Publications by authors named "Engelbert Knosp"

97 Publications

Acute and life-threatening complications in Cushing's syndrome: prevalence, predictors and mortality.

J Clin Endocrinol Metab 2021 Jan 31. Epub 2021 Jan 31.

Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel, Vienna, Austria.

Context: Cushing's syndrome (CS) results in significant morbidity and mortality.

Objective: To study acute and life-threatening complications in patients with active CS.

Design: Retrospective cohort study.

Setting: In- and outpatient records of patients with CS in a tertiary center.

Patients: 242 patients with CS, including 213 with benign CS (pituitary n=101, adrenal n=99, ectopic n=13), and 29 with malignant disease.

Main Outcome Measures: We collected acute complications necessitating hospitalization, from appearance of first symptoms of hypercortisolism until one year after biochemical remission. Mortality data were obtained from the national registry. Baseline factors relating to and predicting acute complications were tested using uni- and multivariate analysis.

Results: The prevalence of acute complications was 62% in patients with benign pituitary CS, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Complications observed in patients with benign CS included infections (25%), thromboembolic events (17%), hypokalemia (13%), hypertensive crises (9%), cardiac arrhythmias (5%) and acute coronary events (3%). 23% of these patients were hospitalized for acute complications before CS was suspected, and half of complications occurred after the first surgery. HbA1c and 24-hour urinary free cortisol (UFC) positively correlated with the number of acute complications per patient. Patients with malignant disease had significantly higher rates of acute complications. Mortality during the observation period was 2.8% and 59% in benign and malignant CS, respectively.

Conclusions: This analysis highlights the whole spectrum of acute and life-threatening complications in CS, and their high prevalence even before disease diagnosis and after successful surgery.
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http://dx.doi.org/10.1210/clinem/dgab058DOI Listing
January 2021

5-ALA fluorescence for intraoperative visualization of spinal ependymal tumors and identification of unexpected residual tumor tissue: experience in 31 patients.

J Neurosurg Spine 2020 Dec 4:1-9. Epub 2020 Dec 4.

1Department of Neurosurgery.

Objective: Gross-total resection (GTR) is the treatment of choice in the majority of patients suffering from spinal ependymal tumors. In such tumors, the extent of resection (EOR) is considered the key factor for tumor recurrence and thus patient prognosis. However, incomplete resection is not uncommon and leads to increased risk of tumor recurrence. One important cause of incomplete resection is insufficient intraoperative visualization of tumor tissue as well as residual tumor tissue. Therefore, the authors investigated the value of 5-aminolevulinic acid (5-ALA)-induced fluorescence in a series of spinal ependymal tumors for improved tumor visualization.

Methods: Adult patients who underwent preoperative 5-ALA administration and surgery for a spinal ependymal tumor were included in this study. For each tumor, a conventional white-light microsurgical resection was performed. Additionally, the fluorescence status (strong, vague, or no fluorescence) and fluorescence homogeneity (homogenous or inhomogeneous) of the spinal ependymal tumors were evaluated during surgery using a modified neurosurgical microscope. In intramedullary tumor cases with assumed GTR, the resection cavity was investigated for potential residual fluorescing foci under white-light microscopy. In cases with residual fluorescing foci, these areas were safely resected and the corresponding samples were histopathologically screened for the presence of tumor tissue.

Results: In total, 31 spinal ependymal tumors, including 27 intramedullary tumors and 4 intradural extramedullary tumors, were included in this study. Visible fluorescence was observed in the majority of spinal ependymal tumors (n = 25, 81%). Of those, strong fluorescence was noted in 23 of these cases (92%), whereas vague fluorescence was present in 2 cases (8%). In contrast, no fluorescence was observed in the remaining 6 tumors (19%). Most ependymal tumors demonstrated an inhomogeneous fluorescence effect (17 of 25 cases, 68%). After assumed GTR in intramedullary tumors (n = 15), unexpected residual fluorescing foci within the resection cavity could be detected in 5 tumors (33%). These residual fluorescing foci histopathologically corresponded to residual tumor tissue in all cases.

Conclusions: This study indicates that 5-ALA fluorescence makes it possible to visualize the majority of spinal ependymal tumors during surgery. Unexpected residual tumor tissue could be detected with the assistance of 5-ALA fluorescence in approximately one-third of analyzed intramedullary tumors. Thus, 5-ALA fluorescence might be useful to increase the EOR, particularly in intramedullary ependymal tumors, in order to reduce the risk of tumor recurrence.
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http://dx.doi.org/10.3171/2020.6.SPINE20506DOI Listing
December 2020

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

Lasers Surg Med 2021 Mar 1;53(3):300-308. Epub 2020 Jul 1.

Department of Neurosurgery, Medical University Vienna, Waehringer Gürtel 18-20, Vienna, 1090, Austria.

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.
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http://dx.doi.org/10.1002/lsm.23294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048546PMC
March 2021

Expression of additional transcription factors is of prognostic value for aggressive behavior of pituitary adenomas.

J Neurosurg 2020 Apr 17:1-8. Epub 2020 Apr 17.

1Department of Neurosurgery.

Objective: According to the latest WHO classification of tumors of endocrine organs in 2017, plurihormonal adenomas are subclassified by their transcription factor (TF) expression. In the group of plurihormonal adenomas with unusual immunohistochemical combinations (PAWUC), the authors identified a large fraction of adenomas expressing TFs for gonadotroph adenoma (TFGA) cells in addition to other TFs. The aim of this study was to compare clinicopathological parameters of PAWUC with TFGA expression to gonadotroph adenomas that only express TFGA.

Methods: This retrospective single-center series comprises 73 patients with TFGA-positive pituitary adenomas (SF1, GATA3, estrogen receptor α): 22 PAWUC with TFGA (TFGA-plus group) and 51 with TFGA expression only (TFGA-only group). Patient characteristics, outcome parameters, rate of invasiveness (assessed by direct endoscopic inspection), and MIB1 and MGMT status were compared between groups.

