73 results on '"Iy, Eyüpoglu"'
Search Results
2. [Effects of working time recording from the perspective of surgeons].
- Author
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Kramer R, Günther S, Eyüpoglu IY, Juratli T, and Polanski W
- Subjects
- Humans, Germany, Surveys and Questionnaires, Attitude of Health Personnel, Workload, Personnel Staffing and Scheduling, Surgeons
- Abstract
Background: Since 2023 the law in Germany has required that working times are recorded in the field of surgery., Objectives: The consequences of recording of the working hours in surgery are the main topic of this study. The search for ways of harmonization in the team to counteract a limited availability of personnel requires knowledge of the position of surgeons on the issue in question., Material and Methods: The study design is based on the situational approach of organizational research and encompasses 20 qualitative interviews and 186 datasets of an online questionnaire with 24 questions. For the evaluation group comparisons were carried out using the ANOVA analysis. The target groups were surgeons working in German hospitals. The study has an explorative character due to the targeted selection of samples., Results: The results of the online survey showed a strong support for working time recording among surgeons with a general agreement of 82% and a consensus at all levels from residents to medical directors. Less than 50% of the assistants and medical specialists saw an improvement via an in-house dialogue, in comparison to senior physicians and medical directors. The right to compensatory time off by other employees represents a greater burden for senior physicians and chief physicians., Discussion: The decisive result shows that there is a preference for transponder-based systems, especially among surgeons with long working hours. The problems of transparency and the right to compensatory time off, often associated with a lack of personnel, demonstrate the necessity for an improved communication and strategic personnel planning in hospitals. Surgeons have differentiated views on the transparent exchange on the topic of the working hours performed., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: R. Kramer, S. Günther, I.Y. Eyüpoglu, T. Juratli und W. Polanski geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
- Published
- 2025
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3. Discontiguous recurrences of IDH-wildtype glioblastoma share a common origin with the initial tumor and are frequently hypermutated.
- Author
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McDonald MF, Gopakumar S, Juratli TA, Eyüpoglu IY, Rao G, Mandel JJ, and Jalali A
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- Humans, Male, Female, Middle Aged, Aged, Adult, Magnetic Resonance Imaging, Glioblastoma genetics, Glioblastoma pathology, Brain Neoplasms genetics, Brain Neoplasms pathology, Neoplasm Recurrence, Local genetics, Isocitrate Dehydrogenase genetics, Mutation
- Abstract
Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences. In our institutional database, we identified 22 patients with targeted exome sequencing of pairs of initial and recurrent IDH-wildtype glioblastoma. Recurrences were classified as contiguous or discontiguous based on the presence or absence of T2 FLAIR signal connection to the initial site of disease on MRI. Exome analysis revealed shared driver and passenger mutations between discontiguous recurrences and initial tumors, supporting a common origin. Discontiguous recurrences were more likely to be hypermutated compared to contiguous recurrences (p = 0.038). Analysis of 2 glioblastoma cases with discontiguous recurrence at a collaborating institution also exhibited hypermutation. In conclusion, discontiguous glioblastoma recurrences share a common origin with the initial tumor and are more likely to be hypermutated than contiguous recurrences., Competing Interests: Declarations. Ethics approval and consent to participate: Patients provided informed consent for research under an IRB approved protocol. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)
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- 2025
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4. A multi-center, clinical analysis of IDH-mutant gliomas, WHO Grade 4: implications for prognosis and clinical trial design.
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Wetzel EA, Nohman AI, Hsieh AL, Reuss D, Unterberg AW, Eyüpoglu IY, Hua L, Youssef G, Wen PY, Cahill DP, Jungk C, Juratli TA, and Miller JJ
- Subjects
- Humans, Male, Female, Middle Aged, Prognosis, Retrospective Studies, Adult, Aged, Clinical Trials as Topic, Cyclin-Dependent Kinase Inhibitor p15 genetics, Astrocytoma genetics, Astrocytoma pathology, Astrocytoma mortality, Survival Rate, Follow-Up Studies, Research Design, Young Adult, Biomarkers, Tumor genetics, Isocitrate Dehydrogenase genetics, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms mortality, Mutation, Cyclin-Dependent Kinase Inhibitor p16 genetics, Neoplasm Grading, Glioma genetics, Glioma pathology, Glioma diagnosis, Glioma mortality
- Abstract
Purpose: Mutations in the Isocitrate Dehydrogenase (IDH) genes, IDH1 or IDH2, define a group of adult diffuse gliomas associated with a younger age at diagnosis and better prognosis than IDH wild-type glioblastoma. Within IDH mutant gliomas, a small fraction of astrocytic tumors present with grade 4 histologic features and poor prognosis. In molecular studies, homozygous deletion of CDKN2A/B is independently predictive of poor prognosis and short survival. As a consequence, 2021 WHO classification now also recognizes this molecular feature, CDKN2A/B deletion, as sufficient for classifying an astrocytoma as IDH-mutant, WHO Grade 4, regardless of histological grading. Here, we investigate outcomes of patients with WHO Grade 4 IDH-mutant astrocytoma both with and without CDKN2A/B deletion, to compare these groups and evaluate clinical and radiographic factors that contribute to survival., Methods: We retrospectively identified 79 patients with IDH-mutant astrocytoma with CDKN2A/B deletion detected at initial diagnosis across five international institutions as well as a comparison group of 51 patients with IDH-mutant, astrocytoma, histologically Grade 4 without detectable CDKN2A/B deletion. We assembled clinical and radiographic features for all patients., Results: We find that CDKN2A/B deletion was associated with significantly worse overall survival (OS; p = 0.0004) and progression-free survival (PFS; p = 0.0026), with median OS of 5.0 years and PFS of 3.0 years, compared to 10.1 and 5.0 years for tumors with a grade 4 designation based only on histologic criteria. Multivariate analysis confirmed CDKN2A/B deletion as a strong negative prognosticator for both OS (HR = 3.51, p < 0.0001) and PFS (HR = 2.35, p = 0.00095). In addition, in tumors with CDKN2A/B deletion, preoperative contrast enhancement is a significant predictor of worse OS (HR 2.19, 95% CI 1.22-3.93, p = 0.0090) and PFS (HR = 1.74, 95% CI = 1.02-2.97, p = 0.0420)., Conclusions: These findings underscore the severe prognostic impact of CDKN2A/B deletion in IDH-mutant astrocytomas and highlight the need for further refinement of tumor prognostic categorization. Our results provide a key benchmark of baseline patient outcomes for therapeutic trials, underscoring the importance of CDKN2A/B status assessment, in addition to histologic grading, in clinical trial design and therapeutic decision-making for IDH-mutant astrocytoma patients., Competing Interests: Declarations. Competing interests: D. P. C reports grants from NIH and Tawingo Fund during the conduct ofthe study; financial compensation from Servier, Boston Scientific and Pyramid Biosciences for advisory input. PYW reports research support from Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Celgene, Chimerix, Eli Lily, Erasca, Genentech/ Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, VBI Vaccines; personal fees from Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, VBI Vaccines. T.A.J. received honoraria from CSL Behring. J.J.M. reports grants from the National Institute of Neurological Diseases and Stroke, American Cancer Society, Seeman Family Funds, National Cancer Institute, and MGH Transformative Scholar Award during the conduct of the study; personal fees from Servier., (© 2024. The Author(s).)
