Fluorescein-Guided Surgery for Resection of High-Grade Gliomas: A Multicentric Prospective Phase II Study (FLUOGLIO).

Purpose: Sodium fluorescein is a dye that, intravenously injected, selectively accumulates in high-grade glioma (HGG) tissue through a damaged blood-brain barrier. In this article, the final results of a multicentric prospective phase II trial (FLUOGLIO) on fluorescein-guided HGG resection through a dedicated filter on the surgical microscope were reported.Methods: Patients with suspected HGGs considered suitable for removal were eligible to participate in this trial. Fluorescein was intravenously injected at a dose of 5 to 10 mg/kg. The primary endpoint was the percentage of patients with histologically confirmed HGGs, without contrast-enhancing tumor at the immediate postoperative MRI. Secondary endpoints were PFS, residual tumor on postoperative MRI, overall survival, neurologic deficits, and fluorescein-related toxicity. The sensitivity and specificity of fluorescein in identifying tumor tissue were estimated by fluorescent and nonfluorescent biopsies at the tumor margin. The study was registered on the European Regulatory Authorities website (EudraCT 2011-002527-18).Results: Fifty-seven patients aged 45 to 75 years were screened for participation, and 46 were considered for primary and secondary endpoints. Mean preoperative tumor volume was 28.75 cm3 (range, 1.3-87.8 cm3). Thirty-eight patients (82.6%) underwent a complete tumor removal. Median follow-up was 11 months. PFS-6 and PFS-12 were 56.6% and 15.2%. Median survival was 12 months. No adverse reaction related to SF administration was recorded. The sensitivity and specificity of fluorescein in identifying tumor tissue were respectively 80.8% and 79.1%.Conclusions: Fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and enables a high percentage of contrast-enhancing tumor in patients with HGGs. Clin Cancer Res; 24(1); 52-61. ©2017 AACR.

Contrast-enhanced MR Imaging versus Contrast-enhanced US: A Comparison in Glioblastoma Surgery by Using Intraoperative Fusion Imaging.

Purpose To compare contrast material enhancement of glioblastoma multiforme (GBM) with intraoperative contrast-enhanced ultrasonography (US) versus that with preoperative gadolinium-enhanced T1-weighted magnetic resonance (MR) imaging by using real-time fusion imaging. Materials and Methods Ten patients with GBM were retrospectively identified by using routinely collected, anonymized data. Navigated contrast-enhanced US was performed after intravenous administration of contrast material before tumor resection. All patients underwent tumor excision with navigated intraoperative US guidance with use of fusion imaging between real-time intraoperative US and preoperative MR imaging. With use of fusion imaging, glioblastoma contrast enhancement at contrast-enhanced US (regarding location, morphologic features, margins, dimensions, and pattern) was compared with that at gadolinium-enhanced T1-weighted MR imaging. Results Fusion imaging for virtual navigation enabled matching of real-time contrast-enhanced US scans to corresponding coplanar preoperative gadolinium-enhanced T1-weighted MR images in all cases, with a positional discrepancy of less than 2 mm. Contrast enhancement of gadolinium-enhanced T1-weighted MR imaging and contrast-enhanced US was superimposable in all cases with regard to location, margins, dimensions, and morphologic features. The qualitative analysis of contrast enhancement pattern demonstrated a similar distribution in contrast-enhanced US and gadolinium-enhanced T1-weighted MR imaging in nine patients: Seven lesions showed peripheral inhomogeneous ring enhancement, and two lesions showed a prevalent nodular pattern. In one patient, the contrast enhancement pattern differed between the two modalities: Contrast-enhanced US showed enhancement of the entire bulk of the tumor, whereas gadolinium-enhanced T1-weighted MR imaging demonstrated peripheral contrast enhancement. Conclusion Glioblastoma contrast enhancement with contrast-enhanced US is superimposable on that provided with preoperative gadolinium-enhanced T1-weighted MR imaging regarding location, margins, morphologic features, and dimensions, with a similar enhancement pattern in most cases. Thus, contrast-enhanced US is of potential use in the surgical management of GBM. © RSNA, 2017 Online supplemental material is available for this article.

Extraneural metastases in glioblastoma patients: two cases with YKL-40-positive glioblastomas and a meta-analysis of the literature.