Results: Patients in the TFGA-plus group were significantly younger than patients in the TFGA-only group (age 46 vs 56 years, respectively; p = 0.007). In the TFGA-only group, pituitary adenomas were significantly larger (diameter 25 vs 18.3 mm, p = 0.002). Intraoperatively, signs of invasiveness were significantly more common in the TFGA-plus group than in the TFGA-only group (50% vs 16%, p = 0.002). Gross-total resection was significantly lower in the nonfunctioning TFGA-plus group than in the TFGA-only group (44% vs 86%, p = 0.004). MIB1 and MGMT status showed no significant difference between groups.

Conclusions: These data suggest a more aggressive behavior of TFGA-positive adenomas if an additional TF is expressed within the tumor cells. Shorter radiographic surveillance and earlier consideration for retreatment should be recommended in these adenoma types.
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http://dx.doi.org/10.3171/2020.2.JNS2018DOI Listing
April 2020

Optimizing MR imaging for intraoperative image guidance in sellar pathologies.

Pituitary 2020 Jun;23(3):266-272

Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1097, Vienna, Austria.

Purpose: With the advancement of extended endonasal approaches, the ability to surgically reach parasellar tumor extensions increase. The aim of the study was to propose an optimized imaging protocol for surgical guidance in the cavernous sinus (CS) for proper visualization structures at risk.

Methods: Prospective case control analysis of 20 consecutive pituitary adenoma patients scheduled for endoscopic transnasal surgery. Assessment of the capability of three different MRI sequences (MPRAGE, VIBE, CISS) by 4 investigators to correctly visualize sellar and parasellar structures. Invasiveness and position of the normal pituitary gland were compared with the intraoperative findings.

Results: The consensus between the 4 examiners to achieve the same results for all modalities was 40% for MPRAGE, 70% for VIBE and 60% for CISS sequences (p = 0.155). A consensus of Knosp Grade per patient was 80% for MPRAGE, 100% for VIBE and 90% for CISS (overall kappa 0.60). A higher Knosp Grade was found in MPRAGE sequences compared to the other sequences. Intraoperative status of invasiveness was correctly identified in 12/20 (60%) with MPRAGE, 19/20 (95%) with VIBE and 11/20 (55%) with CISS sequences. The position of the normal pituitary gland was most frequent evaluable in 15/20 (75%) and correctly identified in 12/15 (80%) cases.

Conclusion: Our data showed that VIBE sequences obtain the highest degree of consensus with intraoperative findings of invasiveness and position of the normal pituitary gland. VIBE sequences, due to their high spatial resolution and at the same time fast image acquisition could provide improved imaging for neuronavigation.
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http://dx.doi.org/10.1007/s11102-020-01035-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181417PMC
June 2020

High Interobserver Agreement in the Subjective Classification of 5-Aminolevulinic Acid Fluorescence Levels in Newly Diagnosed Glioblastomas.

Lasers Surg Med 2020 11 8;52(9):814-821. Epub 2020 Mar 8.

Department of Neurosurgery, Medical University Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria.

Background And Objectives: Fluorescence-guided resection of glioblastomas (GBM) using 5-aminolevulinic acid (5-ALA) improves intraoperative tumor visualization and is thus widely used nowadays. During resection, different fluorescence levels can usually be distinguished within the same tumor. Recently, we demonstrated that strong, vague, and no fluorescence correspond to distinct histopathological characteristics in newly diagnosed GBM. However, the qualitative fluorescence classification by the neurosurgeon is subjective and currently no comprehensive data on interobserver variability is available. The aim of this study was thus to investigate the interobserver variability in the classification of 5-ALA fluorescence levels in newly diagnosed GBM.

Study Design/materials And Methods: A questionnaire investigating the interobserver variability in 5-ALA fluorescence quantification was performed at a nation-wide neurosurgical oncology meeting. The participants involved in the neurosurgical/neurooncological field were asked to categorize 30 cases of 5-ALA fluorescence images derived from GBM resection on a lecture hall screen according to the widely used three-tier fluorescence classification scheme (negative, vague, or strong fluorescence). Additionally, participants were asked for information on their medical background such as specialty, level of training, and experience with 5-ALA fluorescence-guided procedures. Interobserver agreement was defined as the calculated mean κ values for each observer.

Results: A total of 36 questionnaires were included in the final analysis. The mean average κ value in fluorescence classification within the entire cohort was 0.71 ± 0.12 and 29 (81%) participants had a substantial or almost perfect interobserver agreement (κ values 0.6-1.0). Interobserver agreement was significantly higher in neurosurgeons (mean κ: 0.83) as compared with non-neurosurgeons involved in the neurooncological field (mean κ: 0.52; P < 0.001). Furthermore, interobserver agreement was significantly higher in participants who had experience with at least 25 5-ALA fluorescence-guided surgeries (mean κ: 0.87) compared with less experienced colleagues (mean κ: 0.82; P = 0.039).

Conclusion: Our study found a high interobserver agreement in the qualitative classification of different 5-ALA fluorescence levels in newly diagnosed GBM. Interobserver agreement increases significantly in more experienced participants and therefore a high level of experience is crucial for reliable intraoperative fluorescence classification. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586784PMC
November 2020

Ectopic Cushing's syndrome in a patient with inferior petrosal sinus sampling indicating pituitary-dependent ACTH secretion.

Clin Case Rep 2020 Jan 14;8(1):104-107. Epub 2019 Dec 14.

Department of Internal Medicine III Division of Endocrinology and Metabolism Medical University Vienna Vienna Austria.

In an unclear case of Cushing's syndrome, IPSS identifies the origin of ACTH secretion, and together with MRI enables the localization of an ectopic corticotroph adenoma in the parasellar or cavernous sinuses region.
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http://dx.doi.org/10.1002/ccr3.2586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982514PMC
January 2020

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

Neurosurg Focus 2019 12;47(6):E7

1Department of Neurosurgery.

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.
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http://dx.doi.org/10.3171/2019.9.FOCUS19489DOI Listing
December 2019

Detailed analysis of 5-aminolevulinic acid induced fluorescence in different brain metastases at two specialized neurosurgical centers: experience in 157 cases.

