Development of a Triple-Negative Breast Cancer Leptomeningeal Disease Model in Zebrafish.

Leptomeningeal disease occurs when cancer cells migrate into the ventricles of the brain and spinal cord and then colonize the meninges of the central nervous system. The triple-negative subtype of breast cancer often progresses toward leptomeningeal disease and has a poor prognosis because of limited treatment options. This is due, in part, to a lack of animal models with which to study leptomeningeal disease. Here, we developed a translucent zebrafish casper (roy-/-; nacre-/-) xenograft model of leptomeningeal disease in which fluorescent labeled MDA-MB-231 human triple-negative breast cancer cells are microinjected into the ventricles of zebrafish embryos and then tracked and measured using fluorescent microscopy and multimodal plate reader technology. We then used these techniques to measure tumor area, cell proliferation, and cell death in samples treated with the breast cancer drug doxorubicin and a vehicle control. We monitored MDA-MB-231 cell localization and tumor area, and showed that samples treated with doxorubicin exhibited decreased tumor area and proliferation and increased apoptosis compared to control samples.

Case report: Side-firing intraoperative ultrasound guided endoscopic endonasal resection of a clival chordoma.

Clival chordomas are locally invasive midline skull base tumors arising from remnants of the primitive notochord. Intracranial vasculature and cranial nerve involvement of tumors in the paraclival region necessitates image guidance that provides accurate real-time feedback during resection. Several intraoperative image guidance modalities have been introduced as adjuncts to endoscopic endonasal surgery, including stereotactic neuronavigation, intraoperative ultrasound, intraoperative MRI, and intraoperative CT. Gross total resection of chordomas is associated with a lower recurrence rate; therefore, intraoperative imaging may improve long-term outcomes by enhancing the extent of resection. However, among these options, effectiveness and accessibility vary between institutions. We previously published the first use of an end-firing probe in the resection of a clival chordoma. End-firing probes provide a single field of view, primarily limited to depth estimation. In this case report, we discuss the benefits of employing a novel minimally invasive side-firing ultrasound probe as a cost-effective and time-efficient option to navigate the anatomy of the paraclival region and guide endoscopic endonasal resection of a large complex clival chordoma.

Side-Firing Intraoperative Ultrasonograhy for Resection of Giant Pituitary Adenomas.

BACKGROUND: Suprasellar extension, cavernous sinus invasion, and involvement of intracranial vascular structures and cranial nerves are among the challenges faced by surgeons operating on giant pituitary macroadenomas. Intraoperative tissue shifts may render neuronavigation techniques inaccurate. Intraoperative magnetic resonance imaging can solve this problem, but it may be costly and time consuming. However, intraoperative ultrasonography (IOUS) allows for quick, real-time feedback and may be particularly useful when facing giant invasive adenomas. Here, we present the first study examining technique for IOUS-guided resection specifically focusing on giant pituitary adenomas. OBJECTIVE: To describe the use of a side-firing ultrasound probe in the resection of giant pituitary macroadenomas. METHODS: We describe an operative technique using a side-firing ultrasound probe (Fujifilm/Hitachi) to identify the diaphragma sellae, confirm optic chiasm decompression, identify vascular structures related to tumor invasion, and maximize extent of resection in giant pituitary macroadenomas. RESULTS: Side-firing IOUS allows for identification of the diaphragma sellae to help prevent intraoperative cerebrospinal fluid leak and maximize extent of resection. Side-firing IOUS also aids in confirmation of decompression of the optic chiasm via identification of a patent chiasmatic cistern. Furthermore, direct identification of the cavernous and supraclinoid internal carotid arteries and arterial branches is achieved when resecting tumors with significant parasellar and suprasellar extension. CONCLUSIONS: We describe an operative technique in which side-firing IOUS may assist in maximizing extent of resection and protecting vital structures during surgery for giant pituitary adenomas. Use of this technology may be particularly valuable in settings in which intraoperative magnetic resonance imaging is not available.

Side-firing intraoperative ultrasound applied to resection of pituitary macroadenomas and giant adenomas: A single-center retrospective case-control study.

