Automated online safety margin (GLIOVIS) for glioma surgery model.

Purpose: Glioblastoma is the most common type of primary brain malignancy and has a poor prognosis. The standard treatment strategy is based on maximal safe surgical resection followed by radiotherapy and chemotherapy. Surgical resection can be optimized by using 5-delta-aminolevulinic acid (5-ALA)-induced fluorescence, which is the current mainstay. Although 5-ALA-induced fluorescence has gained general acceptance, it is also limited by inter-observer variability and non-standardized fluorescence parameters. We present a new software for processing images analysis to better recognize the tumor infiltration margins using an intraoperative immediate safety map of 5-ALA-induced fluorescence. We tested this in a brain model using a commercial surgical exoscope. Methods: A dedicated software GLIOVIS (ACQuF-II, Advanced Colorimetry-based Quantification of Fluorescence) was designed for processing analysis of images taken on the Intraoperative Orbital Camera Olympus Orbeye (IOC) to determine the relative quantification of Protoporphyrin IX (5-ALA metabolite) fluorescence. The software allows to superpose the new fluorescence intensity map and the safety margins over the original images. The software was tested on gel-based brain models. Results: Two surrogate models were developed: PpIX agarose gel-integrated in gelatin-based brain model at different scales (1:25 and 1:1). The images taken with the IOC were then processed using GLIOVIS. The intensity map and safety margins could be obtained for all available models. Conclusions: GLIOVIS for 5-ALA-guided surgery image processing was validated on various gelatin-based brain models. Different levels of fluorescence could be qualitatively digitalized using this technique. These results need to be further confirmed and corroborated in vivo and validated clinically in order to define a new standard of care for glioblastoma resection.

Clinical Relevance and Interplay between miRNAs in Influencing Glioblastoma Multiforme Prognosis.

Glioblastoma multiforme (GBM) is usually treated with surgery followed by adjuvant partial radiotherapy combined with temozolomide (TMZ) chemotherapy. Recent studies demonstrated a better survival and good response to TMZ in methylguanine-DNA methyltransferase (MGMT)-methylated GBM cases. However, approximately 20% of patients with MGMT-unmethylated GBM display an unexpectedly favorable outcome. Therefore, additional mechanisms related to the TMZ response need to be investigated. As such, we decided to investigate the clinical relevance of six miRNAs involved in brain tumorigenesis (miR-181c, miR-181d, miR-21, miR-195, miR-196b, miR-648) as additional markers of response and survival in patients receiving TMZ for GBM. We evaluated miRNA expression and the interplay between miRNAs in 112 IDH wt GBMs by applying commercial assays. Then, we correlated the miRNA expression with patients' clinical outcomes. Upon bivariate analyses, we found a significant association between the expression levels of the miRNAs analyzed, but, more interestingly, the OS curves show that the combination of low miR-648 and miR-181c or miR-181d expressions is associated with a worse prognosis than cases with other low-expression miRNA pairs. To conclude, we found how specific miRNA pairs can influence survival in GBM cases treated with TMZ.

Identification of MGMT Downregulation Induced by miRNA in Glioblastoma and Possible Effect on Temozolomide Sensitivity.

Glioblastoma multiforme (GBM) remains one of the tumors with the worst prognosis. In recent years, a better overall survival (OS) has been described in cases subjected to Gross Total Resection (GTR) that were presenting hypermethylation of Methylguanine-DNA methyltransferase (MGMT) promoter. Recently, also the expression of specific miRNAs involved in MGMT silencing has been related to survival. In this study, we evaluate MGMT expression by immunohistochemistry (IHC), MGMT promoter methylation and miRNA expression in 112 GBMs and correlate the data to patients' clinical outcomes. Statistical analyses demonstrate a significant association between positive MGMT IHC and the expression of miR-181c, miR-195, miR-648 and miR-767.3p between unmethylated cases and the low expression of miR-181d and miR-648 and between methylated cases and the low expression of miR-196b. Addressing the concerns of clinical associations, a better OS has been described in presence of negative MGMT IHC, in methylated patients and in the cases with miR-21, miR-196b overexpression or miR-767.3 downregulation. In addition, a better progression-free survival (PFS) is associated with MGMT methylation and GTR but not with MGMT IHC and miRNA expression. In conclusion, our data reinforce the clinical relevance of miRNA expression as an additional marker to predict efficacy of chemoradiation in GBM.