J Neurosurg 2019 Sep 27:1-12. Epub 2019 Sep 27.

2Department of Neurosurgery, Medical University of Vienna, Austria.

Objective: Incomplete neurosurgical resection of brain metastases (BM) due to insufficient intraoperative visualization of tumor tissue is a major clinical challenge and might result in local recurrence. Recently, visible 5-aminolevulinic acid (5-ALA) induced fluorescence was first reported in patients with BM. The aim of this study was thus to investigate, for the first time systematically, the value of 5-ALA fluorescence for intraoperative visualization of BM in a large patient cohort.

Methods: Adult patients (≥ 18 years) with resection of suspected BM after preoperative 5-ALA administration were prospectively recruited at two specialized neurosurgical centers. During surgery, the fluorescence status (visible or no fluorescence); fluorescence quality (strong, vague, or none); and fluorescence homogeneity (homogeneous or heterogeneous) of each BM was investigated. Additionally, these specific fluorescence characteristics of BM were correlated with the primary tumor type and the histopathological subtype. Tumor diagnosis was established according to the current WHO 2016 criteria.

Results: Altogether, 157 BM were surgically treated in 154 patients. Visible fluorescence was observed in 104 BM (66%), whereas fluorescence was absent in the remaining 53 cases (34%). In detail, 53 tumors (34%) showed strong fluorescence, 51 tumors (32%) showed vague fluorescence, and 53 tumors (34%) had no fluorescence. The majority of BM (84% of cases) demonstrated a heterogeneous fluorescence pattern. According to primary tumor, visible fluorescence was less frequent in BM of melanomas compared to all other tumors (p = 0.037). According to histopathological subtype, visible fluorescence was more common in BM of ductal breast cancer than all other subtypes (p = 0.008). It is of note that visible fluorescence was observed in the surrounding brain tissue after the resection of BM in 74 (67%) of 111 investigated cases as well.

Conclusions: In this largest series to date, visible 5-ALA fluorescence was detected in two-thirds of BM. However, the characteristic heterogeneous fluorescence pattern and frequent lack of strong fluorescence limits the use of 5-ALA in BM and thus this technique needs further improvements.
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http://dx.doi.org/10.3171/2019.6.JNS1997DOI Listing
September 2019

Challenging the osseous component of sphenoorbital meningiomas.

Acta Neurochir (Wien) 2019 11 1;161(11):2241-2251. Epub 2019 Aug 1.

Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1080, Vienna, Austria.

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 cm (range 0.2-23.7 cm) 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.
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http://dx.doi.org/10.1007/s00701-019-04015-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820812PMC
November 2019

ICAR: endoscopic skull-base surgery.

Int Forum Allergy Rhinol 2019 07;9(S3):S145-S365

University of Pittsburgh, Pittsburgh, PA.

Background: Endoscopic skull-base surgery (ESBS) is employed in the management of diverse skull-base pathologies. Paralleling the increased utilization of ESBS, the literature in this field has expanded rapidly. However, the rarity of these diseases, the inherent challenges of surgical studies, and the continued learning curve in ESBS have resulted in significant variability in the quality of the literature. To consolidate and critically appraise the available literature, experts in skull-base surgery have produced the International Consensus Statement on Endoscopic Skull-Base Surgery (ICAR:ESBS).

Methods: Using previously described methodology, topics spanning the breadth of ESBS were identified and assigned a literature review, evidence-based review or evidence-based review with recommendations format. Subsequently, each topic was written and then reviewed by skull-base surgeons in both neurosurgery and otolaryngology. Following this iterative review process, the ICAR:ESBS document was synthesized and reviewed by all authors for consensus.

Results: The ICAR:ESBS document addresses the role of ESBS in primary cerebrospinal fluid (CSF) rhinorrhea, intradural tumors, benign skull-base and orbital pathology, sinonasal malignancies, and clival lesions. Additionally, specific challenges in ESBS including endoscopic reconstruction and complication management were evaluated.

Conclusion: A critical review of the literature in ESBS demonstrates at least the equivalency of ESBS with alternative approaches in pathologies such as CSF rhinorrhea and pituitary adenoma as well as improved reconstructive techniques in reducing CSF leaks. Evidence-based recommendations are limited in other pathologies and these significant knowledge gaps call upon the skull-base community to embrace these opportunities and collaboratively address these shortcomings.
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http://dx.doi.org/10.1002/alr.22326DOI Listing
July 2019

A New Clip Generation for Microsurgical Treatment of Intracranial Aneurysms-The First Case Series.

World Neurosurg 2019 Oct 13;130:e160-e165. Epub 2019 Jun 13.

Department of Neurosurgery, Saarland University Medical Center, Homburg, Germany.

Objective: Considerable effort has been made in order to reduce surgical invasiveness while maintaining optimal exploiting of the operative space in aneurysm surgery. One aspect of this evolution is represented by the Lazic (Peter Lazic GmbH, Tuttlingen, Germany) aneurysm clip system. The purpose of this study was to illustrate the new generation clip system in practiced aneurysm surgery.

Methods: A retrospective analysis of all aneurysm surgeries in our departments between December 2015 and January 2018 using the new D-Clip system was performed. Evaluation included standardized retrospective review of the main surgeon, the nursing staff, as well as an analysis of surgical video documentation by objective reviewers.

Results: Forty-five patients with 50 intracranial aneurysms underwent surgical clipping using the D-Clip system. A total of 64 permanent and 19 temporary D-Clips were applied. Nine clips needed to be replaced. All aneurysms could be occluded totally. Surgeons considered handling and manoeuvrability of clip application as feasible and good in all cases (100%), even under impaired visibility circumstances (14%). Objective video analysis revealed comparable results. Nursing staff scored handling and practicability of D-Clips equivalent to the preceding L-Clip generation. There were no intraoperative complications. Surgery-related postoperative morbidity was 6.7%.

