Ivo S. Muskens

Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results

BackgroundFluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In this paper, we systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.MethodsWe searched the PubMed and Embase databases for all potentially relevant studies through March 2016. We assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression-free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.ResultsThe search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5-aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.Conclusions5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives.

Venous thromboembolism and intracranial hemorrhage after craniotomy for primary malignant brain tumors: a National Surgical Quality Improvement Program analysis

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), frequently complicates the postoperative course of primary malignant brain tumor patients. Thromboprophylactic anticoagulation is commonly used to prevent VTE at the risk of intracranial hemorrhage (ICH). We extracted all patients who underwent craniotomy for a primary malignant brain tumor from the National Surgical Quality Improvement Program (NSQIP) registry (2005–2015) to perform a time-to-event analysis and identify relevant predictors of DVT, PE, and ICH within 30 days after surgery. Among the 7376 identified patients, the complication rates were 2.6, 1.5, and 1.3% for DVT, PE, and ICH, respectively. VTE was the second-most common major complication and third-most common reason for readmission. ICH was the most common reason for reoperation. The increased risk of VTE extends beyond the period of hospitalization, especially for PE, whereas ICH occurred predominantly within the first days after surgery. Older age and higher BMI were overall predictors of VTE. Dependent functional status and longer operative times were predictive for VTE during hospitalization, but not for post-discharge events. Admission two or more days before surgery was predictive for DVT, but not for PE. Preoperative steroid usage and male gender were predictive for post-discharge DVT and PE, respectively. ICH was associated with various comorbidities and longer operative times. This multicenter study demonstrates distinct critical time periods for the development of thrombotic and hemorrhagic events after craniotomy. Furthermore, the VTE risk profile depends on the type of VTE (DVT vs. PE) and clinical setting (hospitalized vs. post-discharge patients).

Innovation in neurosurgery: less than IDEAL? A systematic review

BackgroundSurgical innovation is different from the introduction of novel pharmaceuticals. To help address this, in 2009 the IDEAL Collaboration (Idea, Development, Exploration, Assessment, Long-term follow-up) introduced the five-stage framework for surgical innovation. To evaluate the framework feasibility for novel neurosurgical procedure introduction, two innovative surgical procedures were examined: the endoscopic endonasal approach for skull base meningiomas (EEMS) and the WovenEndobridge (WEB device) for endovascular treatment of intracranial aneurysms.MethodsThe published literature on EEMS and WEB devices was systematically reviewed. Identified studies were classified according to the IDEAL framework stage. Next, studies were evaluated for possible categorization according to the IDEAL framework.ResultsFive hundred seventy-six papers describing EEMS were identified of which 26 papers were included. No prospective studies were identified, and no studies reported on ethical approval or patient informed consent for the innovative procedure. Therefore, no clinical studies could be categorized according to the IDEAL Framework. For WEB devices, 6229 articles were screened of which 21 were included. In contrast to EEMS, two studies were categorized as 2a and two as 2b.ConclusionThe results of this systematic review demonstrate that both EEMS and WEB devices were not introduced according to the (later developed in the case of EEMS) IDEAL framework. Elements of the framework such as informed consent, ethical approval, and rigorous outcomes reporting are important and could serve to improve the quality of neurosurgical research. Alternative study designs and the use of big data could be useful modifications of the IDEAL framework for innovation in neurosurgery.

The Woven Endobridge Device for Treatment of Intracranial Aneurysms: A Systematic Review

INTRODUCTION The Woven Endobridge (WEB) device is an innovative endovascular device for treatment of intracranial aneurysms, especially bifurcation and wide-neck aneurysms. Although not approved by the U.S. Food and Drug Administration, it has been available in Europe since 2011. The aim of this review is to evaluate the outcomes of WEB device use for intracranial aneurysm treatment. METHODS A systematic review was conducted with MEDLINE search engines PubMed and Embase from 2011. The search strategy provided 6229 articles, and 19 articles were included. RESULTS A total of 19 papers were identified describing the use of WEB devices in 687 patients with 718 aneurysms. The 2 largest prospective multicenter studies (WEBCAST and the French Observatory Trial) reported successful treatment, defined as complete closure or a neck remnant, in 85% and 79% of aneurysms, respectively. The use of a WEB device in combination with coiling or stenting was described with varying results in multiple small series. Outcomes of WEB device use in ruptured aneurysms in 2 studies showed 94% and 80% adequate treatment. Thromboembolic events were described in 71 patients (10.3% of all patients) and infarctions in 8 patients (1.2% of all patients). CONCLUSIONS Despite initial promising results, the WEB device should be used with caution given its potentially large learning curve and because it has primarily been investigated only in wide-neck and bifurcation aneurysms. In addition, currently available prospective studies have short follow-up, and the device has not been directly compared with other treatment modalities.