Prediction of Long-Term Restenosis After Carotid Endarterectomy Using Quantitative Magnetic Resonance Angiography.

Background: To detect restenosis after carotid endarterectomy (CEA), long-term monitoring is required. However, non-selective follow-up is controversial and can be limited by costs and logistical considerations. Objective: To examine the value of immediate perioperative vessel flow measurements after CEA using quantitative magnetic resonance angiography (QMRA) to detect patients at risk of long-term restenosis. Methods: A prospective cohort study with long-term sonographic follow-up after CEA for symptomatic internal carotid artery stenosis (ICAs) > 50%. In all patients, vessel flow has been assessed both pre- and postoperatively using QMRA within ±3 days of surgery. Data on QMRA assessment were analyzed to identify patients at risk of restenosis for up to 10 years. Results: Restenosis was recorded in 4 of 24 patients (17%) at a median follow-up of 6.8 ± 2.6 years. None of them experienced an ischemic event. Perioperative flow differences were significantly greater in patients without long-term restenosis, both for the ipsilateral ICA (p < 0.001) and MCA (p = 0.03), compared to those with restenosis (p = 0.22 and p = 0.3, respectively). The ICA mean flow ratio (p = 0.05) tended to be more effective than the MCA ratio in predicting restenosis over the long term (p = 0.35). Conclusion: Our preliminary findings suggest that QMRA-based mean flow increases after CEA may be predictive of restenosis over the long term. Perioperative QMRA assessment could become an operator-independent screening tool to identify a subgroup of patients at risk for restenosis, in whom long-term monitoring is advised.

Ruptured MCA Aneurysm Mimicking MCA Territory Ischemic Stroke: A Case Report and Review of the Literature.

Intracerebral hemorrhage (ICH) can be considered one of the major neurologic and neurosurgical emergencies that need a time-dependent diagnosis and treatment. On rare occasions, an aneurysmal rupture may also present with isolated ICH without subarachnoid hemorrhage. We present the case of a 48-year-old woman presenting in our neurosurgical department with ICH and a right middle cerebral artery (MCA) occlusion that, 6 weeks after the initial surgical management, unveiled a large MCA aneurysm treated with a clipping. In this study, we discuss our hypothesis about the etiology and the pathophysiology of this rare phenomenon in the light of the literature in the field.

Longer survival of glioblastoma complicated by bacterial infections after surgery: what is known today.

INTRODUCTION: Glioblastoma is the most common primary brain tumor in adults with the worst overall survival. Post-craniotomy intracranial infections are not infrequent after surgery; however, their impact on overall survival of glioblastoma patients remains unclear. Here we report the case of an unusual longer survival of a glioblastoma patient affected by multiple infections and the review of the literature on this topic. EVIDENCE ACQUISITION: PubMed, Embase and Cochrane search engines were reviewed for papers describing outcome of patients suffering from glioblastoma and associated cerebral infections. EVIDENCE SYNTHESIS: Four papers accounting a total of 29 patients met the eligibility criteria. Staphylococcus aureus and Staphylococcus epidermidis resulted the most common bacteria causing post-craniotomy intracranial infections in brain tumor patients. The overall median survival rate was 18±18.12 months when adding all 29 patients. Only one study described a significant higher survival rate for the infected group. CONCLUSIONS: Glioblastoma is the most frequent malignant brain tumor with a very poor outcome/survival. In the literature few cases described an exceptional longer survival often associated with a postoperative infection. To date, the pathophysiology behind this longer survival remains unclear, but it seems that Staphylococcus species could have an influence on the progression of this aggressive brain tumor.

Fitness-to-drive for glioblastoma patients: Guidance from the Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM).