Conclusions: The new D-Clip system combines an attenuated design for minimally invasive clipping procedures with traditional mechanisms of common clip systems. It therefore appears to be highly versatile in the context of variable different aneurysm morphologies and locations while maintaining high standard surgical safety and efficacy.
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http://dx.doi.org/10.1016/j.wneu.2019.06.023DOI Listing
October 2019

Challenging Knosp high-grade pituitary adenomas.

J Neurosurg 2019 May 31;132(6):1739-1746. Epub 2019 May 31.

1Department of Neurosurgery.

Objective: Parasellar growth is one of the most important prognostic variables of pituitary adenoma surgery, with adenomas regarded as not completely resectable if they invade the cavernous sinus (CS) but potentially curable if they displace CS structures. This study was conducted to correlate surgical treatment options and outcomes to the different biological behaviors (invasion vs displacement) of adenomas with parasellar extension into the superior or inferior CS compartments or completely encasing the carotid artery (Knosp high grades 3A, 3B, and 4).

Methods: This was a retrospective cohort analysis of 106 consecutive patients with Knosp high-grade pituitary adenomas with parasellar extension who underwent surgery via a primary endoscopic transsphenoidal approach between 2003 and 2017. Biological tumor characteristics (surgical status of invasiveness and tumor texture, 2017 WHO classification, proliferation rate), extent of resection, and complication rate were correlated with parasellar extension grades 3A, 3B, and 4 on preoperative MRI studies.

Results: Invasiveness was significantly less common in grade 3A (44%) than in grade 3B (72%, p = 0.037) and grade 4 (100%, p < 0.001) adenomas. Fibrous tumor texture was significantly more common in grade 4 (52%) compared to grade 3A (20%, p = 0.002), but not compared to grade 3B (28%) adenomas. Functioning macroadenomas had a significantly higher rate of invasiveness than nonfunctioning adenomas (91% vs 55%, p = 0.002). Mean proliferation rate assessed by MIB-1 was > 3% in all groups but without significant difference between the groups (grade 3A, 3.2%; 3B, 3.9%; 4, 3.7%). Rates of endocrine remission/gross-total resection were significantly higher in grade 3A (64%) than in grade 3B (33%, p = 0.021) and grade 4 (0%, p < 0.001) adenomas. In terms of complication rates, no significant difference was observed between grades.

Conclusions: According to the authors' data, the biological behavior of pituitary adenomas varies significantly between parasellar extension patterns. Adenomas with extension into the superior CS compartment have a lower rate of invasive growth than adenomas extending into the inferior CS compartment or encasing the carotid artery. Consequently, a significantly higher rate of remission can be achieved in grade 3A than in grade 3B and grade 4 adenomas. Therefore, the distinction into grades 3A, 3B, and 4 is of importance for prediction of adenoma invasion and surgical treatment considerations.
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http://dx.doi.org/10.3171/2019.3.JNS19367DOI Listing
May 2019

An advanced protocol for intraoperative visualization of sinunasal structures: experiences from pituitary surgery.

J Neurosurg 2019 May 31:1-9. Epub 2019 May 31.

Departments of1Neurosurgery and.

Objective: The transsphenoidal route to pituitary adenomas challenges surgeons because of the highly variable sinunasal anatomy. Orientation may be improved if the appropriate information is provided intraoperatively by image guidance. The authors developed an advanced image guidance protocol dedicated to sinunasal surgery that extracts information from multiple modalities and forms it into a single image that includes fine sinunasal structures and arteries.The aim of this study was to compare the advantages of this novel image guidance protocol with the authors' previous series, with emphasis on anatomical structures visualized and complication rate.

Methods: This retrospective analysis comprised 200 patients who underwent surgery for pituitary adenoma via a transnasal transsphenoidal endoscopic approach. The authors' standard image guidance protocol consisting of CT for solid bone, T1CEMRI for soft tissues, and MRA for the carotid artery was applied in 100 consecutive cases. The advanced image guidance protocol added a first-hit ray casting of the CT scan for visualization of fine sinunasal structures, and adjustments to the MRA to visualize the sphenopalatine artery (SPA) were applied in a subsequent 100 consecutive cases.

Results: A patent sphenoid ostium-i.e., an ostium not covered by a mucosal layer-was visualized significantly more often by the advanced protocol than the standard protocol (89% vs 40%, p < 0.001) in primary surgeries. The SPA and its branches were only visualized by the advanced protocol (87% and 91% of cases in primary surgeries and reoperations, respectively) and not once by the standard protocol. The number of visualized complete and incomplete sphenoid septations matched significantly more commonly with the surgical view when using the advanced protocol than the standard protocol at primary operation (mean 1.9 vs 1.6, p < 0.001). However, in 25% of all cases a complex and not a simple sinus anatomy was present. In comparison with the intraoperative results, a complex sphenoid sinus anatomy was always detected by the advanced but not by the standard protocol (25% vs 8.5%, p = 0.001).Furthermore, application of the advanced protocol reduced the cumulative rate of complications (25% vs 18% [standard vs advanced group]). Although an overall significant difference could not be determined (p = 0.228), a subgroup analysis of reoperations (35/200) revealed a significantly lower rate of complications in the advanced group (5% vs 30%, p = 0.028).

Conclusions: The data show that the advanced image guidance protocol could intraoperatively visualize the fine sinunasal sinus structures and small arteries with a high degree of detail. By improving intraoperative orientation, this may help to reduce the rate of complications in endoscopic transsphenoidal surgery, especially in reoperations.
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http://dx.doi.org/10.3171/2019.3.JNS1985DOI Listing
May 2019

Ex-vivo analysis of quantitative 5-ALA fluorescence intensity in diffusely infiltrating gliomas using a handheld spectroscopic probe: Correlation with histopathology, proliferation and microvascular density.

Photodiagnosis Photodyn Ther 2019 Sep 16;27:354-361. Epub 2019 May 16.