Stereotactic radiosurgery versus whole-brain radiotherapy after intracranial metastasis resection: a systematic review and meta-analysis

BackgroundIn patients with one to three brain metastases who undergo resection, options for post-operative treatments include whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) of the resection cavity. In this meta-analysis, we sought to compare the efficacy of each post-operative radiation modality with respect to tumor recurrence and survival.MethodsPubmed, Embase and Cochrane databases were searched through June 2016 for cohort studies reporting outcomes of SRS or WBRT after metastasis resection. Pooled effect estimates were calculated using fixed-effect and random-effect models for local recurrence, distant recurrence, and overall survival.ResultsEight retrospective cohort studies with 646 patients (238 with SRS versus 408 with WBRT) were included in the analysis. Comparing SRS to WBRT, the overall crude risk ratio using the fixed-effect model was 0.59 for local recurrence (95%-CI: 0.32–1.09, I2: 3.35%, P-heterogeneity = 0.36, 3 studies), 1.09 for distant recurrence (95%-CI: 0.74–1.60, I2: 50.5%, P-heterogeneity = 0.13; 3 studies), and 2.99 for leptomeningeal disease (95% CI 1.55–5.76; I2: 14.4% p-heterogeneity: 0.28; 2 studies). For the same comparison, the risk ratio for median overall survival was 0.47 (95% CI: 0.41–0.54; I2: 79.1%, P-heterogeneity < 0.01; 4 studies) in a fixed-effect model, but was no longer significant (0.63; 95%-CI: 0.40–1.00) in a random-effect model. SRS was associated with a lower risk of leukoencephalopathy (RR: 0.15, 95% CI: 0.07–0.33, 1 study), yet with a higher risk of radiation-necrosis (RR: 19.4, 95% CI: 1.21–310, 1 study).ConclusionBased on retrospective cohort studies, the results of this study suggest that SRS of the resection cavity may offer comparable survival and similar local and distant control as adjuvant WBRT, yet may be associated with a higher risk for developing leptomeningeal disease. Future research on SRS should focus on achieving a better understanding of the various factors that may favor SRS over WBRT.

Risk of aspirin continuation in spinal surgery: a systematic review and meta-analysis

BACKGROUND CONTEXT Aspirin is typically discontinued in spinal surgery because of increased risk of hemorrhagic complications. The risk of perioperative continuation of aspirin in neurosurgery needed to be evaluated. PURPOSE This study aimed to evaluate all available evidence about continuation of aspirin and to compare peri- and postoperative blood loss and complication rates between patients that continued aspirin and those who discontinued aspirin perioperatively in spinal surgery. STUDY SETTING Systematic review and meta-analysis were carried out. METHOD A meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing aspirin continuation with discontinuation were included. Studies using a combination of anticlotting agents or non-spinal procedures were excluded. Operative outcomes (blood loss and operative length) and different complications (surgical site infection [SSI]), stroke, myocardial infarction within 30 days postoperatively) were extracted. Overall prevalence and means were calculated for the reported outcomes in fixed-effects models with heterogeneity (I-squared [I2]) and effect modification (P-interaction) assessment. RESULTS Out of 1,339 studies, three case series were included in the meta-analysis. No significant differences in mean operating time were seen between the aspirin-continuing group (mean=201.8 minutes, 95% confidence interval [CI]=193.3; 210.3; I2=95.4%; 170 patients) and the aspirin-discontinuing group (mean=178.4 minutes, 95% CI=119.1; 237.6; I2=93.5%; 200 patients); (P-interaction=0.78). No significant differences in mean perioperative blood loss were seen between the aspirin-continuing group (mean=553.9 milliliters, 95% CI=468.0; 639.9; I2=83.4%; 170 patients) and the aspirin-discontinuing group (mean=538.7 milliliters, 95% CI=427.6; 649.8; I2=985.5%; 200 patients); (P-interaction=0.96). Similar non-significant differences between the two groups were found for cardiac events, stroke, and surgical site infections. CONCLUSIONS This meta-analysis showed an absence of significant differences in perioperative complications between aspirin continuation and discontinuation. Because of the paucity of included studies, further well-designed prospective trials are imperative to demonstrate potential benefit and safety.

