Postoperative CT scans after resection of brain metastases: neurosurgical routine or added value?

BACKGROUND: Metastasis is the most common brain tumor in adults. It is the standard of care at most North American centers to obtain an early postoperative imaging after their resection. However, the necessity of this practice in the absence of a new postoperative deficit remains unclear. METHODS: We retrospectively reviewed our surgical cohort of patients who underwent resection of brain metastases from July 2018 to June 2019. We collected demographic data and reviewed results of routine postoperative CT scans and neurological morbidities to examine the diagnostic and therapeutic yield of an early postoperative scan. In addition, we performed a systematic review of the topic. RESULTS: Our review included 130 patients, all of whom underwent gross total resection of one or more brain metastases. On postoperative CT, none had unexpected findings such as cavity hematoma or new ischemia; no changes in management resulted from postoperative imaging. One patient required a higher dose of dexamethasone on postoperative day 4 for delayed hemiparesis and aphasia due to cerebral edema. Three additional patients underwent a wound washout for delayed infection during a subsequent admission. Our systematic review identified three additional studies; in a combined cohort of 450 patients (including our own), no patients had clinically actionable findings on routine postoperative CT. CONCLUSIONS: Following resection of brain metastases, a routine postoperative CT scan has low diagnostic yield and did not change patient management in any cases examined in this work.

High Diagnostic Accuracy of Visible 5-ALA Fluorescence in Meningioma Surgery According to Histopathological Analysis of Tumor Bulk and Peritumoral Tissue.

BACKGROUND AND OBJECTIVES: Complete neurosurgical resection of intracranial meningiomas is essential to avoid residual tumor tissue and thus minimize the risk of tumor recurrence. However, local recurrence of meningiomas is not uncommon mainly due to insufficient intraoperative detection of residual tumor tissue within the tumor bulk or peritumoral tissue such as bone and satellite lesions. Although 5-aminolevulinic acid (5-ALA) induced fluorescence was found to visualize the majority of meningiomas, no comprehensive histopathological assessment of fluorescing samples from the tumor bulk and peritumoral tissue is available. The aim of our study was thus to histopathologically analyze a large series of tissue samples derived from meningioma surgery to assess the positive predictive value (PPV) of visible 5-ALA fluorescence. STUDY DESIGN/MATERIALS AND METHODS: In this study, we retrospectively investigated a series of tissue samples with visible 5-ALA fluorescence collected during surgery of intracranial meningiomas from the tumor bulk and peritumoral tissue including the bone flap, dura/dural tail, arachnoidea, adjacent cortex, and satellite lesions. The tumor diagnosis was established according to the World Health Organization (WHO) criteria and all collected fluorescing samples were screened for presence of tumor tissue to calculate the PPV. RESULTS: Altogether, 191 tissue samples with visible 5-ALA fluorescence derived during surgery of 85 meningiomas (63 WHO grade I, 17 WHO grade II, and 5 WHO grade III) were included. In detail, 158 samples from the tumor bulk and 33 specimens from the peritumoral tissue were investigated. According to histopathological analysis, the PPV of 5-ALA fluorescence was significantly higher in samples from the tumor bulk (100%) as compared with peritumoral tissue (73%; P < 0.001). With regard to peritumoral tissue, tumor tissue was present in most fluorescing samples from the satellite lesions (100%), the bone flap (92%), arachnoidea (83%), and dura/dural tail (75%). In contrast, tumor tissue was absent in the majority of samples from fluorescing cortex (six of seven samples; 86%). However, distinct reactive tissue alterations were found in all six tumor-free fluorescing cortex samples and additional vascular proliferation in two cases. CONCLUSION: In this largest series to date, visible 5-ALA fluorescence is characterized by a high PPV detecting tumor bulk and peritumoral tissue in intracranial meningiomas. Thus, 5-ALA fluorescence supports the neurosurgeon in identifying residual tumor tissue at relevant surgical sites to optimize meningioma surgery and minimize the risk of local recurrence. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

Endoscopic extra-capsular resection of a giant pituitary adenoma: how I do it.