Introduction: Multiple intraoperative navigation and imaging modalities are currently available as an adjunct to endoscopic transsphenoidal resection of pituitary adenomas, including intraoperative CT and MRI, fluorescence guidance, and neuronavigation. However, these imaging techniques have several limitations, including intraoperative tissue shift, lack of availability in some centers, and the increased cost and time associated with their use. The side-firing intraoperative ultrasound (IOUS) probe is a relatively new technology in endoscopic endonasal surgery that may help overcome these obstacles. Methods: A retrospective analysis was performed on patients admitted for resection of pituitary adenomas by a single surgeon at the University of Mississippi Medical Center. The control (non-ultrasound) group consisted of twelve (n=12) patients who received surgery without IOUS guidance, and the IOUS group was composed of fifteen (n=15) patients who underwent IOUS-guided surgery. Outcome measures used to assess the side-firing IOUS were the extent of tumor resection, postoperative complications, length of hospital stay (LOS) in days, operative time, and self-reported surgeon confidence in estimating the extent of resection intraoperatively. Results: Preoperative data analysis showed no significant differences in patient demographics or presenting symptoms between the two groups. Postoperative data revealed no significant difference in the rate of gross total resection between the groups (p = 0.716). Compared to the non-US group, surgeon confidence was significantly higher (p < 0.001), and operative time was significantly lower for the US group in univariate analysis (p = 0.011). Multivariate analysis accounting for tumor size, surgeon confidence, and operative time confirmed these findings. Interestingly, we noted a trend for a lower incidence of postoperative diabetes insipidus in the US group, although this did not quite reach our threshold for statistical significance. Conclusion: Incorporating IOUS as an aid for endonasal resection of pituitary adenomas provides real-time image guidance that increases surgeon confidence in intraoperative assessment of the extent of resection and decreases operative time without posing additional risk to the patient. Additionally, we identified a trend for reduced diabetes insipidus with IOUS.

The impact of craniotomy for brain tumor case volume on patient safety indicators and in-hospital mortality.

OBJECTIVES: The relationship between outcomes, patient safety indicators and volume has been well established in patient's undergoing craniotomy for brain tumor. However, the determination of "high" and "low" volume centers have been subjectively derived. We present a paper with a novel method of objectively determining "high" volume centers for craniotomy for brain tumor. METHODS: Patients from 2002 to 2011 were identified in the Nationwide Inpatient Sample database using ICD-9 codes related to craniotomy for brain tumor. Primary endpoints of interest were hospital PSI event rate, in-hospital mortality rate, observed-to-expected PSI event ratio, and O/E in-hospital mortality ratio. Using a zero-inflated gamma model analysis and a cutpoint analysis we determined the volume threshold between and "high" and "low" volume hospitals. We then completed an analysis using this determined threshold to look at PSI events and mortality as they relate to "high" volume and "low" volume hospitals. RESULTS: 12.4 % of hospitals were categorized as good performers using O/E ratios. Regarding in-hospital mortality, 16.8 % were good performers. Using the above statistical analysis the threshold to define high vs. low volume centers was determined to be 27 craniotomies. High volume centers had significantly lower O/E ratios for both PSI and mortality events. The PSI O/E ratio was reduced 55 % and mortality O/E ratio reduced 73 % at high volume centers as defined by our analysis. CONCLUSIONS: Patients treated at institutions performing >27 craniotomies per year for brain tumors have a lower likelihood of PSI events and decreased in-hospital morbidity and mortality.

Relationship between patient safety indicator events and comprehensive stroke center volume status in the treatment of unruptured cerebral aneurysms.