Glioblastoma (GBM) are high-grade gliomas that severely impact on overall survival (OS). GBM cell motility and the breakdown of the blood-brain barrier could favor GBM cell communication with the systemic circulation. In spite of this, extracranial GBM metastases are rare. Here, we describe two YKL-40-positive GBM patients with extra-CNS (central nervous system) metastases, and we present a meta-analysis of 94 cases. The analysis concluded that extra-CNS metastases occurred 8.5 months after first GBM diagnosis and OS was 12 months; surgical GBM excision was associated at a longer interval to extra-CNS metastasis than biopsy only, and even longer if followed by radiotherapy and chemotherapy. Both our case reports were adult males who developed extra-CNS, YKL-40-positive metastases at lymph nodes, lung and subcutaneous sites, after 86 and 24 months from initial diagnosis of GBM. At first GBM local recurrence, they were treated with bevacizumab (BV), an anti-vascular endothelial growth factor antibody. They died after 4 and 1 month from the occurrence of metastases. Both cases expressed YKL-40 and lacked EGFR amplification, suggesting a mesenchymal phenotype, and maintained such profile at extra-CNS recurrence; they did not show MGMT promoter methylation, IDH1/2 mutations, or c-Met upregulation. Our two cases and the meta-analysis support the idea that prolonged survival of GBM patients increases the probability of GBM cells shedding to lymphatic and hematic system. Interestingly, the present two cases showed the features of mesenchymal profile, usually related with worst prognosis that was maintained in extracranial metastases.

Towards the Personalized Treatment of Glioblastoma: Integrating Patient-Specific Clinical Data in a Continuous Mechanical Model.

Glioblastoma multiforme (GBM) is the most aggressive and malignant among brain tumors. In addition to uncontrolled proliferation and genetic instability, GBM is characterized by a diffuse infiltration, developing long protrusions that penetrate deeply along the fibers of the white matter. These features, combined with the underestimation of the invading GBM area by available imaging techniques, make a definitive treatment of GBM particularly difficult. A multidisciplinary approach combining mathematical, clinical and radiological data has the potential to foster our understanding of GBM evolution in every single patient throughout his/her oncological history, in order to target therapeutic weapons in a patient-specific manner. In this work, we propose a continuous mechanical model and we perform numerical simulations of GBM invasion combining the main mechano-biological characteristics of GBM with the micro-structural information extracted from radiological images, i.e. by elaborating patient-specific Diffusion Tensor Imaging (DTI) data. The numerical simulations highlight the influence of the different biological parameters on tumor progression and they demonstrate the fundamental importance of including anisotropic and heterogeneous patient-specific DTI data in order to obtain a more accurate prediction of GBM evolution. The results of the proposed mathematical model have the potential to provide a relevant benefit for clinicians involved in the treatment of this particularly aggressive disease and, more importantly, they might drive progress towards improving tumor control and patient's prognosis.

The lateral infratrigeminal transpontine window to deep pontine lesions.

OBJECT: Surgery of brainstem lesions is increasingly performed despite the fact that surgical indications and techniques continue to be debated. The deep pons, in particular, continues to be a critical area in which the specific risks related to different surgical strategies continue to be examined. With the intention of bringing new knowledge into this important arena, the authors systematically examined the results of brainstem surgeries that have been performed through the lateral infratrigeminal transpontine window. METHODS: Between 1990 and 2013, 29 consecutive patients underwent surgery through this window for either biopsy sampling or for removal of a deep pontine lesion. All of this work was performed at the Department of Neurosurgery of the Istituto Nazionale Neurologico "Carlo Besta", in Milan, Italy. A retrospective analysis of the findings was conducted with the intention of bringing further clarity to this important surgical strategy. RESULTS: The lateral infratrigeminal transpontine window was exposed through 4 different approaches: 1) classic retrosigmoid (15 cases), 2) minimally invasive keyhole retrosigmoid (10 cases), 3) translabyrinthine (1 case), and 4) combined petrosal (3 cases). No deaths occurred during the entire clinical study. The surgical complications that were observed included hydrocephalus (2 cases) and CSF leakage (1 case). In 6 (20.7%) of 29 patients the authors encountered new neurological deficits during the immediate postoperative period. All 6 of these patients had undergone lesion removal. In only 2 of these 6 patients were permanent sequelae observed at 3 months follow-up. These findings show that 93% of the patients studied did not report any permanent worsening of their neurological condition after this surgical intervention. CONCLUSIONS: This retrospective study supports the idea that the lateral infratrigeminal transpontine window is both a low-risk and safe corridor for either biopsy sampling or for removal of deep pontine lesions.

Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging, and investigational cell-based therapies.

Stroke continues to be a significant cause of death and disability worldwide. Although major advances have been made in the past decades in prevention, treatment, and rehabilitation, enormous challenges remain in the way of translating new therapeutic approaches from bench to bedside. Thrombolysis, while routinely used for ischemic stroke, is only a viable option within a narrow time window. Recently, progress in stem cell biology has opened up avenues to therapeutic strategies aimed at supporting and replacing neural cells in infarcted areas. Realistic experimental animal models are crucial to understand the mechanisms of neuronal survival following ischemic brain injury and to develop therapeutic interventions. Current studies on experimental stroke therapies evaluate the efficiency of neuroprotective agents and cell-based approaches using primarily rodent models of permanent or transient focal cerebral ischemia. In parallel, advancements in imaging techniques permit better mapping of the spatial-temporal evolution of the lesioned cortex and its functional responses. This review provides a condensed conceptual review of the state of the art of this field, from models and magnetic resonance imaging techniques through to stem cell therapies.

Is fluorescein-guided technique able to help in resection of high-grade gliomas?

OBJECT: Fluorescein, a dye that is widely used as a fluorescent tracer, accumulates in cerebral areas where the blood-brain barrier is damaged. This quality makes it an ideal dye for the intraoperative visualization of high-grade gliomas (HGGs). The authors report their experience with a new fluorescein-guided technique for the resection of HGGs using a dedicated filter on the surgical microscope. METHODS: The authors initiated a prospective Phase II trial (FLUOGLIO) in September 2011 with the objective of evaluating the safety of fluorescein-guided surgery for HGGs and obtaining preliminary evidence regarding its efficacy for this purpose. To be eligible for participation in the study, a patient had to have suspected HGG amenable to complete resection of the contrast-enhancing area. The present report is based on the analysis of the short- and long-term results in 20 consecutive patients with HGGs (age range 45-74 years), enrolled in the study since September 2011. In all cases fluorescein (5-10 mg/kg) was injected intravenously after intubation. Tumor resection was performed with microsurgical technique and fluorescence visualization by means of BLUE 400 or YELLOW 560 filters on a Pentero microscope. RESULTS: The median preoperative tumor volume was 30.3 cm(3) (range 2.4-87.8 cm(3)). There were no adverse reactions related to fluorescein administration. Complete removal of contrast-enhanced tumor was achieved in 80% of the patients. The median duration of follow-up was 10 months. The 6-months progression-free survival rate was 71.4% and the median survival was 11 months. CONCLUSIONS: Analysis of these 20 cases suggested that fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and allows a high rate of complete resection of contrast-enhanced tumor as determined on early postoperative MRI. Clinical trial registration no.: 2011-002527-18 (EudraCT).

Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function.

OBJECTIVES: The aim of this study was to compare the prevalence of silent cerebral ischemia (SCI) and cognitive performance in patients with paroxysmal and persistent atrial fibrillation (AF) and controls in sinus rhythm. BACKGROUND: Large registries have reported a similar risk for symptomatic stroke in both paroxysmal and persistent AF. The relationship among paroxysmal and persistent AF, SCI, and cognitive impairment has remained uncharted. METHODS: Two hundred seventy subjects were enrolled: 180 patients with AF (50% paroxysmal and 50% persistent) and 90 controls. All subjects underwent clinical assessment, neurological examination, cerebral magnetic resonance, and the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: At least 1 area of SCI was present in 80 patients (89%) with paroxysmal AF, 83 (92%) with persistent AF (paroxysmal vs. persistent, p = 0.59), and 41 (46%) controls (paroxysmal vs. controls and persistent vs. controls, p < 0.01). The number of areas of SCI per subject was higher in patients with persistent AF than in those with paroxysmal AF (41.1 ± 28.0 vs. 33.2 ± 22.8, p = 0.04), with controls reporting lower figures (12.0 ± 26.7, p < 0.01 for both). Cognitive performance was significantly worse in patients with persistent and paroxysmal AF than in controls (Repeatable Battery for the Assessment of Neuropsychological Status scores 82.9 ± 11.5, 86.2 ± 13.8, and 92.4 ± 15.4 points, respectively, p < 0.01). CONCLUSIONS: Patients with paroxysmal and persistent AF had a higher prevalence and number of areas of SCI per patient than controls and worse cognitive performance than subjects in sinus rhythm.