BACKGROUND: Giant pituitary adenomas are characterized by their large size and potential to invade parasellar and suprasellar regions leading to visual decline and hypopituitarism. Thus, they remain a significant surgical challenge, and gross total removal is only achieved in the minority of cases. METHOD: We aim to describe the key surgical steps for endoscopic extra-capsular resection of a giant pituitary adenoma with the aim of achieving complete tumor resection with description of the relevant surgical anatomy, indications and limitations. CONCLUSION: Endoscopic extra-capsular resection of giant pituitary tumors when feasible allows for complete tumor resection, early identification of the gland and avoidance of manipulation of the optic apparatus.

New-onset seizures after cranioplasty-a different view on a putatively frequently observed phenomenon.

BACKGROUND: New-onset seizures after cranioplasty (NOSAC) are reported to be a frequent complication of cranioplasty (CP) after decompressive hemicraniectomy (DHC). There are considerable differences in the incidence of NOSAC and contradictory data about presumed risk factors in the literature. We suggest NOSAC to be a consequence of patients' initial condition which led to DHC, rather than a complication of subsequent CP. We conducted a retrospective analysis to verify our hypothesis. METHODS: The medical records of all patients ≥ 18 years who underwent CP between 2002 and 2017 at our institution were evaluated including incidence of seizures, time of seizure onset, and presumed risk factors. Indication for DHC, type of implant used, timing of CP, patient age, presence of a ventriculoperitoneal shunt (VP shunt), and postoperative complications were compared between patients with and without NOSAC. RESULTS: A total of 302 patients underwent CP between 2002 and 2017, 276 of whom were included in the outcome analysis and the incidence of NOSAC was 23.2%. Although time between DHC and CP differed significantly between DHC indication groups, time between DHC and seizure onset did not differ, suggesting the occurrence of seizures to be independent of the procedure of CP. Time of follow-up was the only factor associated with the occurrence of NOSAC. CONCLUSION: New-onset seizures may be a consequence of the initial condition leading to DHC rather than of CP itself. Time of follow-up seems to play a major role in detection of new-onset seizures.

Cranioplasty following ventriculoperitoneal shunting: lessons learned.

OBJECTIVE: Cranioplasty (CP) is considered as a straightforward and technically unchallenging operation; however, complication rates are high reaching up to 56%. Presence of a ventriculoperitoneal shunt (VPS) and timing of CP are reported risk factors for complications. Pressure gradients and scarring at the site of the cranial defect seem to be critical in this context. The authors present their experiences and lessons learned. METHODS: A consecutive series of all patients who underwent CP at the authors' institution between 2002 and 2017 were included in this retrospective analysis. Complications were defined as all events that required reoperation. Logistic regression analysis and chi-squared test were conducted to evaluate the complication rates according to suspected risk factors. RESULTS: A total of 302 patients underwent cranioplasty between 2002 and 2017. The overall complication rate was 17.5%. Complications included epi-/subdural fluid collection (7.3%) including hemorrhage (4.6%) and hygroma (2.6%), bone graft resorption (5.3%), bone graft infection (2.0%), and hydrocephalus (5.7%). Overall, 57 patients (18.9%) had undergone shunt implantation prior to CP. The incidence of epi-/subdural fluid collection was 19.3% in patients with VPS and 4.5% in patients without VPS, OR 5.1 (95% CI 2.1-12.4). Incidence of hygroma was higher in patients who underwent early CP. Patients with temporary shunt ligation for CP did not suffer from complications. CONCLUSION: CP in patients with a VPS remains a high-risk procedure. Any effort to understand the pressure dynamics and to reduce factors that may trigger the formation of a large epidural space must be undertaken.

5-aminolevulinic acid induced protoporphyrin IX (ALA-PpIX) fluorescence guidance in meningioma surgery.

INTRODUCTION: 5-aminolevulinic acid induced protoporphyrin IX (5-ALA-PpIX) fluorescence guidance has emerged as a valuable surgical adjunct for resection of intracranial tumors. METHODS: Here we present a focused review on 5-ALA-PpIX fluorescence guidance for meningiomas. RESULTS: We discuss the clinical studies and specific applications to date as well as the two main intraoperative fluorescence technologies applied to meningiomas. CONCLUSIONS: The use of 5-ALA-PpIX in meningiomas holds promising potential so neurosurgeons can improve surgical outcomes for patients with meningiomas as well as be pioneers in developing improved fluorescence imaging technologies.