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- 2025
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5. Clinical confocal laser endomicroscopy for imaging of autofluorescence signals of human brain tumors and non-tumor brain.
- Author
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Reichenbach M, Richter S, Galli R, Meinhardt M, Kirsche K, Temme A, Emmanouilidis D, Polanski W, Prilop I, Krex D, Sobottka SB, Juratli TA, Eyüpoglu IY, and Uckermann O
- Subjects
- Humans, Male, Female, Middle Aged, Optical Imaging methods, Aged, Brain pathology, Brain diagnostic imaging, Adult, Glioblastoma pathology, Glioblastoma diagnostic imaging, Microscopy, Confocal methods, Brain Neoplasms pathology, Brain Neoplasms diagnostic imaging
- Abstract
Purpose: Analysis of autofluorescence holds promise for brain tumor delineation and diagnosis. Therefore, we investigated the potential of a commercial confocal laser scanning endomicroscopy (CLE) system for clinical imaging of brain tumors., Methods: A clinical CLE system with fiber probe and 488 nm laser excitation was used to acquire images of tissue autofluorescence. Fresh samples were obtained from routine surgeries (glioblastoma n = 6, meningioma n = 6, brain metastases n = 10, pituitary adenoma n = 2, non-tumor from surgery for the treatment of pharmacoresistant epilepsy n = 2). Additionally, in situ intraoperative label-free CLE was performed in three cases. The autofluorescence images were visually inspected for feature identification and quantification. For reference, tissue cryosections were prepared and further analyzed by label-free multiphoton microscopy and HE histology., Results: Label-free CLE enabled the acquisition of autofluorescence images for all cases. Autofluorescent structures were assigned to the cytoplasmic compartment of cells, elastin fibers, psammoma bodies and blood vessels by comparison to references. Sparse punctuated autofluorescence was identified in most images across all cases, while dense punctuated autofluorescence was most frequent in glioblastomas. Autofluorescent cells were observed in higher abundancies in images of non-tumor samples. Diffuse autofluorescence, fibers and round fluorescent structures were predominantly found in tumor tissues., Conclusion: Label-free CLE imaging through an approved clinical device was able to visualize the characteristic autofluorescence patterns of human brain tumors and non-tumor brain tissue ex vivo and in situ. Therefore, this approach offers the possibility to obtain intraoperative diagnostic information before resection, importantly independent of any kind of marker or label., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)
- Published
- 2024
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6. Raman and autofluorescence spectroscopy for in situ identification of neoplastic tissue during surgical treatment of brain tumors.
- Author
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Uckermann O, Ziegler J, Meinhardt M, Richter S, Schackert G, Eyüpoglu IY, Hijazi MM, Krex D, Juratli TA, Sobottka SB, and Galli R
- Subjects
- Humans, Male, Female, Middle Aged, Glioma surgery, Glioma pathology, Meningioma surgery, Meningioma pathology, Aged, Optical Imaging methods, Adult, Spectrometry, Fluorescence methods, Brain Neoplasms surgery, Brain Neoplasms pathology, Spectrum Analysis, Raman methods
- Abstract
Purpose: Raman spectroscopy (RS) is a promising method for brain tumor detection. Near-infrared autofluorescence (AF) acquired during RS provides additional useful information for tumor identification and was investigated in comparison with RS for delineating brain tumors in situ., Methods: Raman spectra were acquired together with AF in situ within the solid tumor and at the tumor border during routine brain tumor surgeries (218 spectra; glioma WHO II-III, n = 6; GBM, n = 10; metastases, n = 10; meningioma, n = 3). Tissue classification for tumor identification in situ was trained on ex vivo data (375 spectra; glioma/GBM patients, n = 20; metastases, n = 11; meningioma, n = 13; and epileptic hippocampi, n = 4)., Results: Both in situ and ex vivo data showed that AF intensity in brain tumors was lower than that in border regions and normal brain tissue. Moreover, a positive correlation was observed between the AF intensity and the intensity of the Raman band corresponding to lipids at 1437 cm
- 1 , while a negative correlation was found with the intensity of the protein band at 1260 cm- 1 . The classification of in situ AF and RS datasets matched the surgeon's evaluation of tissue type, with correct rates of 0.83 and 0.84, respectively. Similar correct rates were achieved in comparison to histopathology of tissue biopsies resected in selected measurement positions (AF: 0.80, RS: 0.83)., Conclusions: Spectroscopy was successfully integrated into existing neurosurgical workflows, and in situ spectroscopic data could be classified based on ex vivo data. RS confirmed its ability to detect brain tumors, while AF emerged as a competitive method for intraoperative tumor delineation., Competing Interests: Declarations. Ethical approval: All procedures involving humans were performed in accordance with the Helsinki Declaration. The study was approved by the Ethics Commission of the TU Dresden (study n. EK 323,122,008 and EK 24012019). Mouse brains were obtained from the Heart Center Dresden. No animals were additionally killed in the sense of the 3R in animal protection, but brains from other experiments were used (study n. DD24-5131/338/26); brain explantation took place after regular mouse killing and had no influence on the planning or execution of animal experiments. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)- Published
- 2024
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7. Technical challenges and outcomes of stereotactic biopsies in the posterior fossa: Experience with ZD-inomed and leksell vantage frames.