OBJECTIVE: The management of brain tumour patients who would like to resume driving is complex, and needs multidisciplinary input and a consensus among treating physicians. The Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM) aim to provide guidance on how to assess "fitness-to-drive" of glioblastoma patients and to harmonise the relevant procedures in Switzerland. METHODS: At several meetings, Swiss neuro-oncologists discussed common practices on how to advise patients with a stable, i.e., non-progressive, glioblastoma, who wish to resume driving after the initial standard tumour treatment. All participants of the SwissNOS meetings were invited twice to return a questionnaire (modified Delphi process) on specific tools/procedures they commonly use to assess "fitness-to-drive" of their patients. Answers were analysed to formulate a tentative consensus for a structured and reasonable approach. RESULTS: Consensus on minimum requirements for a "fitness-to-drive" programme for glioblastoma patients could be reached among Swiss neuro-oncologists. The recommendations were based on existing guidelines and expert opinions regarding patients with seizures, visual disturbances, cognitive impairment or focal deficits for safe driving. At this point in time, the Swiss neuro-oncologists agreed on the following requirements for glioblastoma patients after the initial standard therapy and without a seizure for at least 12 months: (1) stable cranial magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria, to be repeated every 3 months; (2) thorough medical history, including current or new medication, a comprehensive neurological examination at baseline (T0) and every 3 months thereafter, optionally an electrocencephalogram (EEG) at baseline; (3) ophthalmological examination including visual acuity and intact visual fields; and (4) optional neuropsychological assessment with a focus on safe driving. Test results have to be compatible with safe driving at any time-point. Patients should be informed about test results and optionally sign a document. CONCLUSIONS: We propose regular thorough clinical neurological examination and brain MRI, optional EEG, neuropsychological and visual assessments to confirm "fitness-to-drive" for glioblastoma patients after initial tumour-directed therapy. The proposed "fitness-to-drive" assessments for glioblastoma patients serves as the basis for a prospective Swiss Pilot Project GLIODRIVE (BASEC ProjectID 2020-00365) to test feasibility, adherence and safety in a structured manner for patients who wish to resume driving. Research will focus on confirming the usefulness of the proposed tools in predicting "fitness-to-drive" and match results with events obtained from the road traffic registry (Strassenverkehrsamt).

Stellate ganglion block combined with intra-arterial treatment: a "one-stop shop" for cerebral vasospasm after aneurysmal subarachnoid hemorrhage-a pilot study.

PURPOSE: Delayed cerebral ischemia (DCI) is a frequent cause of morbidity and mortality in patients with cerebral vasospasm (CV) following aneurysmal subarachnoid hemorrhage (aSAH). Refractory CV remains challenging to treat and often leads to permanent deficits and death despite aggressive therapy. We hereby report the feasibility and safety of stellate ganglion block (SGB) performed with a vascular roadmap-guided technique to minimize the risk of accidental vascular puncture and may be coupled to a diagnostic or therapeutic cerebral angiography. METHODS: In addition to a detailed description of the technique, we performed a retrospective analysis of a series of consecutive patients with refractory CV after aSAH that were treated with adjuvant roadmap-guided SGB. Clinical outcomes at discharge are reported. RESULTS: Nineteen SGB procedures were performed in 10 patients, after failure of traditional hemodynamic and endovascular treatments. Each patient received 1 to 3 SGB, usually interspaced by 24 h. In 4 patients, an indwelling microcatheter for continuous infusion was inserted. First SGB occurred on average 7.3 days after aSAH. SGB was coupled to intra-arterial nimodipine infusion or balloon angioplasty in 9 patients. SGB was technically successful in all patients. There were no technical or clinical complications. CONCLUSION: Adjuvant SGB may be coupled to endovascular therapy to treat refractory cerebral vasopasm within the same session. To guide needle placement, using a roadmap of the supra-aortic arteries may decrease the risk of complications. More prospective data is needed to evaluate the therapeutic efficacy, durability, and safety of SGB compared with the established standard of care.

Clinical and radiological outcomes in relation with the anatomical orientation of clipped middle cerebral artery bifurcation aneurysms.