Focal irregularities in 7-Tesla MRI of unruptured intracranial aneurysms as an indicator for areas of altered blood-flow parameters.

OBJECTIVE: In the last several decades, various factors have been studied for a better evaluation of the risk of rupture in incidentally discovered intracranial aneurysms (IAs). With advanced MRI, attempts were made to delineate the wall of IAs to identify weak areas prone to rupture. However, the field strength of the MRI investigations was insufficient for reasonable image resolution in many of these studies. Therefore, the aim of this study was to analyze findings of IAs in ultra-high field MRI at 7 Tesla (7 T). METHODS: Patients with incidentally found IAs of at least 5 mm in diameter were included in this study and underwent MRI investigations at 7 T. At this field strength a hyperintense intravascular signal can be observed on nonenhanced images with a brighter "rim effect" along the vessel wall. Properties of this rim effect were evaluated and compared with computational fluid dynamics (CFD) analyses. RESULTS: Overall, 23 aneurysms showed sufficient image quality for further evaluation. In 22 aneurysms focal irregularities were identified within this rim effect. Areas of such irregularities showed significantly higher values in wall shear stress and vorticity compared to areas with a clearly visible rim effect (p = 0.043 in both). CONCLUSIONS: A hyperintense rim effect along the vessel wall was observed in most cases. Focal irregularities within this rim effect showed higher values of the mean wall shear stress and vorticity when compared by CFD analyses. Therefore, these findings indicate alterations in blood flow in IAs within these areas.

Challenging the osseous component of sphenoorbital meningiomas.

BACKGROUND: Intraosseous growth is a unique feature of sphenoorbital meningiomas (SOM). Its close relation to neurovascular structures limits complete surgical resection and possibly contributes to the high recurrence rate. OBJECTIVE: To evaluate the growth behavior of intraosseous remnants and develop a protocol for precise intraoperative visualization of intraosseous SOM. METHODS: We included 31 patients operated for SOM from 2004 to 2017. The growth velocity of the intraosseous tumor component was volumetrically calculated in 20 cases. To improve accuracy of image guidance, we implemented a specialized bone surface-based registration algorithm. For intraoperative bone visualization, we included CT in multimodality continuous image guidance in 23 patients. The extent of resection (EOR) was compared with a standard MR-only navigation group (n = 8). RESULTS: In 11/20 cases (55%), a progressive regrowth of the intraosseous SOM remnant was noted during a mean follow-up of 52 months (range 20-132 months). We observed a mean increase of 6.2 cm3 (range 0.2-23.7 cm3) per patient and side during the follow-up period. Bone surface-based registration was significantly more accurate than skin surface-based registration (mean 0.7 ± 0.4 mm and 1.9 ± 0.7 mm, p < 0.001). The EOR of the intraosseous component was significantly higher using CT + MRI navigation compared with controls (96% vs. 81%, p = 0.044). CONCLUSION: Quantitative assessment of the biological behavior of intraosseous remnants revealed a continuous slow growth rate independent of the soft tumor component of more than half of SOM. According to our data, application of a multimodal image guidance provided high accuracy and significantly increased the resection rate of the intraosseous component of SOM.

MGMT assessment in pituitary adenomas: comparison of different immunohistochemistry fixation chemicals.

PURPOSE: Despite the established role of O6-methyl-guanine-DNA methyltransferase (MGMT) as a marker for temozolomide response, consensus of the most reliable method to assess MGMT expression in pituitary adenomas is still missing. Currently, immunohistochemistry (IHC) assessment of formaldehyde fixed tissue samples is most widely used in a semiquantitative description. As formaldehyde fails to completely preserve nucleic acids, RCL2, an alcohol-based formaldehyde-free fixative, has been proposed as a more reliable alternative in terms of cell stability. Furthermore, as the current method of IHC is semiquantitative and observer-dependent, pyrosequencing, an objective tool to evaluate the methylation status of the MGMT promoter, has emerged as a reliable and accurate alternative. The aim of this study was to validate the current IHC method for assessment of MGMT protein expression in pituitary adenomas. METHODS: The tissue samples of 8 macroadenomas with positive IHC MGMT expression (> 50%) were investigated: first, we compared the time dependent stability of MGMT protein expression after pituitary adenoma removal between formaldehyde vs. RCL2. Then, we compared positive IHC MGMT expression with methylated promoter status using pyrosequencing. RESULTS: In the first 12 h after adenoma removal, tissue samples remained MGMT positive in significantly more samples when fixated with formaldehyde than with RCL2, respectively (96 vs. 81%, p = 0.025). CONCLUSION: Our data confirm that the current method using formaldehyde tissue fixation and IHC reveals stable and reliable results of MGMT assessment in pituitary adenomas.