- Author
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Prilop I, Sobottka SB, Buszello C, Eyüpoglu IY, and Polanski WH
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- Humans, Male, Female, Middle Aged, Aged, Adult, Cranial Fossa, Posterior surgery, Cranial Fossa, Posterior pathology, Cranial Fossa, Posterior diagnostic imaging, Biopsy methods, Aged, 80 and over, Magnetic Resonance Imaging methods, Stereotaxic Techniques
- Abstract
Introduction: Stereotactic brain biopsies are essential for obtaining tissue samples from brain lesions, crucial for comprehensive histological analysis and subsequent adjuvant therapies. While most biopsies target supratentorial lesions, those involving the posterior fossa are less frequent but pose significant technical and surgical challenges, necessitating careful patient management., Methods: We present our experience with stereotactic biopsies of the posterior fossa using the Leksell Vantage frame (Elekta, Stockholm, Sweden) and the ZD Inomed frame (Inomed Medizintechnik GmbH, Emmendingen, Germany). For the ZD frame, we either mounted it upside down or employed a frontal approach, while for the Leksell Vantage frame, we utilized a reverse x-axis orientation. Planning was based on 3-T MRI scans and preoperative MRI merged with stereotactic CT for coordinate generation., Results: From 2006 to 2023, we performed 25 stereotactic biopsies of the posterior fossa in our department-9 with the ZD Inomed frame and 16 with the Leksell Vantage frame. The cohort included 14 male and 11 female patients, with an average age of 60.6 years (range 36-80 years). The average surgery duration was shorter with the Leksell Vantage frame (32.6 min vs. 44.8 min, p = 0.05). The average length of the planned trajectory was 41.7 mm for the Leksell Vantage frame and 52.2 mm for the ZD Inomed frame. Postoperativ bleeding occurred in two cases-one managed conservatively, the other required surgical intervention. Additionally, two other cases presented new postoperative focal neurological deficit. The overall mortality rate was 34.8% and a 40-day postoperative mortality rate of 13.0%., Conclusion: Our experience demonstrates that stereotactic biopsies of lesions in the posterior fossa can be effectively managed with different frame systems, though they present a higher degree of complexity. Notably, the Leksell Vantage frame was associated with a significantly shorter surgery duration. This technical note provides valuable insights and detailed technical guidance for neurosurgeons facing similar challenges., Competing Interests: Declarations. Ethical approval: This study protocol was reviewed and approved by ethic committee of the technical university of Dresden, approval number EK224072012. Consent to participate: For using human participant data for this study, in every case the written informed consent was obtained from participants. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)
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- 2024
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8. Efficacy of BRAF/MEK-inhibitor therapy for epithelioid glioblastoma with a novel BRAFV600 mutation.
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Steininger J, Buszello C, Oertel R, Meinhardt M, Schmid S, Engellandt K, Herold S, Stasik S, Ebrahimi A, Renner B, Thiede C, Eyüpoglu IY, Schackert G, Beissert S, Meier F, Radke J, Westphal D, and Juratli TA
- Subjects
- Humans, Male, Adult, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases metabolism, Mitogen-Activated Protein Kinase Kinases genetics, Proto-Oncogene Proteins B-raf genetics, Glioblastoma genetics, Glioblastoma drug therapy, Glioblastoma pathology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Brain Neoplasms genetics, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Mutation
- Abstract
Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography-tandem mass spectrometry analysis confirmed the drugs' presence in the patient's cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies., (© 2024. The Author(s).)
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- 2024
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9. Prediction of WHO grade and methylation class of aggressive meningiomas: Extraction of diagnostic information from infrared spectroscopic data.
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Galli R, Lehner F, Richter S, Kirsche K, Meinhardt M, Juratli TA, Temme A, Kirsch M, Warta R, Herold-Mende C, Ricklefs FL, Lamszus K, Sievers P, Sahm F, Eyüpoglu IY, and Uckermann O
- Abstract
Background: Infrared (IR) spectroscopy allows intraoperative, optical brain tumor diagnosis. Here, we explored it as a translational technology for the identification of aggressive meningioma types according to both, the WHO CNS grading system and the methylation classes (MC)., Methods: Frozen sections of 47 meningioma were examined by IR spectroscopic imaging and different classification approaches were compared to discern samples according to WHO grade or MC., Results: IR spectroscopic differences were more pronounced between WHO grade 2 and 3 than between MC intermediate and MC malignant, although similar spectral ranges were affected. Aggressive types of meningioma exhibited reduced bands of carbohydrates (at 1024 cm
-1 ) and nucleic acids (at 1080 cm-1 ), along with increased bands of phospholipids (at 1240 and 1450 cm-1 ). While linear discriminant analysis was able to discern spectra of WHO grade 2 and 3 meningiomas (AUC 0.89), it failed for MC (AUC 0.66). However, neural network classifiers were effective for classification according to both WHO grade (AUC 0.91) and MC (AUC 0.83), resulting in the correct classification of 20/23 meningiomas of the test set., Conclusions: IR spectroscopy proved capable of extracting information about the malignancy of meningiomas, not only according to the WHO grade, but also for a diagnostic system based on molecular tumor characteristics. In future clinical use, physicians could assess the goodness of the classification by considering classification probabilities and cross-measurement validation. This might enhance the overall accuracy and clinical utility, reinforcing the potential of IR spectroscopy in advancing precision medicine for meningioma characterization., Competing Interests: None., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)- Published
- 2024
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10. Correlation of Molecular Status with Preoperative Olfactory Function in Olfactory Groove Meningioma.
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Podlesek D, Beyer F, Alkhatib M, Daubner D, Hijazi MM, Juratli JH, Weise S, Eyüpoglu IY, Schackert G, Juratli TA, and Hummel T
- Abstract
Purpose: The study aims to examine the possible correlation between genomic alterations and preoperative olfactory function in patients with olfactory groove meningioma (OGM), due to the frequent presence of olfactory impairment., Methods: We utilised next-generation sequencing to analyse samples from 22 individuals with OGM in order to detect driver mutations. Tumour morphology was assessed using preoperative imaging, whereas olfactory function was examined using Sniffin' Sticks., Results: In a study of 22 OGM patients, mutations were as follows: 10 with SMO/SUFU , 7 with AKT1 , and 5 as wild type. Planum sphenoidale hyperostosis (PSH) was present in 75% of patients, showing significant variation by mutation ( p = 0.048). Tumour volumes, averaging 25 cm
3 , significantly differed among groups. PSH negatively impacted olfaction, notably affecting odour threshold, discrimination, identification, and global olfactory performance score (TDI) ( p values ranging from <0.001 to 0.003). Perifocal oedema was associated with lower TDI ( p = 0.009) and altered threshold scores ( p = 0.038). Age over 65 and female gender were linked to lower thresholds and discrimination scores ( p = 0.037 and p = 0.019)., Conclusion: The study highlights PSH and perifocal oedema's significant effect on olfactory function in OGM patients but finds no link between olfactory impairment and tumour mutations, possibly due to the small sample size. This suggests that age and gender affect olfactory impairment. Additional research with a larger group of participants is needed to explore the impact of OGM driver mutations on olfactory performance.- Published
- 2024
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11. The Impact of Magnetic Resonance Imaging Findings in Predicting Neurological Status Pre- and Post-Treatment of Spinal Dural Arteriovenous Fistulas: A 22-Year Experience in a Neurovascular and Spine Center.