BACKGROUND: The middle cerebral artery (MCA) bifurcation represents the most frequent location for intracranial aneurysms. Often, the aneurysmal dome can hide the origin of perforating arteries from the M1 segment during the surgical clipping causing ischemic lesions and worse clinical outcome. The aim of this paper is to analyze the association between the orientation of the aneurysm sac and the clinical and radiological outcomes after surgical clipping. METHODS: Data from 50 MCA bifurcation clipped aneurysms in 47 patients were collected retrospectively. Three different groups were identified according to the aneurysmal sac orientation: anterior-inferior, posterior and superior. A possible association between the aneurysmal sac projection and the outcome was searched through a univariable logistic regression analysis. RESULTS: Statistical analysis showed significant correlation between the radiologic evidence of post-operative ischemia in the posterior group (p = 0.046, RR = 1.65) and an increased risk in the superior orientation group (p = 0.145, RR = 1.38). The anterior-inferior group was, instead, significantly associated with no evidence of radiologic ischemia (p = 0.0019, RR = 0.58). CONCLUSION: The orientation of the aneurysmal dome and sac represents a fundamental feature to be considered during the surgical clipping of the MCA aneurysms. Indeed, its posterior and superior projection is associated with a higher incidence of radiologic ischemic lesions due to the origin of perforating arteries from M1 segment behind the aneurysmal sac. The anterior-inferior orientation, on the contrary, is associated with a lower risk.

Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS).

BACKGROUND AND PURPOSE: The purpose of this study was to assess nationwide incidence and outcomes of aneurysmal subarachnoid hemorrhage (aSAH). The Swiss SOS (Swiss Study on Subarachnoid Hemorrhage) was established in 2008 and offers the unique opportunity to provide this data from the point of care on a nationwide level. METHODS: All patients with confirmed aneurysmal subarachnoid hemorrhage admitted between January 1, 2009 and December 31, 2014, within Switzerland were recorded in a prospective registry. Incidence rates were calculated based on time-matched population data. Admission parameters and outcomes at discharge and at 1 year were recorded. RESULTS: We recorded data of 1787 consecutive patients. The incidence of aneurysmal subarachnoid hemorrhage in Switzerland was 3.7 per 100 000 persons/y. The number of female patients was 1170 (65.5%). With a follow-up rate of 91.3% at 1 year, 1042 patients (58.8%) led an independent life according to the modified Rankin Scale (0-2). About 1 in 10 patients survived in a dependent state (modified Rankin Scale, 3-5; n=185; 10.4%). Case fatality was 20.1% (n=356) at discharge and 22.1% (n=391) after 1 year. CONCLUSIONS: The current incidence of aneurysmal subarachnoid hemorrhage in Switzerland is lower than expected and an indication of a global trend toward decreasing admissions for ruptured intracranial aneurysms. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03245866.

Use of Intraoperative CT Improves Accuracy of Spinal Navigation During Screw Fixation in Cervico-thoracic Region.

STUDY DESIGN: A retrospective analysis of a single-center consecutive series of patients. OBJECTIVE: To test the hypothesis that using a mobile intraoperative computed tomography in combination with spinal navigation would result in better accuracy of lateral mass and pedicle screws between C3 and T5 levels, compared to cone-beam computed tomography and traditional 2D fluoroscopy. SUMMARY OF BACKGROUND DATA: Use of spinal navigation associated with 3D imaging has been shown to improve accuracy of screw positioning in the cervico-thoracic region. However, use of iCT imaging compared to a cone-beam CT has not been fully investigated in these types of surgical interventions. METHODS: We retrospectively analyzed a series of patients who underwent posterior cervico-thoracic fixations using different intraoperative imaging systems in a single hospital. We identified three different groups of patients: Group A, operated under 2D-fluoroscopic guidance without navigation; Group B: O-arm guidance with navigation; Group C: iCT AIRO guidance with navigation. Primary outcome was the rate of accurately placed screws, measured on intra or postoperative CT scan with Neo et al. classification for cervical pedicles screws and Gertzbein et al. for thoracic pedicle screws. Screws in cervical lateral masses were evaluated according to a new classification created by the authors. RESULTS: Data on 67 patients and 495 screws were available. Overall screw accuracy was 92.8% (95.6% for lateral mass screws, 81.6% for cervical pedicle screws, and 90% for thoracic pedicle screws). Patients operated with iCT AIRO navigation had significantly fewer misplaced screws (2.4%) compared to 2D-fluoroscopic guidance (9.1%) and O-arm navigation (9.7%) (P = 0.0152). Accuracy rate of iCT navigation versus O-arm navigation was significantly higher (P = 0.0042), and there was no statistically significant difference in surgical time between the three Groups (P = 0.5390). CONCLUSION: Use of high-quality CT associated with spinal navigation significantly improved accuracy of screw positioning in the cervico-thoracic region.Level of Evidence: 3.

