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Scott Y. Rahimi, John H. Brown, Samuel D. Macomson, Michael A. Jensen and Cargill H. Alleyne Jr.

✓ Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a disease process for which the lack of effective treatments has plagued neurosurgeons for decades. Historically, successful treatment after SAH in the acute setting was often followed by a rapid, uncontrollable deterioration in the subacute interval. Little was known regarding the nature and progression of this condition until the mid-1800s, when the disease was first described by Gull. Insight into the origin and natural history of cerebral vasospasm came slowly over the next 100 years, until the 1950s. Over the past five decades our understanding of cerebral vasospasm has expanded exponentially. This newly discovered information has been used by neurosurgeons worldwide for successful treatment of complications associated with vasospasm. Nevertheless, although great strides have been made toward elucidating the causes of cerebral vasospasm, a lasting cure continues to elude experts and the disease continues to wreak havoc on patients after aneurysmal SAH.

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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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Michael Karsy, Mohammed A. Azab, Hussam Abou-Al-Shaar, Jian Guan, Ilyas Eli, Randy L. Jensen and D. Ryan Ormond

Meningiomas are among the most common intracranial pathological conditions, accounting for 36% of intracranial lesions treated by neurosurgeons. Although the majority of these lesions are benign, the classical categorization of tumors by histological type or World Health Organization (WHO) grade has not fully captured the potential for meningioma progression and recurrence. Many targeted treatments have failed to generate a long-lasting effect on these tumors. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor–associated factor 7), KLF4 (Kruppel-like factor 4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least 6 distinct mutational classes of meningiomas. In addition, 6 methylation classes of meningioma have been appreciated, enabling improved prediction of prognosis compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell–like origin. However, despite these exciting findings, the clinical relevance of these findings remains elusive. The authors review the key findings from recent genomic studies in meningiomas, specifically focusing on how these findings relate to clinical insights for the practicing neurosurgeon.

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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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Jian Guan, Michael Karsy, Andrea A. Brock, William T. Couldwell, John R. W. Kestle, Randy L. Jensen, Andrew T. Dailey and Richard H. Schmidt

OBJECTIVE

Recently, overlapping surgery has been a source of controversy both in the popular press and within the academic medical community. There have been no studies examining the possible effects of more stringent overlapping surgery restrictions. At the authors’ institution, a new policy was implemented that restricts attending surgeons from starting a second case until all critical portions of the first case that could require the attending surgeon’s involvement are completed. The authors examined the impact of this policy on complication rates, neurosurgical resident education, and wait times for neurosurgical procedures.

METHODS

The authors performed a retrospective chart review of nonemergency neurosurgical procedures performed over two periods—from June 1, 2014, to October 31, 2014 (pre–policy change) and from June 1, 2016, to October 31, 2016 (post–policy change)—by any of 4 senior neurosurgeons at a single institution who were authorized to schedule overlapping cases. Information on preoperative evaluation, patient demographics, premorbid conditions, surgical variables, and postoperative course were collected and analyzed.

RESULTS

Six hundred fifty-three patients met inclusion criteria for complications analysis. Of these, 378 (57.9%) underwent surgery before the policy change. On multivariable regression analysis, neither overlapping surgery (odds ratio [OR] 1.072, 95% confidence interval [CI] 0.710–1.620) nor the overlapping surgery policy change (OR 1.057, 95% CI 0.700–1.596) was associated with overall complication rates. Similarly, neither overlapping surgery (OR 1.472, 95% CI 0.883–2.454) nor the overlapping surgery policy change (OR 1.251, 95% CI 0.748–2.091) was associated with numbers of serious complications. After the policy change, the percentage of procedures in which the senior assistant was a postresidency fellow increased significantly, from 11.9% to 34.2% (p < 0.001). In a multiple linear regression analysis of surgery wait times, patients undergoing surgery after the policy change had significantly longer delays from the decision to operate until the actual neurosurgical procedure (p < 0.001).

CONCLUSIONS

At the authors’ institution, further restriction of overlapping surgery was not associated with a reduction in overall or serious complications. Resident involvement in neurosurgical procedures decreased significantly after the policy change, and this study suggests that wait times for neurosurgical procedures also significantly lengthened.