5-ALA-induced fluorescence as a marker for diagnostic tissue in stereotactic biopsies of intracranial lymphomas: experience in 41 patients.

OBJECTIVE Stereotactic needle biopsies are usually performed for histopathological confirmation of intracranial lymphomas to guide adequate treatment. During biopsy, intraoperative histopathology is an effective tool to avoid acquisition of nondiagnostic samples. In the last years, 5-aminolevulinic acid (5-ALA)-induced fluorescence has been increasingly used for visualization of diagnostic brain tumor tissue during stereotactic biopsies. Recently, visible fluorescence was reported in the first cases of intracranial lymphomas as well. The aim of this study is thus to investigate the technical and clinical utility of 5-ALA-induced fluorescence in a large series of stereotactic biopsies for intracranial lymphoma. METHODS This prospective study recruited adult patients who underwent frameless stereotactic needle biopsy for a radiologically suspected intracranial lymphoma after oral 5-ALA administration. During biopsy, samples from the tumor region were collected for histopathological analysis, and presence of fluorescence (strong, vague, or no fluorescence) was assessed with a modified neurosurgical microscope. In tumors with available biopsy samples from at least 2 different regions the intratumoral fluorescence homogeneity was additionally investigated. Furthermore, the influence of potential preoperative corticosteroid treatment or immunosuppression on fluorescence was analyzed. Histopathological tumor diagnosis was established and all collected biopsy samples were screened for diagnostic lymphoma tissue. RESULTS The final study cohort included 41 patients with intracranial lymphoma. Stereotactic biopsies with assistance of 5-ALA were technically feasible in all cases. Strong fluorescence was found as maximum level in 30 patients (75%), vague fluorescence in 2 patients (4%), and no visible fluorescence in 9 patients (21%). In 28 cases, samples were obtained from at least 2 different tumor regions; homogenous intratumoral fluorescence was found in 16 of those cases (57%) and inhomogeneous intratumoral fluorescence in 12 (43%). According to histopathological analysis, all samples with strong or vague fluorescence contained diagnostic lymphoma tissue, resulting in a positive predictive value of 100%. Analysis showed no influence of preoperative corticosteroids or immunosuppression on fluorescence. CONCLUSIONS The data obtained in this study demonstrate the technical and clinical utility of 5-ALA-induced fluorescence in stereotactic biopsies of intracranial lymphomas. Thus, 5-ALA can serve as a useful tool to select patients not requiring intraoperative histopathology, and its application should markedly reduce operation time and related costs in the future.

Local image variance of 7 Tesla SWI is a new technique for preoperative characterization of diffusely infiltrating gliomas: correlation with tumour grade and IDH1 mutational status.

OBJECTIVES: To investigate the value of local image variance (LIV) as a new technique for quantification of hypointense microvascular susceptibility-weighted imaging (SWI) structures at 7 Tesla for preoperative glioma characterization. METHODS: Adult patients with neuroradiologically suspected diffusely infiltrating gliomas were prospectively recruited and 7 Tesla SWI was performed in addition to standard imaging. After tumour segmentation, quantification of intratumoural SWI hypointensities was conducted by the SWI-LIV technique. Following surgery, the histopathological tumour grade and isocitrate dehydrogenase 1 (IDH1)-R132H mutational status was determined and SWI-LIV values were compared between low-grade gliomas (LGG) and high-grade gliomas (HGG), IDH1-R132H negative and positive tumours, as well as gliomas with significant and non-significant contrast-enhancement (CE) on MRI. RESULTS: In 30 patients, 9 LGG and 21 HGG were diagnosed. The calculation of SWI-LIV values was feasible in all tumours. Significantly higher mean SWI-LIV values were found in HGG compared to LGG (92.7 versus 30.8; p < 0.0001), IDH1-R132H negative compared to IDH1-R132H positive gliomas (109.9 versus 38.3; p < 0.0001) and tumours with significant CE compared to non-significant CE (120.1 versus 39.0; p < 0.0001). CONCLUSIONS: Our data indicate that 7 Tesla SWI-LIV might improve preoperative characterization of diffusely infiltrating gliomas and thus optimize patient management by quantification of hypointense microvascular structures. KEY POINTS: • 7 Tesla local image variance helps to quantify hypointense susceptibility-weighted imaging structures. • SWI-LIV is significantly increased in high-grade and IDH1-R132H negative gliomas. • SWI-LIV is a promising technique for improved preoperative glioma characterization. • Preoperative management of diffusely infiltrating gliomas will be optimized.