A contemporary perspective on the diagnosis and treatment of diffuse gliomas in adults.

Gliomas are intrinsic brain tumours, which are classified by the World Health Organization (WHO) into different grades of malignancy, with glioblastoma being the most frequent and most malignant subtype (WHO grade IV). Mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes are frequent in lower (WHO II/III) grade tumours but typically absent in classical glioblastoma. IDH mutations are associated with a better prognosis compared with IDH wild-type tumours of the same WHO grade. Following detection of a tumour mass by imaging, maximum safe surgery as feasible is commonly performed to reduce mass effect and to obtain tissue allowing histopathological diagnosis and molecular assessment. Radiotherapy has been the mainstay in the treatment of diffuse gliomas for several decades. It provides improved local control, but is not curative. Furthermore, several randomised trials have shown that the addition of alkylating chemotherapy, either temozolomide or nitrosourea-based regimens, to radiotherapy results in prolonged survival. Tumour-treating fields (TTFields) have emerged as an additional treatment option in combination with maintenance temozolomide treatment for patients with newly diagnosed glioblastoma. Treatment at recurrence is less standardised and depends on the patient’s performance status, symptom burden and prior treatments. Bevacizumab prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, but does not impact overall survival. However, in Switzerland and some other countries, it is still considered a valuable treatment option to reduce clinical symptom burden. Given the generally poor outcome for these patients, various novel treatment approaches are currently being explored within clinical trials including immunotherapeutic strategies such as immune checkpoint inhibition and the brain-penetrant proteasome inhibitor marizomib.

Cervical Radiculopathy Caused by a Vertebral Artery Loop: Is a Focused Fluoroscopic-Guided Cervical Epidural Steroid Injection a Possible Treatment Modality?

We describe a case of a patient suffering with cervical radiculopathy due to vertebral artery loop with nerve root compression, treated with an epidural steroid injection. A 37-year-old man presented with a 2-year history of right-sided radicular pain along the C7 dermatome. Imaging showed a right-sided loop of the vertebral artery at the V1-V2 transition with contact on the C7 nerve root. The pain was resistant to conservative treatment, and the decision was made to perform a focused fluoroscopy-guided translaminar epidural steroid injection near the C7 nerve root. The procedure was uneventful, and the symptoms resolved completely after the procedure. Targeted epidural steroid injection might be a useful and safe diagnostic and therapeutic approach in patients affected by cervical radiculopathy due to a VA loop. To our knowledge, this is the first case of a VA loop associated with cervical radiculopathy treated with this technique.

Corrigendum: Quantitative Modulation of PpIX Fluorescence and Improved Glioma Visualization.

[This corrects the article DOI: 10.3389/fsurg.2019.00041.].

Corrigendum to "Protoporphyrin IX tracer fluorescence modulation for improved brain tumor cell lines visualization".

Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase (FECH) and heme oxygenase-1 (HO-1) and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).

Plaque vulnerability in patients with high- and moderate-grade carotid stenosis - comparison of plaque features on MRI with histopathological findings.