Ischemic stroke after radiation therapy for pituitary adenomas: a systematic review

Radiation therapy is widely used for the treatment of residual and recurrent pituitary adenomas and proved to effectively control tumor growth. However, it is suggested that this treatment might result in an increased risk of ischemic stroke. This review aims to evaluate the radiotherapy-related risk of stroke in pituitary adenoma patients. PubMed and Embase databases were systematically searched for current literature on ischemic stroke risk after radiotherapy in pituitary adenoma, in accordance with the PRISMA statement. Two authors independently selected eligible studies and extracted data. The New Castle Ottawa-scale was used for quality assessment. Out of 264 publications, 11 studies were selected, including 4394 irradiated patients. Incidence of ischemic stroke ranged from 0 to 11.6% (mean 6.7%). While one large, long term follow-up study showed a threefold increased risk of stroke after radiation therapy, another nationwide study of high quality found no significant difference in stroke risk after irradiation. Four studies, which applied stereotactic radiosurgery (SRS) or Gamma-knife surgery (GKS), found no ischemic strokes. Included studies described different radiation techniques and regimens and different lengths of follow-up. In conclusion, complications of cerebral ischemia after radiotherapy for pituitary adenoma are infrequently reported. Moreover, after correction for several confounders, no significant difference in ischemic stroke rate between irradiated and non-irradiated patients could be identified.

Defining Innovation in Neurosurgery: Results from an International Survey

BACKGROUND Innovation is a part of the daily practice of neurosurgery. However, a clear definition of what constitutes innovation is lacking and opinions vary from continent to continent, from hospital to hospital, and from surgeon to surgeon. METHODS In this study, we distributed an online survey to neurosurgeons from multiple countries to investigate what neurosurgeons consider innovative, by gathering opinions on several hypothetical cases. The anonymous survey consisted of 52 questions and took approximately 10 minutes to complete. RESULTS A total of 355 neurosurgeons across all continents excluding Antarctica completed the survey. Neurosurgeons achieved consensus (>75%) in considering specific cases to be innovative, including laser resection of meningioma, focused ultrasonography for tumor, oncolytic virus, deep brain stimulation for addiction, and photodynamic therapy for tumor. Although the new dura substitute case was not considered innovative, there was consensus among neurosurgeons indicating that institutional review board approval was still necessary to maintain ethical standards. Furthermore, although 90% of neurosurgeons considered an oncolytic virus for glioblastoma multiforme to be innovative, only 78% believed that institutional review board approval was necessary before treatment. CONCLUSIONS Our results indicate that innovation is a heterogeneous concept among neurosurgeons that necessitates standardization to ensure appropriate patient safety without stifling progress. We discuss both the ethical drawbacks of not having a clear definition of innovation and the challenges in achieving a unified understanding of innovation in neurosurgery and offer suggestions for uniting the field.

Oversight in Surgical Innovation: A Response to Ethical Challenges

BackgroundSurgical innovation has advanced outcomes in the field, but carries inherent risk for surgeons and patients alike. Oversight mechanisms exist to support surgeon-innovators through difficulties associated with the innovation process.MethodsA literature review of ethical risks and oversight mechanisms was conducted.ResultsOversight mechanisms range from the historical concept of surgical exceptionalism to departmental, hospital, and centralized committees. These fragmentary and non-standardized oversight mechanisms leave surgeon-innovators and patients open to significant risk of breaching the ethical principles at the core of surgical practice. A systematized approach that mitigates these risks while maintaining the independence and dignity of the surgical profession is necessary. We propose an oversight framework that incorporates multiple structures tailored toward the ethical risk introduced by different forms of innovation.DiscussionWe summarize ethical risks and current regulatory structures, and we then use these findings to outline an oversight framework that may be applied to surgical practice.

Oversight and Ethical Regulation of Conflicts of Interest in Neurosurgery in the United States

BACKGROUND Developmental incentives are fundamental to surgical progress, yet financial and professional incentives inherently create conflicts of interest (COI). Understanding how to manage COI held by neurosurgeons, industry, hospitals, and journal editors, without thwarting progress and innovation is critical. OBJECTIVE To present an overview of COI associated with innovation in neurosurgery, and review ways to manage these in an ethically sound manner. METHODS A review of the literature was performed to assess conflicts of interest that affect neurosurgical innovation, and review ways to manage COI of various parties while adhering to ethical standards. RESULTS COI are inherent to collaboration and innovation, and are therefore an unavoidable component of neurosurgery. The lack of a clear distinction between clinical practice and innovation, ability to use devices off-label, and unstandardized disclosure requirements create inconsistencies in the way that conflicts of interest are handled. Additionally, lack of requirements to compare innovation to the standard of care and inherent bias that affects study design and interpretation can have profound effects on the medical literature. Conflicts of interest can have both direct and downstream effects on neurosurgical practice, and it is possible to manage them while improving the quality of research and innovation. CONCLUSION Conflicts of interest are inherent to surgical innovation, and can be handled in an ethically sound manner. Neurosurgeons, device companies, hospitals, and medical journals can take steps to proactively confront bias and ensure patient autonomy and safety. These steps can preserve public trust and ultimately improve evidence-based neurosurgical practice.