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Filis A, Engellandt K, Romualdo SMF, El-Battrawy I, Podlesek D, Juratli TA, Eyüpoglu IY, and Hijazi MM
- Abstract
Background: Successful treatment of spinal dural arteriovenous fistulas (SDAVF) requires prompt diagnosis with definitive fistula localization and non-delayed treatment. Magnetic resonance imaging (MRI) is used for the screening and follow-up of SDAVF, although the value of MRI signs such as myelopathy and flow voids is controversial. Therefore, we investigated the predictive value of MRI signs pre- and post-treatment and their correlation with the neurological status of SDAVF patients., Methods: We retrospectively analyzed the clinical records of 81 patients who underwent surgical or endovascular treatment for SDAVF at our hospital between 2002 and 2023. A total of 41 SDAVF patients with follow-up MRI of 4.6 [2.9-6.5] months (median [interquartile range]) post-treatment and clinical follow-up of 3, 6, and 12 months were included., Results: The extent of pretreatment myelopathy was seven [6-8] vertebral levels, with follow-up MRI showing no myelopathy in 70.7% of cases. The pretreatment flow voids extended over seven [4.5-10] vertebral levels and completely disappeared on follow-up MRI in 100% of cases. The modified Aminoff-Logue scale of disability (mALS) was four [2-7] pretreatment and two [0-4.5] at the third follow-up, with improvement in 65.9% of patients. The American Spinal Injury Association motor score (ASIA-MS) was 97 [88-100] pretreatment and 100 [95-100] at the third follow-up assessment, with 78% of patients improving. Pretreatment ASIA-MS correlated with the extent of myelopathy at admission (R
2 : 0.179; 95% CI: -0.185, -0.033; p = 0.006) but not with flow voids at admission, while pretreatment mALS showed no correlation with either MRI signs. The improvement in ASIA-MS and mALS between admission and the last follow-up showed no correlation with the extent of pretreatment myelopathy and flow voids or with pos-treatment MRI changes. The diagnostic sensitivity of magnetic resonance angiography (MRA) for localization of the fistula was 68.3% (28/41)., Conclusions: The severity of the clinical condition in SDAVF patients has a multifactorial cause, whereby the ASIA-MS correlates with the extent of myelopathy pretreatment. MRI changes after treatment showed no correlation with the clinical outcome and cannot be used as a prognostic factor.- Published
- 2024
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12. Diagnostic, clinical management, and outcomes in patients with spinal dural arteriovenous fistula.
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Filis A, Romualdo SMF, Engellandt K, El-Battrawy I, Podlesek D, Juratli TA, Eyüpoglu IY, Schackert G, and Hijazi MM
- Abstract
Background: Spinal dural arteriovenous fistulas (SDAVFs) are rare spinal vascular malformations, but account for 70 to 80% of all spinal arteriovenous malformations. SDAVFs can be treated either surgically or endovascularly, with surgical treatment appearing to lead to higher closure rates. Our aim was to analyze the demographic data, diagnostic history, treatment characteristics and clinical short- and long-term outcomes., Methods: The medical records of 81 patients who underwent surgical ( n = 70, 86.4%) and endovascular ( n = 11, 13.6%) treatment for SDAVF at a university hospital between 2002 and 2023 were retrospectively analyzed., Results: SDAVF was observed more frequently in men than women (61, 75.3% vs. 20, 24.7%) with a mean age of 63.5 ± 12.7 years and a mean duration of symptoms to diagnosis of 12.0 ± 12.8 months. The most common first symptom was gait disturbance (36, 44.4%), followed by sensory disturbance (24, 29.6%). The location of the fistula point was most common in the lower thoracic region (36, 44.5%), followed by the lumbar region (23, 28.4%). Incomplete or failed occlusion of the fistula occurred in 8 patients (9.9%), with 6 patients (7.4%) undergoing further treatment either surgically or endovascularly. Treatment- or hospital-related complications were observed in 16 patients (19.8%). A single-level laminectomy was the most common approach (31, 44.3%), followed by single-level hemilaminectomy (28, 40.0%), and unilateral interlaminar fenestration (11, 15.7%). Back pain or radiculopathy was observed in 58% of patients (47/81) pre-treatment and had already decreased to 24.7% at hospital discharge ( p < 0.001). No significant differences were observed in sensory disturbances ( p = 0.681). The median of American Spinal Injury Association motor score (ASIA-MS) was 94 [82.5-100] at admission, 98 [86.5-100] at hospital discharge, 100 [90-100] at the first, second, and third follow-up ( p = 0.019). The median modified Aminoff-Logue scale (mALS) was 5 [2-7] at admission, 3 [1-6] at hospital discharge, 2 [1-5] at the first follow-up, 2 [0.5-5] at the second follow-up and 2 [1-7] at the third follow-up ( p = 0.006)., Conclusions: SDAVF occurs predominantly in men in the 6th decade of life and can be safely and effectively treated surgically and endovascularly, improving symptoms such as pain and motor deficits, gait disturbances as well as bowel and bladder dysfunction, but not sensory disturbances., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Filis, Romualdo, Engellandt, El-Battrawy, Podlesek, Juratli, Eyüpoglu, Schackert and Hijazi.)
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- 2024
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13. The importance of considering competing risks in recurrence analysis of intracranial meningioma.
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Mirian C, Jensen LR, Juratli TA, Maier AD, Torp SH, Shih HA, Morshed RA, Young JS, Magill ST, Bertero L, Stummer W, Spille DC, Brokinkel B, Oya S, Miyawaki S, Saito N, Proescholdt M, Kuroi Y, Gousias K, Simon M, Moliterno J, Prat-Acin R, Goutagny S, Prabhu VC, Tsiang JT, Wach J, Güresir E, Yamamoto J, Kim YZ, Lee JH, Koshy M, Perumal K, Baskaya MK, Cannon DM, Shrieve DC, Suh CO, Chang JH, Kamenova M, Straumann S, Soleman J, Eyüpoglu IY, Catalan T, Lui A, Theodosopoulos PV, McDermott MW, Wang F, Guo F, Góes P, de Paiva Neto MA, Jamshidi A, Komotar R, Ivan M, Luther E, Souhami L, Guiot MC, Csonka T, Endo T, Barrett OC, Jensen R, Gupta T, Patel AJ, Klisch TJ, Kim JW, Maiuri F, Barresi V, Tabernero MD, Skyrman S, Broechner A, Bach MJ, Law I, Scheie D, Kristensen BW, Munch TN, Meling T, Fugleholm K, Blanche P, and Mathiesen T
- Subjects
- Humans, Aged, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local pathology, Retrospective Studies, Risk Assessment, Meningioma pathology, Meningeal Neoplasms pathology
- Abstract
Background: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated., Methods: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions., Results: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions)., Conclusion: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions., (© 2024. The Author(s).)
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- 2024
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14. Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study.