  BACKGROUND: Plaque vulnerability plays an important role in determining the risk of subsequent cerebrovascular events in patients with carotid stenosis. Plaque morphology magnetic resonance imaging (MRI) can be used to assess plaque vulnerability. We therefore set out to examine the diagnostic accuracy of plaque morphology MRI compared with histopathological findings as gold standard in moderate- to high-grade carotid stenosis at our centre. METHODS: A total of 36 patients with moderate- to high-grade carotid stenosis underwent plaque morphology MRI with a multisequence protocol (time of flight sequence, dark blood T1- [native and post-gadolinium] and T2-weighted sequence with fat suppression). The status of the fibrous cap, calcification, lipid-rich necrotic core (LRNC) and intraplaque haemorrhage (IPH) were assessed by means of qualitative MR analysis of plaque characteristics and compared with the histopathological findings. Detection statistics (sensitivity, specificity), chi-squared test, Cohen’s kappa (κ), percentage of agreement and phi coefficient (φ) were determined. RESULTS: Carotid stenosis was symptomatic (transient ischaemic attack, amaurosis fugax or ischaemic stroke in the territory of the stenosed carotid artery) in 25 patients (69.5%). Twenty-eight patients (77.8%) had a high-grade and eight patients (12.2%) a moderate-grade stenosis. Significant congruence between MRI and histology was found for plaque calcification (89% histology, 75% MRI, κ = 0.364, p = 0.013), for LRNC (89% histology, 53% MRI, κ = 0.245, p = 0.025) and IPH (75% histology, 53% MRI, κ = 0.314, p = 0.035). In a subgroup of patients with symptomatic stenosis, the agreement for LRNC and IPH was slightly better (LRNC κ = 0.390, p = 0.014; IPH κ = 0.386, p = 0.045). Status of the fibrous cap, essentially ulceration, did not show any significant agreement (κ = 0.032, p = 0.842). There was significant correlation between LRNC on MRI and symptomatic carotid stenosis (φ = 0.339, p = 0.042). CONCLUSION: Plaque morphology MRI is capable of identifying the main components of atherosclerotic plaques with moderate to good accuracy as compared with histopathological findings as gold standard. LRNC seems to be a useful marker of plaque vulnerability and warrants its use in clinical decision making.  .

The Morphology of Somatosensory Evoked Potentials During Middle Cerebral Artery Aneurysm Clipping (MoSAC): A Pilot Study.

Somatosensory evoked potential (SEP) monitoring is a standard tool during clipping of aneurysms of the middle cerebral artery (MCA), and the parameter used to detect a state of cortical ischemia is amplitude. We think that the sensitivity of SEP can however be improved by using other parameters. Our study moves in this direction via SEP morphology. In this pilot preliminary study, involving a small sample without postoperative neurological deficit, we aimed at investigating the value of SEP morphology (in the 15- to 35-ms time frame), in comparison with SEP amplitude (N20 peak-to-peak), as a measure of sensitivity to blood flow reduction. The changes in the SEP morphology of 16 patients undergoing clipping of an unruptured MCA aneurysm was studied. We applied the Morph-Fréchet index for each recorded SEP (at 30-second intervals), quantifying the pattern shape change with regard to the average SEP recorded after dura opening (baseline). We also compared 3 measurements of the SEP morphology, without and with GARCH-derived filter. Filtered Morph-Fréchet never exceeded the individual's "normality" range in baseline but did so in 81% of the risk phase on average across the 16 subjects, which is more than that for amplitude (36%, P = .002). This pilot study indicates that a measurement derived from the networking nature of the brain was sensitive to blood flow reduction. The SEP morphology approach promises to improve SEP monitoring sensitivity during clipping of unruptured MCA aneurysms. New and Noteworthy. The higher sensitivity to blood flow reduction of SEP morphology than amplitude promises to improve the effectiveness of intraoperative monitoring during MCA aneurysm clipping procedures.

Stent screw-assisted internal fixation (SAIF): clinical report of a novel approach to stabilizing and internally fixating vertebrae destroyed by malignancy.