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Sangeetha Sukumari-Ramesh, Nagendra Singh, Michael A. Jensen, Krishnan M. Dhandapani and John R. Vender

Object

Pituitary adenomas, which are common intracranial tumors, are associated with significant patient morbidity due to hormone secretion or mass effect or as a complication of therapy. Epigenetic regulation has emerged as an important component of malignant tumor pathogenesis, although the contribution in the progression of benign pituitary tumors remains largely unexplored. The present study evaluates the effect of anacardic acid (6-pentadecyl salicylic acid), a natural histone acetyltransferase inhibitor, on pituitary adenoma cells.

Methods

The concentration- and time-dependent effects of anacardic acid on the viability of GH3 and MMQ pituitary adenoma cells were determined by 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle phase distribution, protein expression, and percentage of apoptotic cells were assessed by flow cytometry and Western blotting. Colony forming assays were used to study the radiosensitizing effect of anacardic acid.

Results

The present study identifies a novel antiproliferative and cytotoxic effect of anacardic acid on pituitary adenoma cells. These effects were associated with an increase in poly([adenosine diphosphate]-ribose) polymerase cleavage, sub-G1 arrest, and annexin V staining, consistent with apoptotic cell death; however, the pancaspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone failed to reverse anacardic acid–induced cell death, suggesting a possible nonclassical apoptotic mechanism. Anacardic acid also reduced the expression of survivin and X-linked inhibitor of apoptosis protein, antiapoptotic proteins associated with cellular survival and radioresistance, and radiosensitized pituitary adenoma cells.

Conclusions

These findings warrant further exploration of anacardic acid as a single agent or as an adjunct to radiation therapy for the treatment of pituitary tumors.

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Hussam Abou-Al-Shaar, Mohammed A. Azab, Michael Karsy, Jian Guan, Gmaan Alzhrani, Yair M. Gozal, Randy L. Jensen and William T. Couldwell

OBJECTIVE

Microsurgical resection and radiosurgery remain the most widely used interventions in the treatment of vestibular schwannomas. There is a growing demand for cost-effectiveness analyses to evaluate these two treatment modalities and delineate the factors that drive their total costs. Here, the authors evaluated specific cost drivers for microsurgical and radiosurgical management of vestibular schwannoma by using the Value Driven Outcomes system available at the University of Utah.

METHODS

The authors retrospectively reviewed all cases involving microsurgical and radiosurgical treatment of vestibular schwannomas at their institution between November 2011 and September 2017. Patient and tumor characteristics, subcategory costs, and potential cost drivers were analyzed.

RESULTS

The authors identified 163 vestibular schwannoma cases, including 116 managed microsurgically and 47 addressed with stereotactic radiosurgery (SRS). There were significant differences between the two groups in age, tumor size, and preoperative Koos grade (p < 0.05), suggesting that indications for treatment were markedly different. Length of stay (LOS) and length of follow-up were also significantly different. Facility costs were the most significant contributor to both microsurgical and SRS groups (58.3% and 99.4%, respectively); however, physician professional fees were not specifically analyzed. As expected, microsurgical treatment resulted in an average 4-fold greater overall cost of treatment than for SRS cases (p < 0.05), and there was a greater variation in costs for open cases as well. Costs remained stable over time for both open resection and SRS. Multivariable analysis showed that LOS (β = 0.7, p = 0.0001), discharge disposition (β = 0.2, p = 0.004), nonserviceable hearing (β = 0.1, p = 0.02), and complications (β = 0.2, p = 0.005) affected cost for open surgery, whereas no specifically examined factor could be identified as driving costs for SRS.

CONCLUSIONS

This analysis identified the fact that facility utilization constitutes the majority of total costs for both microsurgery and SRS treatment modalities of vestibular schwannomas. LOS, discharge disposition, nonserviceable hearing, and complications contributed significantly to the total costs for the microsurgical group, whereas none of the factors could be identified as driving total costs for the SRS group. This information may be used to establish policies and protocols to reduce facility costs, with the goal of decreasing the total costs without jeopardizing patient care.