Department of Neurosurgery, Medical University of Vienna Waehringer Guertel 18 - 20, 1090 Vienna, Austria; Institute of Cancer Research, Medical University of Vienna Waehringer Guertel 18 - 20, 1090 Vienna, Austria. Electronic address:

Background: Intraoperative semiquantitative classification of different visible 5-aminolevulinic acid (5-ALA) fluorescence levels by the neurosurgeon is subjective. Recently, handheld spectroscopic probes were introduced enabling quantitative analysis of 5-ALA induced fluorescence intensity (FI). The aim of this ex-vivo study was to correlate the FI in gliomas of different grades with histopathology, proliferation and microvasular density (MVD).

Patients And Methods: Patients with suspected World Health Organization (WHO) grade II-IV gliomas were included and tissue samples from different visible fluorescence levels (strong, vague or none) were intraoperatively collected. After resection, the FI of each sample was investigated ex-vivo by a handheld spectroscopic probe. The FI values were correlated with visible fluorescence, histopathology (WHO grade, quality of tissue, histopathological parameters of anaplasia), proliferation (MIB-1) and MVD.

Results: Altogether, 143 tumor samples with strong (n = 61), vague (n = 21) and no fluorescence (n = 61) were collected in 68 patients. We found significantly different median FI values between all three visible fluorescence levels. Moreover, the median FI value was significantly higher in WHO grade III/IV samples and compact tumor tissue compared to WHO grade II samples and infiltrated tumor tissue. Further, significant differences in median FI values were observed in specific histopathological parameters of anaplasia (mitotic rate, cell density, nuclear pleomorphism and microvascular proliferation) in multivariable analysis. Finally, a significant correlation between the proliferation rate and FI, but not between MVD and FI was noted.

Conclusion: Our data indicate that handheld spectroscopic probes are capable of visualizing intratumoral glioma heterogeneity by objective assessment of fluorescence and may thus optimize future glioma surgery.
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http://dx.doi.org/10.1016/j.pdpdt.2019.05.013DOI Listing
September 2019

Is Intraoperative Pathology Needed if 5-Aminolevulinic-Acid-Induced Tissue Fluorescence Is Found in Stereotactic Brain Tumor Biopsy?

Neurosurgery 2020 03;86(3):366-373

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.

Background: Intraoperative histopathology and acquisition of multiple tissue samples in stereotactic biopsies results in a prolonged length of surgery and potentially increased complication rate.

Objective: To investigate the clinical benefits of a novel strategy for stereotactic brain tumor biopsies with the assistance of 5-aminolevulinic acid (5-ALA) induced fluorescence.

Methods: Patients that received 5-ALA prior to stereotactic biopsy of a suspected brain tumor were included. According to our strategy, the procedure was terminated in the case of strong fluorescence of the biopsy samples. In contrast, intraoperative histology was demanded in the case of vague/no fluorescence. Length of surgery, number of biopsy samples, diagnostic rate, and periprocedural complications were compared between these 2 groups.

Results: Altogether, 79 patients were included, and strong fluorescence was present in 62 cases (79%), vague fluorescence was in 4 cases (5%), and no fluorescence was in 13 cases (16%). The diagnostic rate was comparable in biopsies with strong fluorescence without intraoperative histopathology and cases with vague/no fluorescence with intraoperative histopathology (98% vs 100%; P = 1.000). A significantly shorter length of surgery (41 vs 77 min; P < .001) and reduced average number of biopsy samples (3.6 vs 4.9; P = .011) was found in patients with strong compared to vague/no fluorescence. However, no statically significant difference in periprocedural complications between cases with strong and vague/no fluorescence was found (7% vs 18%; P = .166).

Conclusion: Our data demonstrate the clinical benefits of a novel strategy for stereotactic brain tumor biopsies with assistance of 5-ALA. Thus, this biopsy strategy will increase the efficiency of this standard neurosurgical procedure in the future.
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http://dx.doi.org/10.1093/neuros/nyz086DOI Listing
March 2020

Multiple Pituitary Apoplexy-Cavernous Sinus Invasion as Major Risk Factor for Recurrent Hemorrhage.

World Neurosurg 2019 Jun 7;126:e723-e730. Epub 2019 Mar 7.

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: Pituitary apoplexy is a rare but potentially life-threatening disorder that occurs in up to 10% of adenomas. Whereas risk factors for the initial hemorrhagic event are well described, there is minor knowledge on clinical symptomatic recurrent pituitary apoplexies.

Methods: At the Medical University of Vienna, 76 patients were surgically treated for clinical symptomatic pituitary apoplexy between 1990 and 2017. Four patients (5.3%) suffered multiple pituitary apoplexies after initial surgery. In this retrospective study, neuroradiologic images, clinical data, and intraoperative findings were reviewed for potential risk factors of multiple apoplexies in pituitary adenomas.

Results: Patients with multiple apoplexies had significantly higher Knosp grading on preoperative imaging (median grade 4), and more frequently observed cavernous sinus invasion intraoperatively (P = 0.01). Consequently, all cases with multiple pituitary apoplexies remained with residual adenoma postoperatively. In cases of residual tumor within the cavernous sinus, recurrent apoplexy occurred in 23.5% of patients. A tumor recurrence/residual was resected significantly earlier in patients with single apoplexy (median 2.2 years) than in patients with multiple apoplexies (median 5.4 years; P = 0.05). Multiple pituitary apoplexies caused significantly greater rates of ophthalmoplegia (75% vs. 14.1%; P = 0.01) and long-term hormone-replacement therapy was necessary in all cases.

Conclusions: Cavernous sinus invasion and subtotal resection are high risk factors for multiple apoplexies in pituitary adenomas. Early treatment is recommended for residual tumor in the cavernous sinus to minimize the risk of recurrent apoplexy with subsequent worse clinical outcome.
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http://dx.doi.org/10.1016/j.wneu.2019.02.138DOI Listing
June 2019

Management of choroid plexus tumors-an institutional experience.

Acta Neurochir (Wien) 2019 04 19;161(4):745-754. Epub 2019 Feb 19.

Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Choroid plexus tumors are rare entities. Resection is the mainstay of treatment in grade I and grade II tumors and adjuvant treatment is usually reserved for the less frequent choroid plexus carcinoma (CPC). Outcome is not only related to their histological grade but also dependent on their size, location, and presence of often multifactorial disturbances of cerebrospinal fluid (CSF) circulation.

