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Michael Karsy, Brian Burnett, Antonio Di Ieva, Michael D. Cusimano and Randy L. Jensen

OBJECTIVE

Quantitative assessment of tumor microvascularity has the potential to improve prognostication, advance understanding of tumor biology, and help narrow potential molecular therapies. While the role of tumor microvascularity has been widely studied in meningiomas, this study examines both the role of automated measurements and the impact on surgical outcome.

METHODS

Two hundred seven patients with Grade I meningiomas underwent surgery between 1996 and 2011. Tissue samples from each patient were retrospectively evaluated for histopathological measures of microvascularity, including staining for von Willebrand factor (vWF), CD31, CD105, hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor, glucose transporter 1, and carbonic anhydrase IX. Manual methods of assessing microvascularity were supplemented by a computational analysis of the microvascular patterns by means of fractal analysis. MIB-1 proliferation staining was also performed on the same tumors. These measures were compared with various patient characteristics, tumor volume, estimated blood loss (EBL) during surgery, progression-free survival (PFS), and overall survival (OS).

RESULTS

The mean patient age was 55.4 ± 14.8 years, and 63 (30.4%) patients were male. Patients harboring tumors ≥ 3 cm were significantly older (56.9 ± 15.2 years vs 53.1 ± 13.6 years; p = 0.07), more frequently male (40.8% vs 14.6%; p = 0.0001), and had greater EBL (446.5 ± 532.2 ml vs 185.4 ± 197.2 ml; p = 0.0001), greater tumor volume (33.9 ± 38.1 ml vs 29.4 ± 23.5 ml; p = 0.0001), higher MIB-1 index values (3.0% ± 5.4% vs 1.7% ± 1.7%; p = 0.03), higher vWF levels (85.6% ± 76.9% vs 54.1% ± 52.4%; p = 0.001), lower HIF-1 expression (1.4 ± 1.3 vs 2.2 ± 1.4; p = 0.004), and worse OS (199.9 ± 7.6 months vs 180.8 ± 8.1 months; p = 0.05) than patients with tumors < 3 cm. In the multivariate logistic regression, MIB-1 (OR 1.14; p = 0.05), vWF (OR 1.01; p = 0.01), and HIF-1 (OR 1.54; p = 0.0001) significantly predicted tumor size. Although multiple factors were predictive of EBL in the univariate linear regression, only vWF remained significant in the multivariate analysis (β = 0.39; p = 0.004). Lastly, MIB-1 was useful via Kaplan-Meier survival analysis for predicting patients with disease progression, whereby an MIB-1 cutoff value of ≥ 3% conferred a 36% sensitivity and 82.5% specificity in predicting disease progression; an MIB-1 value ≥ 3% showed significantly shorter mean PFS (140.1 ± 11.7 months vs 179.5 ± 7.0 months; log-rank test, p = 0.05). The Cox proportional hazards model showed a trend for MIB-1 in predicting disease progression in a hazards model (OR 1.08; 95% CI 0.99–1.19; p = 0.08).

CONCLUSIONS

These results support the importance of various microvascularity measures in predicting preoperative (e.g., tumor size), intraoperative (e.g., EBL), and postoperative (e.g., PFS and OS) outcomes in patients with Grade I meningiomas. An MIB-1 cutoff value of 3% showed good specificity for predicting tumor progression. The predictive ability of various measures to detect aberrant tumor microvasculature differed, possibly reflecting the heterogeneous underlying biology of meningiomas. It may be necessary to combine assays to understand angiogenesis in meningiomas.

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Spencer Twitchell, Michael Karsy, Jian Guan, William T. Couldwell and Philipp Taussky

The term “radiation vasculopathy” defines a heterogeneous and poorly defined complex of vessel injury due to radiation. Radiation vasculopathy remains underrecognized and poorly treated with respect to head and neck radiotherapy. Distinct injury patterns to small (≤ 100-μm), medium (> 100-μm), and large (> 500-μm) vessels can occur, resulting in carotid stenosis, intracranial stenosis, and vascular anomalies (e.g., cavernous malformations, aneurysms). Because of the lack of clinical evidence and guidelines, treatment plans involve medical management, carotid endarterectomy, and carotid artery stenting and are developed on a patient-by-patient basis. In this review, the authors discuss the current pathophysiology, imaging, clinical impact, and potential treatment strategies of radiation vasculopathy with clinical pertinence to practicing neurosurgeons and neurologists. A review of 4 patients with prior head and neck tumors in whom delayed radiation vasculopathy developed after radiotherapy demonstrates the application of various treatment options in a case-by-case manner. Earlier recognition of radiation vasculopathy disease patterns may enable earlier initiation of treatment and monitoring for complications. Standardized terminology and treatments may assist with improving clinical outcomes.

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Vijay M. Ravindra, Michael Karsy, Richard H. Schmidt, Philipp Taussky, Min S. Park and Robert J. Bollo

The authors report the case of a previously healthy 6-month-old girl who presented with right arm and leg stiffening consistent with seizure activity. An initial CT scan of the head demonstrated acute subarachnoid hemorrhage in the basal cisterns extending into the left sylvian fissure. Computed tomography angiography demonstrated a 7 × 6 × 5–mm saccular aneurysm of the inferior M2 division of the left middle cerebral artery. The patient underwent left craniotomy and microsurgical clip ligation with wrapping of the aneurysm neck because the vessel appeared circumferentially dysplastic in the region of the aneurysm. Postoperative angiography demonstrated a small remnant, sluggish distal flow, but no significant cerebral vasospasm. Fifty-five days after the initial aneurysm rupture, the patient presented again with an acute intraparenchymal hemorrhage of the left anterior temporal lobe. Angiogram revealed a circumferentially dysplastic superior division of the M2 branch, with a new 5 × 4–mm saccular aneurysm distinct from the first, with 2 smaller aneurysms distal to the new ruptured aneurysm. Endovascular parent vessel occlusion with Onyx was performed. Genetic testing revealed a mutation of the MYH11. To the authors' knowledge, this is the first report of rapid de novo aneurysm formation in an infant with an MYH11 mutation. The authors review the patient's clinical presentation and management and comprehensively review the literature on this topic.