Analysis of 5-aminolevulinic acid-induced fluorescence in 55 different spinal tumors.

OBJECT: Subtotal resection (STR) of spinal tumors can result in tumor recurrence. Currently, no clinically reliable marker is available for intraoperative visualization of spinal tumor tissue. Protoporphyrin IX (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) is capable of visualizing malignant gliomas. Fluorescence-guided resections of malignant cerebral gliomas using 5-ALA have resulted in an increased rate of complete tumor removal. Recently, the application of 5-ALA has also been described in the first cases of spinal tumors. Therefore, the aim of this observational study was to systematically investigate 5-ALA-induced fluorescence characteristics in different spinal tumor entities. METHODS: Three hours before the induction of anesthesia, 5-ALA was administered to patients with different intra- and extradural spinal tumors. In all patients a neurosurgical resection or biopsy of the spinal tumor was performed under conventional white-light microscopy. During each surgery, the presence of PpIX fluorescence was additionally assessed using a modified neurosurgical microscope. At the end of an assumed gross-total resection (GTR) under white-light microscopy, a final inspection of the surgical cavity of fluorescing intramedullary tumors was performed to look for any remaining fluorescing foci. Histopathological tumor diagnosis was established according to the current WHO classification. RESULTS: Fifty-two patients with 55 spinal tumors were included in this study. Resection was performed in 50 of 55 cases, whereas 5 of 55 cases underwent biopsy. Gross-total resection was achieved in 37 cases, STR in 5, and partial resection in 8 cases. Protoporphyrin IX fluorescence was visible in 30 (55%) of 55 cases, but not in 25 (45%) of 55 cases. Positive PpIX fluorescence was mainly detected in ependymomas (12 of 12), meningiomas (12 of 12), hemangiopericytomas (3 of 3), and in drop metastases of primary CNS tumors (2 of 2). In contrast, none of the neurinomas (8 of 8), carcinoma metastases (5 of 5), and primary spinal gliomas (3 of 3; 1 pilocytic astrocytoma, 1 WHO Grade II astrocytoma, 1 WHO Grade III anaplastic oligoastrocytoma) revealed PpIX fluorescence. It is notable that residual fluorescing tumor foci were detected and subsequently resected in 4 of 8 intramedullary ependymomas despite assumed GTR under white-light microscopy. CONCLUSIONS: In this study, 5-ALA-PpIX fluorescence was observed in spinal tumors, especially ependymomas, meningiomas, hemangiopericytomas, and drop metastases of primary CNS tumors. In cases of intramedullary tumors, 5-ALA-induced PpIX fluorescence is a useful tool for the detection of potential residual tumor foci.

The value of cryoablation in orbital surgery.

Aim of this article is to give an overview of the technical background and the advantages of modern devices for different applications of cryoablation in cranio-orbital neurosurgery.The treatment of orbital lesions is complicated by the complex and potentially inapparent anatomy due to retro-orbital fat. With the help of cryoprobes different well-defined lesions such as cavernous venous malformations can be safely and effectively removed thanks to the cryoadhesive effect. Their use has been described in several different approaches including traditional lateral or transcranial orbitotomy but also anterior transconjunctival as well as transnasal endoscopic approaches. Recently, single-use devices were introduced that allow the use of cryosurgery also without the need for large investment or service costs.

Is location more determining than WHO grade for long-term clinical outcome in patients with meningioma in the first two decades of life?