Methods: Retrospective analysis of 36 consecutive patients operated on a choroid plexus tumor at our institution in a mixed pediatric and adult population between 1991 and 2016.

Results: Twenty-one CPP, 11 atypical choroid plexus papillomas (aCPP), and four CPC were encountered in 17 children and 19 adults. Regardless of histological grading, gross-total resection (GTR) could be achieved in 91.7% of patients. Tumor recurrence (25.0%) was significantly associated with histological grading (p = 0.004), subtotal resection (p = 0.002), and intraoperatively evident zones of tumor infiltration (p = 0.001). Adjuvant therapy was performed in 19.4% of patients, mainly diagnosed with CPC. The 5-year overall survival rate was 95.2% for CPP and 100.0% for both aCPP and CPC. Survival was related to the extent of resection (p = 0.001), tumor progression (p = 0.04), and the presence of leptomeningeal metastases (p = 0.002). Even after resection, either ventricular or subdural shunting was required in 25.0% of patients.

Conclusions: We could confirm that GTR is crucial for treatment of choroid plexus tumors. Parenchymal tumor infiltration as detected intraoperatively was associated with the extent of resection and not limited to CPC. CSF disturbances mandating treatment may persist after resection.
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http://dx.doi.org/10.1007/s00701-019-03832-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431303PMC
April 2019

Correction to: Factors predicting long-term comorbidities in patients with Cushing's syndrome in remission.

Endocrine 2019 Apr;64(1):202

Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

The original version of this article unfortunately published with traditional Springer copyright instead of open access under Springer compact agreement.
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http://dx.doi.org/10.1007/s12020-019-01839-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828201PMC
April 2019

A novel robot-guided minimally invasive technique for brain tumor biopsies.

J Neurosurg 2019 Jan 18:1-9. Epub 2019 Jan 18.

1Department of Neurosurgery, Medical University of Vienna.

OBJECTIVEAs decisions regarding tumor diagnosis and subsequent treatment are increasingly based on molecular pathology, the frequency of brain biopsies is increasing. Robotic devices overcome limitations of frame-based and frameless techniques in terms of accuracy and usability. The aim of the present study was to present a novel, minimally invasive, robot-guided biopsy technique and compare the results with those of standard burr hole biopsy.METHODSA tubular minimally invasive instrument set was custom-designed for the iSYS-1 robot-guided biopsies. Feasibility, accuracy, duration, and outcome were compared in a consecutive series of 66 cases of robot-guided stereotactic biopsies between the minimally invasive (32 patients) and standard (34 patients) procedures.RESULTSApplication of the minimally invasive instrument set was feasible in all patients. Compared with the standard burr hole technique, accuracy was significantly higher both at entry (median 1.5 mm [range 0.2-3.2 mm] vs 1.7 mm [range 0.8-5.1 mm], p = 0.008) and at target (median 1.5 mm [range 0.4-3.4 mm] vs 2.0 mm [range 0.8-3.9 mm], p = 0.019). The incision-to-suture time was significantly shorter (median 30 minutes [range 15-50 minutes] vs 37.5 minutes [range 25-105 minutes], p < 0.001). The skin incision was significantly shorter (median 16.3 mm [range 12.7-23.4 mm] vs 28.4 mm [range 20-42.2 mm], p = 0.002). A diagnostic tissue sample was obtained in all cases.CONCLUSIONSApplication of the novel instrument set was feasible in all patients. According to the authors' data, the minimally invasive robot-guidance procedure can significantly improve accuracy, reduce operating time, and improve the cosmetic result of stereotactic biopsies.
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http://dx.doi.org/10.3171/2018.8.JNS182096DOI Listing
January 2019

Factors predicting long-term comorbidities in patients with Cushing's syndrome in remission.

Endocrine 2019 04 22;64(1):157-168. Epub 2018 Nov 22.

Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Purpose: In Cushing's syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushing's syndrome in remission.

Methods: In a retrospective cross-sectional study, 118 patients with Cushing's syndrome in remission (52 pituitary, 58 adrenal, 8 ectopic) were followed for a median of 7.9 years (range 2-38) after the last surgery. Associations between baseline anthropometric, metabolic, hormonal parameters at diagnosis, and comorbidities (obesity, diabetes, hyperlipidemia, hypertension, osteoporosis, depression) at last follow-up, were tested by uni- and multivariate regression analysis.

Results: In patients with manifest comorbidities at diagnosis, remission of Cushing's syndrome resolved diabetes in 56% of cases, hypertension in 36% of cases, hyperlipidaemia in 23%, and depression in 52% of cases. In a multivariate regression analysis, age, fasting glucose, BMI, and the number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities, while baseline 24-h urinary free cortisol (UFC) negatively correlated with the persistence of long-term comorbidities. The negative relationship between baseline UFC and long-term comorbidities was also found when pituitary and adrenal Cushing's cases were analyzed separately. Baseline UFC was negatively related to the time of exposure to excess glucocorticoids.

Conclusions: Long-term comorbidities after remission of Cushing's syndrome depend not only on the presence of classic cardiovascular risk factors (age, hyperglycemia, BMI), but also on the extent of glucocorticoid excess. Lower baseline UFC is associated with a higher number of long-term comorbidities, possibly due to the longer exposure to excess glucocorticoids in milder Cushing's syndrome.
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http://dx.doi.org/10.1007/s12020-018-1819-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453862PMC
April 2019

Endoscopic Transsphenoidal Surgery of Microprolactinomas: A Reappraisal of Cure Rate Based on Radiological Criteria.

Neurosurgery 2019 10;85(4):508-515

Department of Neurosurgery, Medical University Vienna, Vienna, Austria.

Background: Current standard treatment of microprolactinomas is dopamine agonist therapy. As this drug treatment is lifelong in up to 80% of cases, many patients consult pituitary surgeons regarding a surgical alternative.

Objective: To identify prognostic criteria for surgical remission, we reviewed outcomes of our series of microprolactinomas treated with endoscopic transsphenoidal surgery, with a special emphasis on magnetic resonance adenoma delineation and position.