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Hua L, Alkhatib M, Fujio S, Alhasan B, Herold S, Zeugner S, Zolal A, Hijazi MM, Clark VE, Wakimoto H, Shankar GM, Brastianos PK, Barker FG, Cahill DP, Ren L, Eyüpoglu IY, Gong Y, Schackert G, and Juratli TA
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- Humans, Male, Female, Middle Aged, Adult, Aged, Retrospective Studies, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins genetics, Proto-Oncogene Proteins c-akt genetics, RNA Polymerase III genetics, Class I Phosphatidylinositol 3-Kinases genetics, High-Throughput Nucleotide Sequencing, Kruppel-Like Transcription Factors genetics, Smoothened Receptor genetics, DNA Mutational Analysis, Young Adult, Telomerase, Meningioma genetics, Meningioma pathology, Kruppel-Like Factor 4, Meningeal Neoplasms genetics, Meningeal Neoplasms pathology, Meningeal Neoplasms diagnostic imaging, Mutation, Foramen Magnum, Neurofibromin 2 genetics
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Objective: Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles., Methods: The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated., Results: The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047)., Conclusions: These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.
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- 2024
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15. The impact of concomitant infective endocarditis in patients with spondylodiscitis and isolated spinal epidural empyema and the diagnostic accuracy of the modified duke criteria.
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Hijazi MM, Siepmann T, El-Battrawy I, Aweimer A, Schröttner P, Mirus M, Podlesek D, Schackert G, Juratli TA, Eyüpoglu IY, and Filis A
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Background: The co-occurrence of infective endocarditis (IE) and primary spinal infections (PSI) like spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) has been reported in up to 30% of cases and represents a life-threatening infection that requires multidisciplinary management to be successful. Therefore, we aimed to characterize the clinical phenotypes of PSI patients with concomitant IE and furthermore to assess the accuracy of the modified Duke criteria in this specific population., Methods: We conducted a retrospective cohort study in consecutive SD and ISEE patients treated surgically at our University Spine Center between 2002 and 2022 who have undergone detailed phenotyping comprising demographic, clinical, imaging, laboratory, and microbiologic assessment. Comparisons were performed between PSI patients with IE (PSICIE) and without IE (PSIWIE) to identify essential differences., Results: Methicillin-susceptible Staphylococcus aureu s (MSSA) was the most common causative pathogen in PSICIE group (13 patients, 54.2%) and aortic valve IE was the most common type of IE (12 patients, 50%), followed by mitral valve IE (5 patients, 20.8%). Hepatic cirrhosis ( p < 0.011; OR: 4.383; 95% CI: 1.405-13.671), septic embolism ( p < 0.005; OR: 4.387; 95% CI: 1.555-12.380), and infection with Streptococcus spp. and Enterococcus spp. ( p < 0.003; OR: 13.830; 95% CI: 2.454-77.929) were identified as significant independent risk factors for the co-occurrence of IE and PSI in our cohort. The modified Duke criteria demonstrated a sensitivity of 100% and a specificity of 66.7% for the detection of IE in PSI patients. Pathogens were detected more frequently via blood cultures in the PSICIE group than in the PSIWIE group (PSICIE: 23, 95.8% vs. PSIWIE: 88, 62.4%, p < 0.001). Hepatic cirrhosis (PSICIE: 10, 41.7% vs. PSIWIE: 33, 21.6%, p = 0.042), pleural abscess (PSICIE: 9, 37.5% vs. PSIWIE: 25, 16.3%, p = 0.024), sepsis (PSICIE: 20, 83.3% vs. PSIWIE: 67, 43.8%, p < 0.001), septic embolism (PSICIE: 16/23, 69.6% vs. PSIWIE: 37/134, 27. 6%, p < 0.001) and meningism (PSICIE: 8/23, 34.8% vs. PSIWIE: 21/152, 13.8%, p = 0.030) occurred more frequently in PSICIE than in PSIWIE patients. PSICIE patients received longer intravenous antibiotic therapy (PSICIE: 6 [4-7] w vs. PSIWIE: 4 [2.5-6] w, p < 0.001) and prolonged total antibiotic therapy overall (PSICIE: 11 [7.75-12] w vs. PSIWIE: 8 [6-12] w, p = 0.014). PSICIE patients spent more time in the hospital than PSIWIE (PSICIE: 43.5 [33.5-53.5] days vs. PSIWIE: 31 [22-44] days, p = 0.003)., Conclusions: We report distinct clinical, radiological, and microbiological phenotypes in PSICIE and PSIWIE patients and further demonstrate the diagnostic accuracy of the modified Duke criteria in patients with PSI and concomitant IE. In the high-risk population of PSI patients, the modified Duke criteria might benefit from amending pleural abscess, meningism, and sepsis as minor criteria and hepatic cirrhosis as major criterion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Hijazi, Siepmann, El-Battrawy, Aweimer, Schröttner, Mirus, Podlesek, Schackert, Juratli, Eyüpoglu and Filis.)
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- 2024
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16. The importance of the bacterial spectrum in the clinical diagnostics and management of patients with spontaneous pyogenic spondylodiscitis and isolated spinal epidural empyema: a 20-year cohort study at a single spine center.
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Hijazi MM, Siepmann T, El-Battrawy I, Schröttner P, Podlesek D, Schackert G, Juratli TA, Eyüpoglu IY, and Filis A
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- Humans, Cohort Studies, Retrospective Studies, Bacteria, Staphylococcus aureus, Gram-Negative Bacteria, Gram-Positive Bacteria, Disease Progression, Anti-Bacterial Agents therapeutic use, Discitis diagnosis, Discitis therapy, Discitis complications, Methicillin-Resistant Staphylococcus aureus, Endocarditis, Bacterial complications, Sepsis complications, Empyema complications, Staphylococcal Infections diagnosis, Staphylococcal Infections therapy, Staphylococcal Infections complications
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Background: Personalized clinical management of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) is challenging due to limited evidence of microbiologic findings and their clinical impact during the clinical course of the disease. We aimed to characterize clinico-microbiological and imaging phenotypes of SD and ISEE to provide useful insights that could improve outcomes and potentially modify guidelines., Methods: We performed chart review and collected data on the following parameters: bacterial antibiogram-resistogram, type of primary spinal infection, location of spinal infection, source of infection, method of detection, clinical complications (sepsis, septic embolism, and endocarditis), length of hospital and intensive care unit (ICU) stay, relapse rate, and disease-related mortality in patients with proven pyogenic SD and ISEE treated surgically in a university hospital in Germany between 2002 and 2022., Results: We included data from 187 patients (125 SD, 66.8% and 62 ISEE, 33.2%). Gram-positive bacteria (GPB) were overall more frequently detected than gram-negative bacteria (GNB) (GPB: 162, 86.6% vs. GNB: 25, 13.4%, p < 0.001). Infective endocarditis was caused only by GPB (GPB: 23, 16.5% vs. GNB: 0, 0.0%, p = 0.046). Methicillin-susceptible Staphylococcus aureus was the most frequently isolated strain (MSSA: n = 100, 53.5%), occurred more frequently in the cervical spine compared to other bacteria (OB) (MSSA: 41, 41.0% vs. OB: 18, 20.7%, p = 0.004) and was most frequently detected in patients with skin infection as the primary source of infection (MSSA: 26, 40.6% vs. OB: 11, 16.7%, p = 0.002). Streptococcus spp. and Enterococcus spp. (SE: n = 31, 16.6%) were more often regarded as the cause of endocarditis (SE: 8, 27.6% vs. OB: 15, 11.4%, p = 0.037) and were less frequently detected in intraoperative specimens (SE: 19, 61.3% vs. OB: 138, 88.5%, p < 0.001). Enterobacterales (E: n = 20, 10.7%) were identified more frequently in urinary tract infections (E: 9, 50.0% vs. OB: 4, 3.6%, p < 0.001). Coagulase-negative Staphylococci (CoNS: n = 20, 10.7%) were characterized by a lower prevalence of sepsis (CoNS: 4, 20.0% vs. OB: 90, 53.9%, p = 0.004) and were more frequently detected in intraoperative specimens (CoNS: 20, 100. 0% vs. OB: 137, 82.0%, p = 0.048). Moreover, CoNS-associated cases showed a shorter length of ICU stay (CoNS: 2 [1-18] days vs. OB: 6 [1-53] days, median [interquartile range], p = 0.037), and occurred more frequently due to foreign body-associated infections (CoNS: 8, 61.5% vs. OB: 15, 12.8%, p = 0.008). The presence of methicillin-resistant Staphylococcus aureus (MRSA) prolonged hospital stay by 56 [24-58] days and ICU stay by 16 [1-44] days, whereas patients with Pseudomonas aeruginosa spent only 20 [18-29] days in the hospital and no day in the ICU 0 [0-5] days., Conclusions: Our retrospective cohort study identified distinct bacterial-specific manifestations in pyogenic SD and ISEE regarding clinical course, neuroanatomic targets, method of pathogen detection, and sources of infection. The clinico-microbiological patterns varied depending on the specific pathogens., (© 2023. The Author(s).)