OBJECTIVE The Agency of Healthcare Research and Quality (AHRQ) has defined Patient Safety Indicators (PSIs) for assessments in quality of inpatient care. The hypothesis of this study is that, in the treatment of unruptured cerebral aneurysms (UCAs), PSI events are less likely to occur in hospitals meeting the volume thresholds defined by The Joint Commission for Comprehensive Stroke Center (CSC) certification. METHODS Using the 2002-2011 National (Nationwide) Inpatient Sample, patients treated electively for a nonruptured cerebral aneurysm were selected. Patients were evaluated for PSI events (e.g., pressure ulcers, retained surgical item, perioperative hemorrhage, pulmonary embolism, sepsis) defined by AHRQ-specified ICD-9 codes. Hospitals were categorized by treatment volume into CSC or non-CSC volume status based on The Joint Commission's annual volume thresholds of at least 20 patients with subarachnoid hemorrhage and performance of 15 or more endovascular coiling or surgical clipping procedures for aneurysms. RESULTS A total of 65,824 patients underwent treatment for an unruptured cerebral aneurysm. There were 4818 patients (7.3%) in whom at least 1 PSI event occurred. The overall inpatient mortality rate was 0.7%. In patients with a PSI event, this rate increased to 7% compared with 0.2% in patients without a PSI event (p < 0.0001). The overall rate of poor outcome was 3.8%. In patients with a PSI event, this rate increased to 23.3% compared with 2.3% in patients without a PSI event (p < 0.0001). There were significant differences in PSI event, poor outcome, and mortality rates between non-CSC and CSC volume-status hospitals (PSI event, 8.4% vs 7.2%; poor outcome, 5.1% vs 3.6%; and mortality, 1% vs 0.6%). In multivariate analysis, all patients treated at a non-CSC volume-status hospital were more likely to suffer a PSI event with an OR of 1.2 (1.1-1.3). In patients who underwent surgery, this relationship was more substantial, with an OR of 1.4 (1.2-1.6). The relationship was not significant in the endovascularly treated patients. CONCLUSIONS In the treatment of unruptured cerebral aneurysms, PSI events occur relatively frequently and are associated with significant increases in morbidity and mortality. In patients treated at institutions achieving the volume thresholds for CSC certification, the likelihood of having a PSI event, and therefore the likelihood of poor outcome and mortality, was significantly decreased. These improvements are being driven by the improved outcomes in surgical patients, whereas outcomes and mortality in patients treated endovascularly were not sensitive to the CSC volume status of the hospital and showed no significant relationship with treatment volumes.

Platelet testing in flow diversion: a review of the evidence.

OBJECTIVE Although the use of dual antiplatelet therapy with flow diversion is recommended and commonplace, the testing of platelet inhibition is more controversial. METHODS The authors reviewed the medical literature to establish and describe the physiology of platelet adhesion, the pharmacology of antiplatelet medications, and the mechanisms of the available platelet function tests. Additionally, they present a review of the pertinent neurointerventional and interventional cardiology literature. RESULTS Competing reports in the neurointerventional literature argue for and against the use of routine platelet function testing, with adjustments to the dosage or medications based on the results. The interventional cardiology literature has also wrestled with this dilemma after percutaneous coronary interventions, with conflicting reports of the benefits of platelet function testing. CONCLUSIONS Despite its prevalence, the benefits of platelet function testing prior to flow diversion are unproven. This practice will likely remain controversial until the level of evidence improves through more rigorous testing and reporting.

Comparing routine versus selective use of intraoperative cerebral angiography in aneurysm surgery: a prospective study.

INTRODUCTION: While the use of intraoperative angiography (IA) has been shown to be a useful adjunct in aneurysm surgery, its routine use remains controversial. OBJECTIVE: We wished to determine if IA is required in all patients undergoing aneurysm surgery (ie, routine IA) or if intraoperative assessment can reliably predict the need for IA (ie, select IA). METHODS: We prospectively evaluated all patients undergoing craniotomy for aneurysm clipping. In these patients, the treating surgeons were asked to record whether they felt IA was required at two time points: (1) prior to surgery and (2) immediately after clip application but before IA. All patients underwent IA as per the institutional protocol. IA results and the need for post-IA clip adjustments were recorded. RESULTS: Of the 200 patients enrolled, 197 were included for analysis. IA was deemed necessary on preoperative assessment in 144 cases (73%) and on post-clip assessment in 116 cases (59%). Post-clip IA demonstrated 47 (24%) positive findings and post-IA clip adjustments were made in 19 of 198 cases (10%). On preoperative assessment, there were four cases where IA was deemed unnecessary, yet post-IA clip adjustment was required, resulting in a sensitivity of 79% and false negative rate of 8%. Regarding post-clip assessment, there were five cases where IA was thought to be unnecessary and clip adjustment was required, resulting in a sensitivity of 73% and false negative rate of 6%. CONCLUSIONS: The accuracy of a strategy of select IA was not improved by assessing the need for IA immediately after aneurysm clipping versus prior to surgery onset. This suggests that intraoperative assessment regarding the adequacy of aneurysm clip application should be viewed with caution.