Methods: Our study cohort comprises a single center series of 60 patients operated for histopathologically verified magnetic resonance imaging unequivocally identifiable endosellar microprolactinoma between 2003 and 2017. In 31 patients the adenoma was enclosed by pituitary gland (group ENC), in 29 patients the adenoma was located lateral to the gland adherent to the medial cavernous sinus wall (group LAT).

Results: After a mean follow-up of 37 mo (range 4-143 mo), remission rate was significantly higher in adenomas enclosed by pituitary gland (group ENC) than adenomas located lateral to the gland (group LAT), with 87% vs 45%, P = .01. Intraoperatively, 4 patients showed signs of invasiveness. Preoperative prolactin levels did not differ between the groups (mean 155 and 187 ng/ml in group ENC and LAT, respectively).A binary logistic regression model revealed that only the radiological criteria applied showed a significant correlation (P = .003) with endocrine remission.

Conclusion: According to our results, remission rate is significantly higher in microprolactinomas enclosed by the pituitary gland. However, the decision for surgery should take into account surgeons experience and possibility of complications.
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http://dx.doi.org/10.1093/neuros/nyy385DOI Listing
October 2019

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Nat Med 2018 10 27;24(10):1611-1624. Epub 2018 Aug 27.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.
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http://dx.doi.org/10.1038/s41591-018-0156-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181207PMC
October 2018

Intra-Arterial Papaverine-Hydrochloride and Transluminal Balloon Angioplasty for Neurointerventional Management of Delayed-Onset Post-Aneurysmal Subarachnoid Hemorrhage Vasospasm.

World Neurosurg 2018 Nov 24;119:e301-e312. Epub 2018 Jul 24.

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria; Department of Neurosurgery, Kepler Universitätsklinikum, Johannes Kepler University Linz, Linz, Austria.

Objective: After subarachnoid hemorrhage, delayed onset vasospasm can result in devastating ischemic stroke. The phenomenon of delayed cerebral ischemia (DCI) is not yet fully understood, and the correlation of angiographic vasospasm and cerebral infarction is still unclear. Therefore, we investigated the effect of endovascular treatment on the angiographic response and occurrence of DCI.

Methods: Eighty patients with subarachnoid hemorrhage and serious cerebral vasospasm underwent endovascular treatment using intra-arterial papaverine-hydrochloride (IAP) or transluminal balloon angioplasty (TBA). The angiographic response and infarction rate were classified using the pre- and postinterventional angiographic images and computed tomography scans.

Results: In 90% of patients, vasospasm could be improved. In most cases (78.8%), IAP was used. Retreatment after IAP was necessary in 32.9% of patients but never after TBA. A total of 233 vascular territories were treated in 128 procedures. Angiographic improvement was observed in 66.5% of territories, which was significantly associated with early intervention (P = 0.02), the use of TBA (P = 0.01), and the dose of papaverine-hydrochloride (P = 0.01). DCI occurred in 47.5% of the patients. Territorial infarction was associated with a poor Hunt and Hess grade (P = 0.03), day of aneurysm treatment (P = 0.01), severe vasospasm before (P = 0.02) and after (P = 0.03) treatment, and number of interventions (P = 0.01). However, the infarction rate was independent of the angiographic response.

Conclusion: The discrepancy of excellent angiographic results and the high incidence of DCI might stem from an inaccurate or a delayed diagnosis of impending ischemia. In view of the limited time window, optimized peri-interventional management and continuous cerebral multimodality neuromonitoring might be crucial for the ideal timing of endovascular procedures to prevent cerebral infarctions.
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http://dx.doi.org/10.1016/j.wneu.2018.07.138DOI Listing
November 2018

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

Neurosurg Focus 2018 06;44(6):E7

1Department of Neurosurgery.

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.
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http://dx.doi.org/10.3171/2018.3.FOCUS1859DOI Listing
June 2018

Long-term outcome after Gamma Knife radiosurgery for acoustic neuroma of all Koos grades: a single-center study.

J Neurosurg 2018 Mar 2:1-10. Epub 2018 Mar 2.

Departments of 1 Neurosurgery.

OBJECTIVE The authors present long-term follow-up data on patients treated with Gamma Knife radiosurgery (GKRS) for acoustic neuroma. METHODS Six hundred eighteen patients were radiosurgically treated for acoustic neuroma between 1992 and 2016 at the Department of Neurosurgery, Medical University Vienna. Patients with neurofibromatosis and patients treated too recently to attain 1 year of follow-up were excluded from this retrospective study. Thus, data on 557 patients with spontaneous acoustic neuroma of any Koos grade are presented, as are long-term follow-up data on 426 patients with a minimum follow-up of 2 years. Patients were assessed according to the Gardner-Robertson (GR) hearing scale and the House-Brackmann facial nerve function scale, both prior to GKRS and at the times of follow-up. RESULTS Four hundred fifty-two patients (81%) were treated with radiosurgery alone and 105 patients (19%) with combined microsurgery-radiosurgery. While the combined treatment was especially favored before 2002, the percentage of cases treated with radiosurgery alone has significantly increased since then. The overall complication rate after GKRS was low and has declined significantly in the last decade. The risk of developing hydrocephalus after GKRS increased with tumor size. One case (0.2%) of malignant transformation after GKRS was diagnosed. Radiological tumor control rates of 92%, 91%, and 91% at 5, 10, and 15 years after GKRS, regardless of the Koos grade or pretreatment, were observed. The overall tumor control rate without the need for additional treatment was even higher at 98%. At the last follow-up, functional hearing was preserved in 55% of patients who had been classified with GR hearing class I or II prior to GKRS. Hearing preservation rates of 53%, 34%, and 34% at 5, 10, and 15 years after GKRS were observed. The multivariate regression model revealed that the GR hearing class prior to GKRS and the median dose to the cochlea were independent predictors of the GR class at follow-up. CONCLUSIONS In small to medium-sized spontaneous acoustic neuromas, radiosurgery should be recognized as the primary treatment at an early stage. Although minimizing the cochlear dose seems beneficial for hearing preservation, the authors, like others before, do not recommend undertreating intracanalicular tumors in favor of low cochlear doses. For larger acoustic neuromas, radiosurgery remains a reliable management option with tumor control rates similar to those for smaller acoustic neuromas; however, careful patient selection and counseling are recommended given the higher risk of side effects. Microsurgery must be considered in acoustic neuromas with significant brainstem compression or hydrocephalus.
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http://dx.doi.org/10.3171/2017.8.JNS171281DOI Listing
March 2018

Immediate Flow Disruption as a Prognostic Factor After Flow Diverter Treatment: Long-Term Experience with the Pipeline Embolization Device.