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- 2024
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17. Diagnostics, Management, and Outcomes in Patients with Pyogenic Spinal Intra- or Epidural Abscess.
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Hijazi MM, Siepmann T, El-Battrawy I, Aweimer A, Engellandt K, Podlesek D, Schackert G, Juratli TA, Eyüpoglu IY, and Filis A
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Background: Owing to the lack of evidence on the diagnostics, clinical course, treatment, and outcomes of patients with extremely rare spinal intradural abscess (SIA) and spinal epidural abscess (SEA), we retrospectively analyzed and compared a cohort of patients to determine the phenotyping of both entities., Methods: Over a period of 20 years, we retrospectively analyzed the electronic medical records of 78 patients with SIA and SEA., Results: The patients with SIA showed worse motor scores (MS scores) on admission (SIA: 20 ± 26 vs. SEA: 75 ± 34, p < 0.001), more often with an ataxic gait (SIA: 100% vs. SEA: 31.8%, p < 0.001), and more frequent bladder or bowel dysfunction (SIA: 91.7% vs. SEA: 27.3%, p < 0.001) compared to the SEA patients. Intraoperative specimens showed a higher diagnostic sensitivity in the SEA patients than the SIA patients (SIA: 66.7% vs. SEA: 95.2%, p = 0.024), but various pathogens such as Staphylococcus aureus (SIA 33.3% vs. SEA: 69.4%) and Streptococci and Enterococci (SIA 33.3% vs. SEA: 8.1%, p = 0.038) were detected in both entities. The patients with SIA developed sepsis more often (SIA: 75.0% vs. SEA: 18.2%, p < 0.001), septic embolism (SIA: 33.3% vs. SEA: 8.3%, p = 0.043), signs of meningism (SIA: 100% vs. 18.5%, p < 0.001), ventriculitis or cerebral abscesses (SIA: 41.7% vs. SEA: 3.0%, p < 0.001), and pneumonia (SIA: 58.3% vs. SEA: 13.6%, p = 0.002). The mean MS score improved in both patient groups after surgery (SIA: 20 to 35 vs. SEA: 75 to 90); however, the SIA patients showed a poorer MS score at discharge (SIA: 35 ± 44 vs. SEA: 90 ± 20, p < 0.001). C-reactive protein (CrP) (SIA: 159 to 49 vs. SEA: 189 to 27) and leukocyte count (SIA: 15 to 9 vs. SEA: 14 to 7) were reduced at discharge. The SIA patients had higher rates of disease-related mortality (SIA: 33.3% vs. SEA: 1.5%, p = 0.002), had more pleural empyema (SIA: 58.3% vs. SEA: 13.6%, p = 0.002), required more than one surgery (SIA: 33.3% vs. SEA 13.6%, p = 0.009), were treated longer with intravenous antibiotics (7 ± 4 w vs. 3 ± 2 w, p < 0.001) and antibiotics overall (12 ± 10 w vs. 7 ± 3 w, p = 0.022), and spent more time in the hospital (SIA: 58 ± 36 vs. SEA: 26 ± 20, p < 0.001) and in the intensive care unit (SIA: 14 ± 18 vs. SEA: 4 ± 8, p = 0.002)., Conclusions: Our study highlighted distinct clinical phenotypes and outcomes between both entities, with SIA patients displaying a markedly less favorable disease course in terms of complications and outcomes.
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- 2023
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18. Development of a bleeding scale and hemostasis algorithm in cranial neurosurgery.
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Eyüpoglu IY, Tuettenberg J, Schebesch KM, Buhl R, Hampl JA, Kiriyanthan GD, and Scheiwe C
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Effective hemostasis is crucial in neurosurgery as anatomical and functional considerations reduce tolerance for any bleeding. The classification of bleeding severities is a necessary step to enable neurosurgeons to counteract bleeding during surgery. Even though bleeding scales are used for a variety of surgical specialties, they cannot be transferred to cranial neurosurgery without adaption, and no consensus on the nature of such a classification exists to date. Moreover, there is plethora of topical hemostasis products with diverse mechanisms of action and application available. Clinical studies investigating those products used in neurosurgery did not define standardized procedures. This article demonstrates the systematic establishment of both a bleeding scale and a hemostasis algorithm to close this gap in the assessment of intracranial bleeding. The expert panel consisting of 7 members from different neurosurgical centers developed a qualitative bleeding scale with the peculiarities of neurosurgical procedures, based on the experience of each member in daily practice. The hemostasis algorithm is a recommendation for neurosurgeons to aid in the decision-making process to control any sort of bleeding, taking into account the rational use of available hemostatics, depending on type and location of bleeding, as well as the mechanism of action of such agents. Effectiveness of hemostasis, surgery times and economic costs can be optimized by applying the algorithm in daily practice., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:This work was supported by Baxter Deutschland GmbH, Edisonstr. 4 85,716 Unterschleissheim, Germany. All authors received financial support during advisory board meetings., (© 2023 The Authors. Published by Elsevier Ltd.)