Performance assessment of four 64-slice computed tomographic devices for a typical clinical protocol.

OBJECTIVE: To compare the performances of four 64-slice CT devices, as regards radiation dose and image quality. METHODS: Effective dose was measured with thermoluminescent dosimeters in an Alderson Rando phantom (Alderson Research Laboratories, New York, NY). Quantitative image quality was evaluated in a Catphan 600 phantom (The Phantom Laboratory, New York, NY) using 3 parameters (modulation transfer function, contrast-to-noise ratio, and figure of merit). Effective and main organ doses were measured in 40 patients (10 for each CT device), who underwent an abdominal study with the same standard protocol; moreover, in these patients, clinical image quality, using a 5-grade quality score, was assessed. RESULTS: In-phantom measured doses and quantitative image quality showed some differences among the 4 devices. On the contrary, effective and organ doses provided to the patients were similar; no statistically significant differences were found also for clinical image quality. CONCLUSIONS: Some differences were found among the 4 devices from a physical point of view; on the other hand, the patient data were similar.

Morphologic analysis of left atrial anatomy by magnetic resonance angiography in patients with atrial fibrillation: a large single center experience.

UNLABELLED: LA and PV Anatomy in Patients With AF. INTRODUCTION: Although transcatheter atrial fibrillation (AF) ablation requires accurate anatomic knowledge, pulmonary vein (PV) anatomy has not been fully investigated. Aim of this study is to describe left atrium (LA) and PV anatomy by magnetic resonance angiography (MRA) in a large cohort of patients with AF. METHODS: MRA was performed in 473 patients preceding transcatheter AF ablation (paroxysmal 60.9%; persistent 39.1%). The Venice Chart classification was used to classify PV branching patterns. RESULTS: About 40% of the patients presented typical PV branching pattern (2 left and 2 right PVs). A representative number of patients presented a common left trunk (19.9% and 11.0% short and long, respectively). A right middle PV was described in 12.5% and 2 right middle PVs in 1.5% patients. The remaining patients presented other complex, previously unclassified patterns: 6.3% presented an accessory PV originating from LA areas not describable as right or "upper" and 8.7% a common left trunk plus right middle PV. Diameters and circumference of each PV, LA, and LA appendage volumes resulted larger in patients presenting persistent compared to paroxysmal AF (P < 0.001). CONCLUSION: This study highlights that "typical" PV branching pattern is not a common finding. That 25.6% of the patients present at least 1 accessory PV needs to be kept in careful consideration when planning and performing transcatheter AF ablation. In addition, not only LA volume, but also each PV ostia and LA appendage are significantly enlarged in patients with persistent compared to paroxysmal AF.

Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation.

BACKGROUND: Radiofrequency left atrial catheter ablation has become a routine procedure for treatment of atrial fibrillation. The aim of this study was to assess with preprocedural and postprocedural cerebral magnetic resonance imaging the thromboembolic risk, either silent or clinically manifest, in the context of atrial fibrillation ablation. The secondary end point was the identification of clinical or procedural parameters that correlate with cerebral embolism. METHODS AND RESULTS: A total of 232 consecutive patients with paroxysmal or persistent atrial fibrillation who were candidates for radiofrequency left atrial catheter ablation were included in the study. Pulmonary vein isolation or pulmonary vein isolation plus linear lesions plus atrial defragmentation with the use of irrigated-tip ablation catheters was performed. All of the patients underwent preprocedural and postablation cerebral magnetic resonance imaging. A periprocedural symptomatic cerebrovascular accident occurred in 1 patient (0.4). Postprocedural cerebral magnetic resonance imaging was positive for new embolic lesions in 33 patients (14). No clinical parameters such as age, hypertension, diabetes mellitus, previous history of stroke, type of atrial fibrillation, and preablation antithrombotic treatment showed significant correlation with ischemic cerebral embolism. Procedural parameters such as activated clotting time value and, in particular, electric or pharmacological cardioversion to sinus rhythm correlated with an increased incidence of cerebral embolism. Cardioversion was also associated with an increased risk of 2.75 (95 confidence interval, 1.29 to 5.89; P=0.009). CONCLUSIONS: Radiofrequency left atrial catheter ablation carries a low risk of symptomatic cerebral ischemia but is associated with a substantial risk of silent cerebral ischemia detected on magnetic resonance imaging. Independent risk factors for cerebral thromboembolism are the level of activated clotting time and, in particular, the electric or pharmacological cardioversion to sinus rhythm during the procedure.