OBJECTIVE: To identify factors for tumor relapse and poor outcome in patients with meningiomas in the first two decades of life. METHODS: All patients ≤ 21 years of age who underwent resection of a meningioma at the department of neurosurgery, Medical University of Vienna between 1989 and 2022 were included in this retrospective study. Clinical and radiological data were extracted from the medical records. Outcome and tumor relapse were analyzed for tumor location, histological findings and extent of resection. RESULTS: In this study 18 patients were included, 6 meningiomas were located in the skull base, 5 in the convexity and 7 in other locations including intraventricular and spine (2 patients each), falx, intraparenchymal and optic nerve sheath. Most frequent symptoms were seizures and cranial nerve palsy. In total 56% of the meningiomas were World Health organization (WHO) grade 1, 39% grade 2 and 5% grade 3. Gross total resection was achieved in 67%. The overall relapse rate was 61% and 50% underwent repeat surgery. All patients with convexity meningiomas became seizure free and had a favorable outcome. Relapse and clinical outcome were independent of WHO grade among the whole cohort but the outcome significantly depended on the WHO grade when patients with skull base meningiomas were analyzed as a subgroup. The relapse rate was significantly higher in cases of skull base location (100% vs. 42%, p = 0.038) and after subtotal resection (100% vs. 42%, p = 0.038). Clinical outcome was also significantly worse and the rate of complications was higher in patients with skull base meningiomas. CONCLUSION: Patients with convexity meningiomas in the first two decades of life have a good outcome due to high chance of gross total resection. Patients with skull base meningioma are at high risk of relapse and poor outcome, particularly those with WHO grades 2 and 3. Subtotal resection in patients with skull base location is probably the main reason for this difference.

Distance to thrombus, ischemic lesion volume and clinical outcome after thrombectomy for M1 middle cerebral artery occlusion.

BACKGROUND: Stroke resulting from occlusion of the middle cerebral artery (MCA) can have devastating consequences, potentially leading to a loss of independence. This study aimed to investigate the relationship between the distance to the thrombus (DT) and both ischemic lesion volume (ILV) and clinical outcomes. METHODS: We retrospectively evaluated patients with thromboembolic MCA M1 segment occlusion who underwent neurovascular imaging followed by endovascular thrombectomy (EVT) at two comprehensive stroke centers over a 3-year period (2018-2020). Preinterventional computed tomography (CT) or magnetic resonance (MR) angiography was used to measure DT, defined as the distance from the carotid­T bifurcation to the proximal surface of the M1 occlusion. Postinterventional CT or MR imaging was employed to determine the ILV and clinical outcomes were assessed using the modified Rankin scale (mRS) at 3 months. RESULTS: There were 346 patients evaluated. The median DT was 9.4 mm (interquartile range, IQR 6.0-13.7 mm) and the median ILV was 13.9 ml (IQR 2.2-53.1 ml). After adjustment, an increase in DT was associated with a decrease in odds for a larger ILV (odds ratio, OR 0.96, 95% confidence interval, CI 0.92-0.99, p = 0.041). Through this association, more distal thrombi were associated with good clinical outcome (mRS 0-2; clinical outcome available in 282 patients, p = 0.018). The ILV was inversely associated with better clinical outcome OR 0.52 (95% CI 0.40-0.67). CONCLUSION: Based on the findings, DT was identified as an independent albeit weak predictor for ILV and clinical outcomes in patients with MCA M1 occlusion who underwent EVT.

Comparison of minimal detectable protoporphyrin IX concentrations with a loupe device and conventional 5-ALA fluorescence microscopy: an experimental study.