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- 2023
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19. Tracking cell turnover in human brain using 15 N-thymidine imaging mass spectrometry.
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Roeder SS, Bonnin EA, Wu TD, Guerquin-Kern JL, Jabari S, Brandner S, Eyüpoglu IY, Gollwitzer S, Hamer HM, Gerner ST, Doeppner TR, Rummel C, Englund E, Heimke-Brinck R, Borst T, Daniel C, Amann K, Schlötzer-Schrehardt U, Tonchev AB, Roessler K, Schwab S, Bergmann O, Rizzoli SO, and Huttner HB
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Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with
15 N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns.15 N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with15 N-thymidine. Detection of15 N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain.15 N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the15 N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for15 N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15 N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with15 N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Roeder, Bonnin, Wu, Guerquin-Kern, Jabari, Brandner, Eyüpoglu, Gollwitzer, Hamer, Gerner, Döppner, Rummel, Englund, Heimke-Brinck, Borst, Daniel, Amann, Schlötzer-Schrehardt, Tonchev, Roessler, Schwab, Bergmann, Rizzoli and Huttner.)- Published
- 2023
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20. The Efficacy of Daily Local Antibiotic Lavage via an Epidural Suction-Irrigation Drainage Technique in Spondylodiscitis and Isolated Spinal Epidural Empyema: A 20-Year Experience of a Single Spine Center.
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Hijazi MM, Siepmann T, El-Battrawy I, Schröttner P, Podlesek D, Engellandt K, Schackert G, Juratli TA, Eyüpoglu IY, and Filis A
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Background: Various treatment modalities are available for local antibiotic therapy in spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE), but there is no evidence-based recommendation. Postoperative epidural suction-irrigation drainage (ESID) is thought to reduce bacterial load, which may prevent the development of relapse, wound healing, hematogenous spread, and systemic complications. We evaluated the efficacy of postoperative ESID over 20 years on disease progression and outcome in SD and ISEE., Methods: Detailed demographic, clinical, imaging, laboratory, and microbiological characteristics were examined in our cohorts of 208 SD and ISEE patients treated with and without ESID at a university spine center in Germany between 2002 and 2022. Between-group comparisons were performed to identify meaningful differences for the procedure., Results: We included data from 208 patients (142 SD, 68.3% vs. 66 ISEE, 31.7%) of whom 146 were ESID patients (87 SD, 59.6% vs. 59 ISEE, 40.4%) and 62 were NON-ESID patients (55 SD, 88.7% vs. 7 ISEE, 11.3%). ESID patients with SD showed more frequent SSI (ESID: 22, 25.3% vs. NON-ESID: 3, 5.5%, p = 0.003), reoperations due to empyema persistence or instability (ESID: 37, 42.5% vs. NON-ESID: 12, 21.8%, p = 0.012), and a higher relapse rate (ESID: 21, 37.5% vs. NON-ESID: 6, 16.7%, p = 0.037) than NON-ESID patients with SD. The success rate in NON-ESID patients with SD was higher than in ESID patients with SD (ESID: 26, 29.9% vs. NON-ESID: 36, 65.6%, p < 0.001). Multivariate binary logistic regression analysis showed that ESID therapy ( p < 0.001; OR: 0.201; 95% CI: 0.089-0.451) was a significant independent risk factor for treatment failure in patients with SD., Conclusions: Our retrospective cohort study with more than 20 years of experience in ESID technique shows a negative effect in patients with SD in terms of surgical site infections and relapse rate.
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- 2023
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21. Diagnostic Sensitivity of Blood Culture, Intraoperative Specimen, and Computed Tomography-Guided Biopsy in Patients with Spondylodiscitis and Isolated Spinal Epidural Empyema Requiring Surgical Treatment.
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Hijazi MM, Siepmann T, Disch AC, Platz U, Juratli TA, Eyüpoglu IY, and Podlesek D
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Background: the successful treatment of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) depends on early detection of causative pathogens, which is commonly performed either via blood cultures, intraoperative specimens, and/or image-guided biopsies. We evaluated the diagnostic sensitivity of these three procedures and assessed how it is influenced by antibiotics., Methods: we retrospectively analyzed data from patients with SD and ISEE treated surgically at a neurosurgery university center in Germany between 2002 and 2021., Results: we included 208 patients (68 [23-90] years, 34.6% females, 68% SD). Pathogens were identified in 192 cases (92.3%), including 187 (97.4%) pyogenic and five (2.6%) non-pyogenic infections, with Gram-positive bacteria accounting for 86.6% (162 cases) and Gram-negative for 13.4% (25 cases) of the pyogenic infections. The diagnostic sensitivity was highest for intraoperative specimens at 77.9% (162/208, p = 0.012) and lowest for blood cultures at 57.2% (119/208) and computed tomography (CT)-guided biopsies at 55.7% (39/70). Blood cultures displayed the highest sensitivity in SD patients (SD: 91/142, 64.1% vs. ISEE: 28/66, 42.4%, p = 0.004), while intraoperative specimens were the most sensitive procedure in ISEE (SD: 102/142, 71.8% vs. ISEE: 59/66, 89.4%, p = 0.007). The diagnostic sensitivity was lower in SD patients with ongoing empiric antibiotic therapy (EAT) than in patients treated postoperatively with targeted antibiotic therapy (TAT) (EAT: 77/89, 86.5% vs. TAT: 53/53, 100%, p = 0.004), whereas no effect was observed in patients with ISEE (EAT: 47/51, 92.2% vs. TAT: 15/15, 100%, p = 0.567)., Conclusions: in our cohort, intraoperative specimens displayed the highest diagnostic sensitivity especially for ISEE, whereas blood cultures appear to be the most sensitive for SD. The sensitivity of these tests seems modifiable by preoperative EAT in patients with SD, but not in those with ISEE, underscoring the distinct differences between both pathologies.
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- 2023
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22. Correction: Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas.
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Savaskan NE, Seufert S, Hauke J, Tränkle C, Eyüpoglu IY, and Hahnen E
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- 2023
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23. Parenchymatous hematoma in patients with atraumatic subarachnoid hemorrhage: Characteristics, treatment, and clinical outcomes.