Comparing indocyanine green videoangiography to the gold standard of intraoperative digital subtraction angiography used in aneurysm surgery.

OBJECT: The purpose of aneurysm surgery is complete aneurysm obliteration while sparing associated arteries. Indocyanine green (ICG) videoangiography is a new technique that allows for real-time evaluation of blood flow in the aneurysm and vessels. The authors performed a retrospective study to compare the accuracy of ICG videoangiography with intraoperative angiography (IA), and determine if ICG videoangiography can be used without follow-up IA. METHODS: From June 2007 through September 2009, 155 patients underwent craniotomies for clipping of aneurysms. Operative summaries, angiograms, and operative and ICG videoangiography videos were reviewed. The number, size, and location of aneurysms, the ICG videoangiography and IA findings, and the need for clip adjustment after ICG videoangiography and IA were recorded. Discordance between ICG videoangiography and IA was defined as ICG videoangiography demonstrating aneurysm obliteration and normal vessel flow, but post-IA showing either an aneurysmal remnant and/or vessel occlusion requiring clip adjustment. RESULTS: Thirty-two percent of patients (49 of 155) underwent both ICG videoangiography and IA. The post-ICG videoangiography clip adjustment rate was 4.1% (2 of 49). The overall rate of ICG videoangiography-IA agreement was 75.5% (37 of 49) and the ICG videoangiography-IA discordance rate requiring post-IA clip adjustment was 14.3% (7 of 49). Adjustments were due to 3 aneurysmal remnants and 4 vessel occlusions. These adjustments were attributed to obscuration of the residual aneurysm or the affected vessel from the field of view and the presence of dye in the affected vessel via collateral flow. Although not statistically significant, there was a trend for ICG videoangiography-IA discordance requiring clip adjustment to occur in cases involving the anterior communicating artery complex, with an odds ratio of 3.3 for ICG videoangiography-IA discordance in these cases. CONCLUSIONS: These results suggest that care should be taken when considering ICG videoangiography as the sole means for intraoperative evaluation of aneurysm clip application. The authors further conclude that IA should remain the gold standard for evaluation during aneurysm surgery. However, a combination of ICG videoangiography and IA may ultimately prove to be the most effective strategy for maximizing the safety and efficacy of aneurysm surgery.

Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation.

Cavernous malformations (CMs) are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics. They present with seizure, neurological compromise due to lesion hemorrhage or expansion, or as incidental findings on neuroimaging studies. Treatment options include conservative therapy, medical management of seizures, surgical intervention for lesion resection, and in select cases stereotactic radiosurgery. Optimal management requires a thorough understanding of the natural history of CMs including consideration of issues such as mode of presentation, lesion location, and genetics that may impact the associated neurological risk. Over the past 2 decades, multiple studies have been published, shedding valuable light on the clinical characteristics and natural history of these malformations. The purpose of this review is to provide the reader with a concise consolidation of this published material such that they may better understand the risks associated with CMs and their implications on patient treatment.

Modality independent elastography (MIE): a new approach to elasticity imaging.

The correlation between tissue stiffness and health is an accepted form of organ disease assessment. As a result, there has been a significant amount of interest in developing methods to image elasticity parameters (i.e., elastography). The modality independent elastography (MIE) method combines a nonlinear optimization framework, computer models of soft-tissue deformation, and standard measures of image similarity to reconstruct elastic property distributions within soft tissue. In this paper, simulation results demonstrate successful elasticity image reconstructions in breast cross-sectional images acquired from magnetic resonance (MR) imaging. Results from phantom experiments illustrate its modality independence by reconstructing elasticity images of the same phantom in both MR and computed tomographic imaging units. Additional results regarding the performance of a new multigrid strategy to MIE and the implementation of a parallel architecture are also presented.