF leak (0.3) with EEA were applied to our economic analysis. Supraorbital craniotomy was the preferred strategy, with an expected value of $29,423, compared with an EEA cost of $83,838. On multiple 1-way sensitivity analyses, supraorbital craniotomy remained the preferred strategy, with a minimum cost savings of $46,000 and a maximum savings of $64,000. Probabilistic sensitivity analysis found the lowest cost difference between the 2 surgical options to be $37,431. CONCLUSION: Compared with EEA, supraorbital craniotomy provides substantial cost savings in the treatment of OGMs. Given the potential differences in effectiveness between approaches, a cost-effectiveness analysis should be undertaken.

Top 50 most-cited articles on craniovertebral junction surgery.

BACKGROUND: Craniovertebral junction is a complex anatomical location posing unique challenges to the surgical management of its pathologies. We aimed to identify the fifty most-cited articles that are dedicated to this field. METHODS: A keyword search using the Thomson Reuters Web of Knowledge was conducted to identify articles relevant to the field of craniovertebral junction surgery. The articles were reviewed based on title, abstract, and methods, if necessary, and then ranked based on the total number of citations to identify the fifty most-cited articles. Characteristics of the articles were determined and analyzed. RESULTS: The earliest top-cited article was published in 1948. When stratified by decade, 1990s was the most productive with 16 articles. The most-cited article was by Anderson and Dalonzo on a classification of odontoid fractures. By citation rate, the most-cited article was by Herms and Melcher who described Goel's technique of atlantoaxial fixation using C1 lateral mass screws and C2 pedicle screws with rod fixation. Atlantoaxial fixation was the most common topic. The United States, Barrow Neurological Institute, and VH Sonntag were the most represented country, institute, and author, respectively. The significant majority of articles were designed as case series providing level IV evidence. CONCLUSION: Using citation analysis, we have provided a list of the most-cited articles representing important contributions of various authors from many institutions across the world to the field of craniovertebral junction surgery.

A pilot genome-scale profiling of DNA methylation in sporadic pituitary macroadenomas: association with tumor invasion and histopathological subtype.

Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, P = 0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel KCNAB2 (FDR = 5.11×10-10). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of KCNAB2 and downstream ion-channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs.

The role of epigenetic modification in tumorigenesis and progression of pituitary adenomas: a systematic review of the literature.

BACKGROUND: Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression. METHODS: A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed. RESULTS: Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (CDKN2A, GADD45y, FGFR2, caspase-8, and PTAG) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (CDKN2A; DAPK; Rb1), sex (MAGE-A3), tumor size (GNAS1), and histopathological subtype (CDKN2A; MEG3; p27; RASSF1A; Rb1). CONCLUSIONS: Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.

A review of epigenetic and gene expression alterations associated with intracranial meningiomas.

OBJECT: A more comprehensive understanding of the epigenetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide useful targets for molecular classification and development of targeted therapies for meningiomas. METHODS: The authors performed a review of the current literature to identify the epigenetic modifications associated with the formation and/or progression of meningiomas. RESULTS: Several epigenomic alterations, mainly pertaining to DNA methylation, have been associated with meningiomas. Hypermethylation of TIMP3 inactivates its tumor suppression activity while CDKN2 (p14[ARF]) and TP73 gene hypermethylation and HIST1H1c upregulation interact with the p53 regulation of cell cycle control. Other factors such as HOX, IGF, WNK2, and TGF-ß epigenetic modifications allow either upregulation or downregulation of critical pathways for meningioma development, progression, and recurrence. CONCLUSIONS: Genome-wide methylation profiling demonstrated that global hypomethylation correlates with tumor grades and severity. Identification of additional epigenetic changes, such as histone modification and higher-order chromosomal structure, may allow for a more thorough understanding of tumorigenesis and enable future individualized treatment strategies for meningiomas.

Diagnosis and surgical management of traumatic cerebrospinal fluid oculorrhea: case report and systematic review of the literature.

Background Oculorrhea, or cerebrospinal fluid leakage developing from a cranio-orbital fistula, is a rare development following traumatic injury. Case Report A 22-year-old man involved in a motor vehicle accident developed a blowout fracture of the left orbital roof penetrating the frontal lobe, inducing oculorrhea. He underwent a supraorbital craniotomy for removal of the bony fragment and skull base reconstruction using a pericranial flap. Methods A systematic review of the database was performed to identify all prior cases of traumatic oculorrhea. Results Twenty-two reported cases met inclusion criteria for subsequent analysis. Oculorrhea developed due to blunt and penetrating head injury in 14 (64%) and 8 patients (36%), respectively. The most common mechanisms were car accidents, stab wounds, falls, and gunshot wounds. Ocular signs and symptoms-including visual loss, ophthalmoplegia, and pupillary dysfunction-were commonly associated findings. Initial conservative management was successful in four patients. Thirteen patients underwent initial surgical intervention, and three additional patients required operative intervention following failed conservative treatment. Conclusion Although oculorrhea rarely develops following severe orbital trauma, suspicion should nevertheless be maintained to facilitate more prompt diagnosis and management. The decision for conservative versus surgical management often depends on the severity of the fracture and dural injury.