Left atrial volume at MRI is the main determinant of outcome after pulmonary vein isolation plus linear lesion ablation for paroxysmal-persistent atrial fibrillation.

AIMS: To assess retrospectively clinical and procedural predictors of long-term recurrences after atrial fibrillation ablation. METHODS: Two hundred and forty consecutive patients (201 men; mean age 60 +/- 10 years) undergoing pulmonary vein isolation (PVI) plus linear lesion ablation for antiarrhythmic drug-refractory atrial fibrillation between 2005 and 2007 were studied. Magnetic resonance imaging of the left atrium was performed in all the patients. Patients were followed up with clinical examination and ECG Holter at 1, 3, 6 months and every 6 months thereafter. In case of recurrence, a second procedure was offered. Clinical and procedural data were evaluated with univariate and multivariate analysis. RESULTS: At a mean follow-up of 30.3 +/- 9.2 months after one or two procedures, 99 (41.3%) patients were in sinus rhythm without antiarrhythmic drugs and 50 patients (20.8%) had arrhythmia recurrences. These groups were compared in order to identify the clinical predictors of recurrences. Variables directly related to failure at univariate analysis were: history of persistent atrial fibrillation, number of previous electrical cardioversions, left atrial volume (LAV) at MRI, presence of pulmonary vein anatomical variants and BMI. At multivariate analysis, only left atrial volume measured at MRI was an independent predictor of failure. CONCLUSION: With long-term follow-up, LAV at MRI represents the main determinant of outcome after PVI plus linear lesion for ablation of paroxysmal and persistent atrial fibrillation.

Pulmonary veins branching pattern, assessed by magnetic resonance, does not affect transcatheter atrial fibrillation ablation outcome.

AIM: The aim of the present study is to provide, in a large cohort of patients, a description of the left atrium (LA) and pulmonary veins (PV) anatomy in relation to ablation outcome. BACKGROUND: The role of LA imaging, assessed before transcatheter ablation of atrial fibrillation (AF), is unknown. METHODS: 330 patients referred for transcatheter ablation of AF (paroxysmal 62.7%; persistent 25.5%; long-standing 11.8%) underwent contrast-enhanced magnetic resonance imaging (MRI) before the procedure. Transcatheter ablation was performed aiming to AF interruption and/or absence of inducibility. Patients were followed clinically, by ECG, and 24-hour Holter ECG at 1-3-6-12-18-24 months. RESULTS: The MRI preceding the procedure depicted a typical PV branching pattern, two left and two right, in 130 (39.4%) patients; 117 (35.4%) presented common left trunk (short and long) and 75 (22.7%) at least one accessory PV. Mean atrial volume was 142.0 +/- 48.5 ml. The ablation procedure resulted successful, after 15.6 +/- 7.2 months follow-up, in 174 (52.7%) patients. PV branching pattern did not relate (P = 0.304) to ablation outcome. A multiple Cox proportional hazard model, adjusted for potential confounders, proved that only LA volume was independently related to ablation outcome (HR 1.007, 95% CI 1.003-1.011; P = 0.001). A LA cut-off volume of 135 ml emerged as a significant predictor of ablation failure (ROC curve area 0.651, 95% CI 0.591-0.710; P < 0.001). CONCLUSIONS: Less than half of the patients referred for transcatheter AF ablation present a typical PV branching pattern; the PV branching pattern, however, does not affect ablation outcome. LA volume strongly predicts AF ablation outcome.

Native whole-heart coronary imaging for the identification of anomalous origin of the coronary arteries.

Congenital abnormalities of the coronary arteries are an uncommon cause of chest pain and in some cases may cause sudden cardiac death. We examined with magnetic resonance (MR) a 52 year-old woman presenting with effort angina, and positive treadmill stress test. Whole-heart coronary imaging performed without paramagnetic contrast agents revealed an anomalous origin of a single coronary artery from the right sinus of Valsalva. This is one of the first reports describing whole-heart coronary MR finding of an anomalous origin of the coronary arteries, obtained without contrast agents.