OBJECTIVE: Severe lytic cancerous lesions of the spine are associated with significant morbidity and treatment challenges. Stabilization and restoration of the axial load capability of the vertebral body (VB) are important to prevent or arrest vertebral collapse. Percutaneous stent screw-assisted internal fixation (SAIF), which anchors a VB stent/cement complex with pedicular screws to the posterior vertebral elements, is a minimally invasive, image-guided, 360° internal fixation technique that can be utilized in this patient cohort. The purpose of this study was to assess the feasibility, safety, and stabilization efficacy of VB reconstruction via the SAIF technique in a cohort of patients with extensive lytic vertebral lesions, who were considered to have an unstable or potentially unstable spine according to the Spinal Instability Neoplastic Score (SINS). METHODS: This study was a retrospective assessment of a prospectively maintained database of a consecutive series of patients with neoplastic extensive extracompartmental osteolysis (Tomita type 4-6) of the VB treated with the SAIF technique. VB reconstruction was assessed on postprocedure plain radiographs and CT by two independent raters. Technical and clinical complications were recorded. Clinical and imaging follow-ups were assessed. RESULTS: Thirty-five patients with extensive osteolytic metastatic lesions of the VB underwent 36 SAIF procedures. SAIF was performed as a stand-alone procedure in 31/36 cases and was associated with posterior surgical fixation in 5/36 (4/5 with decompressive laminectomy). In 1 case an epidural cement leak required surgical decompression. VB reconstruction was categorized as satisfactory (excellent or good rating) by the two raters in 34/36 cases (94.5%) with an interrater reliability of 94.4% (Cohen's kappa of 0.8). Follow-up, ranging from 1 to 30 months, was available for 30/36 levels. Long-term follow-up (6-30 months, mean 11.5 months) was available for 16/36 levels. Stability during follow-up was noted in 29/30 cases. CONCLUSIONS: SAIF provides 360° nonfusion internal fixation that stabilizes the VB in patients with extensive lytic lesions that would otherwise be challenging to treat.

Protoporphyrin IX tracer fluorescence modulation for improved brain tumor cell lines visualization.

Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase and heme oxygenase-1 and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).

Quantitative Modulation of PpIX Fluorescence and Improved Glioma Visualization.

5-Aminolevulinic acid (5-ALA) induced fluorescence to augment surgical resection for high grade glioma has become a standard of care. Protoporphyrin IX (PpIX) visibility is however subject to the variability of the single tumor expression and to the interobserver interpretation. We therefore hypothesized that in different glioma cell lines with variable 5-ALA induced fluorescence, the signal can be pharmacologically increased. We therefore analyzed in three different GBM cell lines, with different expression of epidermal growth factor receptor (EGFR), the variability of 5-ALA induced PpIX fluorescence after the pharmacological blockade at different steps of PpIX breakdown and influencing the outbound transport of PpIX. Using flow cytometry, fluorescence microplate reader, and confocal microscopy the PpIX fluorescence was analyzed after exposure to tin protoporphyrin IX (SnPP), deferoxamine (DFO), and genistein. We furthermore constructed a microscope (Qp9-microscope) being able to measure quantitatively the concentration of PpIX. These values were compared with the extraction of PpIX in tumor biopsy taken during the GBM surgery. Although all three cell lines showed an increase to 5-ALA induced fluorescence their baseline activity was different. Treatment with either SnPP, DFO and genistein was able to increase 5-ALA induced fluorescence. Qp9-microscopy of tumor sample produced a color coded PpIX concentration map which was overlaid on the tumor image. The PpIX extraction from tumor sample analyzed using the plate reader gave lower values of the concentration, as compared to the expected values of the Qp9-microscope, however still in the same decimal range of µg/mL. This may be due to homogenization of the values during extraction and cell disaggregation. In conclusion pharmacological augmentation in GBM cell lines of PpIX signal is possible. A quantitative PpIX map for surgery is feasible and may help refine surgical excision. Further correlations of tumor tissue samples and Qp9-microscopy is needed, prior to develop an intraoperative surgical adjunct to the already existing 5-ALA induced surgery.