Significance: The 5-aminolevulinic acid (5-ALA) fluorescence technique is now widely applied for intraoperative visualization of specific central nervous system (CNS) tumors. Previous technical implementations of this technique have relied on specifically modified surgical microscopes to visualize intratumoral fluorescent protoporphyrin (PpIX). While this approach evidently allows for reliable intraoperative tumor visualization, it requires the availability of specifically modified surgical microscopes and their use even in cases where the operating neurosurgeon would prefer to use surgical loupes. Recently, a novel loupe device was introduced that is also capable of visualizing 5-ALA fluorescence. Aim: The aim of this study was therefore to compare the detected PpIX concentrations between the conventional fluorescence microscope and the novel loupe device. Approach: We used fluorescence phantoms of different PpIX concentrations for comparison between a conventional fluorescence microscope and the novel loupe device. For this purpose, we created fluorescence images using the excitation light sources of the conventional fluorescence microscope and the loupe device with both available background illumination modes (low and high). Subsequently, the minimal detectable PpIX concentrations according to each technique were determined by five independent neurosurgeons. Results: Using the conventional fluorescence microscope, the median minimal detectable PpIX concentration was 0.16 µg/ml (range: 0.15 to 0.17 µg/ml). By the loupe device, the median minimal detectable PpIX concentration was 0.12 µg/ml (range: 0.10 to 0.12 µg/ml) and 0.08 µg/ml (range: 0.07 to 0.08 µg/ml) for the high- and low-modes, respectively. Altogether, the minimal detectable PpIX concentrations were significantly lower using the loupe device compared to the conventional fluorescence microscope (p=0.007). Conclusions: Our data indicate that the novel loupe device is able to visualize 5-ALA fluorescence with high sensitivity and thus might serve as a powerful tool for visualization of specific CNS tumors in the future.

CD34 microvascularity in low-grade glioma: correlation with 5-aminolevulinic acid fluorescence and patient prognosis in a multicenter study at three specialized centers.

OBJECTIVE: Early markers are urgently needed in low-grade glioma (LGG) evaluation to rapidly estimate the individual patient's prognosis and to determine the optimal postoperative management. Generally, visible 5-aminolevulinic acid (5-ALA) fluorescence is present in only a few LGGs. Recently, the authors identified visible 5-ALA fluorescence as a powerful intraoperative marker for unfavorable outcome in LGG treatment. However, its precise histopathological correlate is unclear. Neoangiogenesis represents a crucial event in tumor evolution, and CD34 is an established marker for vascular endothelial progenitors potentially indicating tumor progression. The aim of this study was thus to correlate 5-ALA fluorescence and CD34 microvascularity as well as to investigate the prognostic value of CD34 in a large series of LGGs. METHODS: In this retrospective study including 3 specialized centers, patients with histopathologically confirmed isocitrate dehydrogenase-mutated LGGs (WHO grade II) receiving 5-ALA prior to resection were included. During surgery, the presence of visible fluorescence was analyzed and one representative tumor sample from the area with the maximum fluorescence effect (tumor with focal fluorescence or nonfluorescing tumor) was selected for each LGG. All fluorescing or nonfluorescing tumor samples were stained for CD34 and semiquantitatively analyzed for microvascular proliferation patterns (physiological vessels, branching capillaries, or microvessel clusters) as well as automatically quantified for CD34 microvessel density (MVD) by standardized histomorphometry software. These semiquantitative/quantitative CD34 data were correlated to the fluorescence status and patient outcome including progression-free survival (PFS), malignant transformation-free survival (MTFS), and overall survival (OS). RESULTS: In a total of 86 LGGs, visible fluorescence was found during surgery in 13 (15%) cases. First, the semiquantitative CD34 score significantly correlated with intraoperative fluorescence (p = 0.049). Accordingly, the quantitative CD34 MVD was significantly higher in tumors showing fluorescence (p = 0.03). Altogether, the semiquantitative CD34 score showed a strong correlation with quantitative CD34 MVD (p < 0.001). At a mean follow-up of 5.4 ± 2.6 years, microvessel clusters in semiquantitative analysis were a prognostic marker for poor PFS (p = 0.01) and MTFS (p = 0.006), but not OS (p = 0.28). Finally, quantitative CD34 MVD > 10 vessels/mm2 was a prognostic marker for poor PFS (p = 0.01), MTFS (p = 0.008), and OS (p = 0.049). CONCLUSIONS: The data indicate that CD34 microvascularity is associated with intraoperative 5-ALA fluorescence and outcomes in patients with LGG. Thus, visible fluorescence in LGGs might indicate increased CD34 microvascularity, serving as an early prognostic marker for unfavorable patient outcome that is already available during surgery.

Clinico-pathologic predictors of dismal course in atypical meningiomas: a retrospective single-centre analysis.