World Neurosurg 2018 May 23;113:e568-e578. Epub 2018 Feb 23.

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.

Objective: To report long-term results after Pipeline Embolization Device (PED) implantation, characterize complex and standard aneurysms comprehensively, and introduce a modified flow disruption scale.

Methods: We retrospectively reviewed a consecutive series of 40 patients harboring 59 aneurysms treated with 54 PEDs. Aneurysm complexity was assessed using our proposed classification. Immediate angiographic results were analyzed using previously published grading scales and our novel flow disruption scale.

Results: According to our new definition, 46 (78%) aneurysms were classified as complex. Most PED interventions were performed in the paraophthalmic and cavernous internal carotid artery segments. Excellent neurologic outcome (modified Rankin Scale 0 and 1) was observed in 94% of patients. Our data showed low permanent procedure-related mortality (0%) and morbidity (3%) rates. Long-term angiographic follow-up showed complete occlusion in 81% and near-total obliteration in a further 14%. Complete obliteration after deployment of a single PED was achieved in all standard aneurysms with 1-year follow-up. Our new scale was an independent predictor of aneurysm occlusion in a multivariable analysis. All aneurysms with a high flow disruption grade showed complete occlusion at follow-up regardless of PED number or aneurysm complexity.

Conclusions: Treatment with the PED should be recognized as a primary management strategy for a highly selected cohort with predominantly complex intracranial aneurysms. We further show that a priori assessment of aneurysm complexity and our new postinterventional angiographic flow disruption scale predict occlusion probability and may help to determine the adequate number of per-aneurysm devices.
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http://dx.doi.org/10.1016/j.wneu.2018.02.096DOI Listing
May 2018

Multimodality Management of Vein of Galen Malformations-An Institutional Experience.

World Neurosurg 2018 Apr 3;112:e837-e847. Epub 2018 Feb 3.

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria; Department of Neurosurgery, Kepler Universitätsklinikum, Johannes Kepler University Linz, Linz, Austria.

Background: The vein of Galen aneurysmal malformation (VGM) is a rare intracranial arteriovenous fistula with a dramatic manifestation during infancy and 100% mortality without treatment. Therapeutic strategies for VGMs have changed over time as a result of advances in endovascular techniques. We present our experience and multimodality approach within the last 4 decades.

Methods: A retrospective analysis and angiographic review were performed of patients with VGM between 1975 and 2016 at our institution.

Results: Eighteen consecutive patients were identified, including 10 with choroidal and 8 with mural VGMs. In 37 endovascular interventions, a transarterial approach was mostly performed (82.8%). One patient was initially treated surgically and received 2 Gamma Knife treatments after multiple embolizations. The preferred embolization agent was histoacryl for choroidal VGMs and a combination of coils and histoacryl for mural VGMs. Total occlusion was achieved in 87.5% of mural VGMs and 11.1% of choroidal VGMs. Cerebral hemorrhages and infarction occurred only in patients younger than 1 month. At a median follow-up interval of 4.6 years, good outcome was achieved in 53.8% and poor outcome in 46.2%, with an overall mortality of 16.7%. Poor outcome was significantly associated with choroidal-type VGMs, age <1 month at first embolization, and incomplete occlusion.

Conclusions: Endovascular embolization using a transarterial approach is the therapy of choice. Gamma Knife radiosurgery can be considered as second-line therapy in a multimodal approach. Whereas treatment within the first month of life is associated with the highest mortality and complications, we did not detect any severe adverse events thereafter.
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http://dx.doi.org/10.1016/j.wneu.2018.01.172DOI Listing
April 2018

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

Pituitary 2018 Jun;21(3):266-273

Department of Neurosurgery, Medical University Vienna, Waehringer Guertel 18-20, 1097, Vienna, Austria.

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.
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http://dx.doi.org/10.1007/s11102-018-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942339PMC
June 2018

Expression of SRY-related HMG Box Transcription Factors (Sox) 2 and 9 in Craniopharyngioma Subtypes and Surrounding Brain Tissue.

Sci Rep 2017 Nov 20;7(1):15856. Epub 2017 Nov 20.

Department of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Stem cells have been discovered as key players in the genesis of different neoplasms including craniopharyngioma (CP), a rare tumour entity in the sellar region. Sox2 and Sox9 are well-known stem cell markers involved in pituitary development. In this study we analysed the expression of both transcription factors using immunohistochemistry in a large cohort of 64 adamantinomatous (aCP) and 9 papillary CP (pCP) and quantitative PCR in 26 aCP and 7 pCP. Whereas immunohistochemically Sox2+ cells were verifiable in only five aCP (7.8%) and in 39.1% of the respective surrounding cerebral tissue, pCP specimens appeared always negative. In contrast, Sox9 was detectable in all tumours with a significantly higher expression in aCP compared to pCP (protein, p < 0.0001; mRNA p = 0.0484) This was also true for the respective tumour adjacent CNS where 63 aCP (98.4%) and six pCP (66.7%) showed Sox9+ cells. We further confirmed absence of Sox9 expression in nuclear β-catenin accumulating cells of aCP. Our results point to the conclusion that Sox2 and Sox9, seem to play essential roles not only in the specific formation of aCP, but also in processes involving the cerebral tumour environment, which needs to be illuminated in the future.
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http://dx.doi.org/10.1038/s41598-017-15977-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696533PMC
November 2017