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Walavan Sivakumar, Michael Jensen, Julie Martinez, Michael Tanana, Nancy Duncan, Robert Hoesch, Jay K. Riva-Cambrin, Craig Kilburg, Safdar Ansari and Paul A. House

OBJECTIVE

Acute pain control after cranial surgery is challenging. Prior research has shown that patients experience inadequate pain control post-craniotomy. The use of oral medications is sometimes delayed because of postoperative nausea, and the use of narcotics can impair the evaluation of brain function and thus are used judiciously. Few nonnarcotic intravenous (IV) analgesics exist. The authors present the results of the first prospective study evaluating the use of IV acetaminophen in patients after elective craniotomy.

METHODS

The authors conducted a randomized, double-blinded, placebo-controlled investigation. Adults undergoing elective, supratentorial craniotomies between September 2013 and June 2015 were randomized into two groups. The experimental group received 1000 mg/100 ml IV acetaminophen every 8 hours for 48 hours. The placebo group received 100 ml of 0.9% normal saline on the same schedule. Both groups were also treated with a standardized pain control algorithm. The study was powered to detect a 30% difference in the primary outcome measures: narcotic consumption (morphine equivalents, ME) at 24 and 48 hours after surgery. Patient-reported pain scores immediately postoperatively and 48 hours after surgery were also recorded.

RESULTS

A total of 204 patients completed the trial. No significant differences were found in narcotic consumption between groups at either time point (in the treatment and placebo groups, respectively, at 24 hours: 84.3 ME [95% CI 70.2–98.4] and 85.5 ME [95% CI 73–97.9]; and at 48 hours: 123.5 ME [95% CI 102.9–144.2] and 134.2 ME [95% CI 112.1–156.3]). The difference in improvement in patient-reported pain scores between the treatment and placebo groups was significant (p < 0.001).

CONCLUSIONS

Patients who received postoperative IV acetaminophen after craniotomy did not have significantly decreased narcotic consumption but did experience significantly lower pain scores after surgery. The drug was well tolerated and safe in this patient population.

Clinical trial registration no.: NCT01948505 (clinicaltrials.gov)

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Aaron S. Dumont, Avery J. Evans and Mary E. Jensen

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Ning Lin, Ian F. Dunn, Michael Glantz, Dana L. Allison, Randy Jensen, Mark D. Johnson, Robert M. Friedlander and Santosh Kesari

Object

Neoplastic meningitis (NM) is a debilitating and increasingly frequent neurological complication of cancer characterized by infiltration of tumor cells into the leptomeninges and the subarachnoid space. Although NM is rarely curable, combined intrathecal chemotherapy and focal radiation can improve disease-related symptoms and survival. Hydrocephalus occurs in a significant proportion of patients, is associated with poor prognosis and reduced quality of life, and usually precludes the use of intrathecal therapy.

Methods

Since January of 2005, the authors have used a combined treatment approach for patients with both NM and hydrocephalus that employs a subcutaneously placed reservoir connected in series to an on/off valve and a ventriculoperitoneal shunt for both diversion of CSF and injection of intrathecal chemotherapy. They conducted a retrospective, case-controlled study from 2 independent institutions to review their experience.

Results

Twenty-four patients with NM and hydrocephalus underwent placement of a CSF reservoir-on/off valve-ventriculoperitoneal shunt (RO-VPS) construct. There was no perioperative mortality, and there were only 2 minor complications. One shunt failure and no shunt-associated infections were observed over a median of 28 weeks of follow-up. Symptomatic improvement and improved performance status were seen in 20 patients (83.3%) and were sustained over 6 months. Eighteen patients received intraventricular chemotherapy without unexpected toxicity, and cytological responses were found in 11 patients (61.1%). Median progression-free and overall survival was 14 and 31 weeks, respectively. Compared with a contemporaneous comparison group of 24 demographically matched patients with NM who underwent CSF reservoir placement only, those who received RO-VPS constructs (p = 0.02) and had primary diagnosis of breast cancer (p = 0.04) had significant advantage in overall survival.

Conclusions

A combined RO-VPS system is safe and practical to install, results in symptomatic improvement in most patients, and allows uncomplicated and effective administration of intrathecal chemotherapy in patients with NM. Cerebrospinal fluid diversion surgery should be considered in NM patients in conjunction with intrathecal and systemic treatments.