BACKGROUND: Despite continuous refinement of the WHO classification for meningiomas, the biological behaviour of atypical meningiomas remains difficult to predict on the basis of this grading system alone. The aim of this study was to investigate the prognostic significance of clinical and radiological parameters in a series of atypical meningioma with long follow-up of minimum 5 years. METHODS: Of 1675 meningiomas treated at the Medical University Vienna between 1993 and 2015, 179 were atypical meningioma. Of those, 93 patients were identified with follow-up of ≥5 years. Patients were grouped by recurrence and evaluated for overall and progression free survival as well as potential prognostic parameters such as age, gender, tumor size and location, edema, irregular surface, contrast enhancement, bone invasion and hyperostosis, necrosis, EOR and MIB-1. RESULTS: From 42 (45%) patients in group recurrent and 51 (55%) patients in group nonrecurrent, seven independent factors were associated with decreased progression-free survival in univariate analysis: size ≥5 cm, age ≥60 years, male gender, subtotal resection, irregular surface, and necrosis on magnetic resonance imaging, and MIB-1 ≥6%. In multivariable analysis, only larger size, older age, necrosis and higher MIB-1 remained independent prognostic risk factors for recurrence of atypical meningioma. CONCLUSIONS: We identified larger size, older age, presence of necrosis on magnetic resonance imaging, and higher MIB-1, as detrimental parameters for recurrence of atypical meningioma. Until molecular profiling of atypical meningioma becomes routinely available, these parameters may aid the clinician in decision making about surveillance intervals and adjuvant radiation treatment.

Triamcinolone acetonide can be detected in cerebrospinal fluid after intratympanic injection.

Intratympanically applied treatments are of increasing interest to the otologic community to treat sudden sensorineural hearing loss or vestibular disorders but also to deliver gene therapy agents, or biologics to the inner ear. Further diversion from the middle ear and perilymph to blood circulation and cerebrospinal fluid via the cochlear aqueduct are one of the limiting factors and so far not understood well enough. In this study, intratympanically applied triamcinolone acetonide was determined in cerebrospinal fluid. Additionally, perilymph was sampled through the round window membrane as well as at the lateral semicircular canal to determine drug levels. Of the twenty-one included patients, triamcinolone acetonide was quantifiable in cerebrospinal fluid in 43% at very low levels (range 0 ng/ml-6.2 ng/ml) which did not correlate with perilymph levels. Drug levels at the two different perilymph sampling sites were within a range of 13.5 ng/ml to 1180.0 ng/ml. Results suggest an equal distribution of triamcinolone acetonide to semicircular canals, which might support the use of triamcinolone acetonide as a treatment option for vestibular pathologies such as Menièrés disease. On the other hand, the distribution to cerebrospinal fluid might be limiting current approaches in gene therapy where a central distribution is unwanted.

DNA Methylation Associates With Clinical Courses of Atypical Meningiomas: A Matched Case-Control Study.

Background: Accounting for 15-20% of all meningiomas, WHO grade II meningiomas represent an intermediate group regarding risk of tumor recurrence. However, even within this subgroup varying clinical courses are observed with potential occurrence of multiple recurrences. Recently, DNA methylation profiles showed their value for distinguishing biological behaviors in meningiomas. Therefore, aim of this study was to investigate DNA methylation profiles in WHO grade II meningiomas. Methods: All patients that underwent resection of WHO grade II meningiomas between 1993 and 2015 were screened for a dismal course clinical course with ≥2 recurrences. These were matched to control cases with benign clinical courses without tumor recurrence. DNA methylation was assessed using the Infinium Methylation EPIC BeadChip microarray. Unsupervised hierarchical clustering was performed for identification of DNA methylation profiles associated with such a dismal clinical course. Results: Overall, 11 patients with WHO grade II meningiomas with ≥2 recurrences (Group dismal) and matched 11 patients without tumor recurrence (Group benign) were identified. DNA methylation profiles revealed 3 clusters-one comprising only patients of group dismal, a second cluster comprising mainly patients from group benign and a third cluster comprising one group dismal and one group benign patient. Based on differential methylation pattern associations with the Wnt and the related cadherin signaling pathway was observed. Conclusion: DNA methylation clustering showed remarkable differences between two matched subgroups of WHO grade II meningiomas. Thus, DNA methylation profiles may have the potential to support prognostic considerations regarding meningioma recurrence and radiotherapeutic treatment allocation after surgical resection.