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Michael Karsy, Jian Guan and L. Eric Huang

OBJECTIVE

Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.

METHODS

Genomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.

RESULTS

A total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.

CONCLUSIONS

These results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.

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Michael Karsy, Jayson A. Neil, Jian Guan, Mark A. Mahan, Howard Colman and Randy L. Jensen

Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylgua-nine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

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Michael Karsy, Jian Guan, Walavan Sivakumar, Jayson A. Neil, Meic H. Schmidt and Mark A. Mahan

Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, counseling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera-peutic modalities and targeted interventions play an ever-evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatrie patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblastoma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options and its application to clinical practice are discussed.

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Michael Karsy, Daxa M. Patel and Robert J. Bollo

Magnetic resonance imaging–guided stereotactic laser ablation of intracranial targets, including brain tumors, has expanded dramatically over the past decade, but there have been few reports of complications, especially those occurring in a delayed fashion. Laser ablation of subependymal giant cell astrocytomas (SEGAs) is an attractive alternative to maintenance immunotherapy in some children with tuberous sclerosis complex (TSC); however, the effect of treatment on disease progression and the nature and frequency of potential complications remains largely unknown. The authors report the case of a 5-year-old boy with TSC who underwent stereotactic laser ablation of a SEGA at the right foramen of Monro on 2 separate occasions. After the second ablation, immediate posttreatment MRI revealed gadolinium extravasation from the tumor into the lateral ventricle. Nine months later, the patient presented with papilledema and delayed obstructive hydrocephalus secondary to intraventricular adhesions causing a trapped right lateral ventricle. This was successfully treated with endoscopic septostomy. The authors discuss the potential cause and clinical management of a delayed complication not previously reported after a relatively novel surgical therapy.

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Hussam Abou-Al-Shaar, Yair M. Gozal, Gmaan Alzhrani, Michael Karsy, Clough Shelton and William T. Couldwell

OBJECTIVE

Postoperative cerebral venous sinus thrombosis (CVST) is an uncommon complication of posterior fossa surgery. The true incidence of and optimal management strategy for this entity are largely unknown. Herein, the authors report their institutional incidence and management experience of postoperative CVST after vestibular schwannoma surgery.

METHODS

The authors undertook a retrospective review of all vestibular schwannoma cases that had been treated with microsurgical resection at a single institution from December 2011 to September 2017. Patient and tumor characteristics, risk factors, length of stay, surgical approaches, sinus characteristics, CVST management, complications, and follow-up were analyzed.

RESULTS

A total of 116 patients underwent resection of vestibular schwannoma. The incidence of postoperative CVST was 6.0% (7 patients). All 7 patients developed lateral CVST ipsilateral to the lesion. Four cases occurred after translabyrinthine approaches, 3 occurred after retrosigmoid approaches, and none occurred following middle cranial fossa approaches. Patients were managed with anticoagulation or antiplatelet therapy. Although patients were generally asymptomatic, one patient experienced intraparenchymal hemorrhage, epidural hemorrhage, and obstructive hydrocephalus, likely as a result of the anticoagulation therapy. However, all 7 patients had a modified Rankin scale score of 1 at the last follow-up.

CONCLUSIONS

Postoperative CVST is an infrequent complication, with an incidence of 6.0% among 116 patients who had undergone vestibular schwannoma surgery at one institution. Moreover, the management of postoperative CVST with anticoagulation therapy poses a serious dilemma to neurosurgeons. Given the paucity of reports in the literature and the low incidence of CVST, additional studies are needed to better understand the cause of thrombus formation and help to establish evidence-based guidelines for CVST management and prevention.

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Spencer Twitchell, Michael Karsy, Jared Reese, Jian Guan, William T. Couldwell, Andrew Dailey and Erica F. Bisson

OBJECTIVE

Efforts to examine the value of care—combining both costs and quality—are gaining importance in the current health care climate. This thrust is particularly evident in treating common spinal disease where both incidences and costs are generally high and practice patterns are variable. It is often challenging to obtain direct surgical costs for these analyses, which hinders the understanding of cost drivers and cost variation. Using a novel tool, the authors sought to understand the costs of posterior lumbar arthrodesis with interbody devices.

METHODS

The Value Driven Outcomes (VDO) database at the University of Utah was used to evaluate the care of patients who underwent open or minimally invasive surgery (MIS), 1- and 2-level lumbar spine fusion (Current Procedural Terminology code 22263). Patients treated from January 2012 through June 2017 were included.

RESULTS

A total of 276 patients (mean age 58.9 ± 12.4 years) were identified; 46.7% of patients were men. Most patients (82.2%) underwent 1-level fusion. Thirteen patients (4.7%) had major complications and 11 (4.1%) had minor complications. MIS (β = 0.16, p = 0.002), length of stay (β = 0.47, p = 0.0001), and number of operated levels (β = 0.37, p = 0.0001) predicted costs in a multivariable analysis. Supplies and implants (55%) and facility cost (36%) accounted for most of the expenditure. Other costs included pharmacy (7%), laboratory (1%), and imaging (1%).

CONCLUSIONS

These results provide direct cost accounting for lumbar fusion procedures using the VDO database. Efforts to improve the value of lumbar surgery should focus on high cost areas, i.e., facility and supplies/implant.