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Gerner ST, Hülsbrink R, Reichl J, Mrochen A, Eyüpoglu IY, Brandner S, Dörfler A, Engelhorn T, Kuramatsu JB, Schwab S, and Huttner HB
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- Hematoma etiology, Hematoma therapy, Humans, Quality of Life, Treatment Outcome, Intracranial Aneurysm, Stroke, Subarachnoid Hemorrhage complications, Subarachnoid Hemorrhage diagnostic imaging, Subarachnoid Hemorrhage therapy
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Background: Data regarding the influence of concomitant parenchymatous hematoma (PH) on long-term outcomes in patients with atraumatic subarachnoid hemorrhage (SAH) are scarce. Further, it is not established if these patients benefit from surgical intervention., Aim: The aim of this study was to determine the influence of concomitant PH in SAH patients on functional long-term outcome, and whether these patients may benefit from surgical hematoma evacuation., Methods: Over a 5-year period, all consecutive patients with SAH treated at the Departments of Neurology, Neuroradiology, and Neurosurgery, at the University Hospital Erlangen (Germany) were recorded. In addition to the clinical and imaging characteristics of SAH, we documented the presence, location, and volume of PH as well as treatment parameters. Outcome assessment at 12 months included functional outcome (modified Rankin scale (mRS), favorable = 0-2), health-related quality of life, and long-term complications. For outcome analysis, a propensity score matching (ratio 1:1, caliper 0.1) was performed to compare SAH patients with and without PH. Sub-analyses were performed regarding PH treatment (surgical evacuation vs. conservative)., Results: A total of 494 patients with atraumatic SAH were available. Eighty-five (17.2%) had PH on initial imaging. SAH patients with PH had a worse clinical condition on admission and had a greater extent of subarachnoid/intraventricular hemorrhage. Median PH volume was 11.0 ml (5.4-31.8) with largest volumes observed in patients with ruptured middle cerebral artery (MCA)-aneurysm (31.7 ml (16.3-43.2)). After propensity-score matching (PSM), patients with PH had worse functional outcomes at 12 months (modified Rankin scale (mRS) 0-2: PH 31.8% vs. ØPH57.7% p < 0.001), and a lower rate of self-reported health compared to patients without PH (EQ-5D VAS: PH 50(30-70) vs. ØPH 80(65-95); p < 0.001). In PH patients, surgical evacuation was associated with a higher rate of favorable outcome at 12 months compared to those treated conservatively (surgery 14/28 (50.0%) vs. conservative 14/57 (24.6%); adjusted odds-ratio (OR; 95%CI): 1.34 (1.08-1.66); p = 0.001), irrespective of aneurysm location. Subgroup-analysis revealed positive associations of surgical hematoma evacuation with outcome in subgroups with larger PH volumes (>10 ml; OR (95%CI): 1.39 (1.09-1.79)), frontal PH location (OR 1.59 (1.14-2.23)), and early surgery (within 600 min after onset; OR 1.42 (1.03-1.94))., Conclusions: Concomitant PH occurs frequently in patients with SAH and is associated with functional impairment after 1 year. Surgical evacuation of PH may improve outcomes in these patients, irrespective of aneurysm-location.
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- 2021
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24. Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage.
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Custal C, Koehn J, Borutta M, Mrochen A, Brandner S, Eyüpoglu IY, Lücking H, Hoelter P, Kuramatsu JB, Kornhuber J, Schwab S, Huttner HB, and Gerner ST
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- Humans, Treatment Outcome, Subarachnoid Hemorrhage physiopathology, Subarachnoid Hemorrhage therapy
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Background: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far., Objective: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors., Methods: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months., Results: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health., Conclusion: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients., (© 2021 S. Karger AG, Basel.)
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- 2021
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25. Long-Term Complications and Influence on Outcome in Patients Surviving Spontaneous Subarachnoid Hemorrhage.
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Gerner ST, Reichl J, Custal C, Brandner S, Eyüpoglu IY, Lücking H, Hölter P, Kallmünzer B, and Huttner HB
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- Adult, Aged, Databases, Factual, Female, Health Status, Humans, Male, Middle Aged, Recovery of Function, Retrospective Studies, Risk Assessment, Risk Factors, Subarachnoid Hemorrhage diagnosis, Subarachnoid Hemorrhage physiopathology, Time Factors, Treatment Outcome, Return to Work, Social Integration, Social Participation, Subarachnoid Hemorrhage complications, Subarachnoid Hemorrhage rehabilitation, Survivors
- Abstract
Background: While the short-term clinical outcome of patients with subarachnoid hemorrhage (SAH) is well described, there are limited data on long-term complications and their impact on social reintegration. This study aimed to assess the frequency of complications post-SAH and to investigate whether these complications attribute to functional and self-reported outcomes as well as the ability to return to work in these patients., Methods: This retrospective single-center study included patients with atraumatic SAH over a 5-year period at a tertiary care center. Patients received a clinical follow-up for 12 months. In addition to demographics, imaging data, and parameters of acute treatment, the rate and extent of long-term complications after SAH were recorded. The functional outcome was assessed using the modified Rankin Scale (mRS; favorable outcome defined as mRS = 0-2). Further outcomes comprised self-reported subjective health measured by the EQ-5D and return to work for SAH patients with appropriate age. Multivariable analyses including in-hospital parameters and long-term complications were conducted to identify parameters independently associated with outcomes in SAH survivors., Results: This study cohort consisted of 505 SAH patients of whom 405 survived the follow-up period of 12 months (i.e., mortality rate of 19.8%). Outcome data were available in 359/405 (88.6%) patients surviving SAH. At 12 months, a favorable functional outcome was achieved in 287/359 (79.9%) and 145/251 (57.8%) SAH patients returned to work. The rates of post-acute complications were headache (32.3%), chronic hydrocephalus requiring permanent ventriculoperitoneal shunting (VP shunt 25.4%) and epileptic seizures (9.5%). Despite patient's and clinical characteristics, both presence of epilepsy and need for VP shunt were independently and negatively associated with a favorable functional outcome (epilepsy: adjusted odds ratio [aOR] (95% confidence interval [95% CI]): 0.125 [0.050-0.315]; VP shunt: 0.279 [0.132-0.588]; both p < 0.001) as well as with return to work (aOR [95% CI]: epilepsy 0.195 [0.065-0.584], p = 0.003; VP shunt 0.412 [0.188-0.903], p = 0.027). Multivariable analyses revealed presence of headache, VP shunt, or epilepsy to be significantly related to subjective health impairment (aOR [95% CI]: headache 0.248 [0.143-0.430]; epilepsy 0.223 [0.085-0.585]; VP shunt 0.434 [0.231-0.816]; all p < 0.01)., Conclusions: Long-term complications occur frequently after SAH and are associated with an impairment of functional and social outcomes. Further studies are warranted to investigate if treatment strategies specifically targeting these complications, including preventive aspects, may improve the outcomes after SAH., (© 2020 S. Karger AG, Basel.)
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- 2020
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26. Treatment of severe traumatic brain injury in German pediatric intensive care units-a survey of current practice.
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Regensburger AP, Konrad V, Trollmann R, Eyüpoglu IY, Huebner H, Zierk J, Völkl TMK, and Fahlbusch FB
- Subjects
- Adolescent, Child, Child, Preschool, Female, Germany epidemiology, Humans, Infant, Infant, Newborn, Male, Treatment Outcome, Young Adult, Brain Injuries, Traumatic epidemiology, Brain Injuries, Traumatic therapy, Intensive Care Units, Pediatric standards, Practice Guidelines as Topic standards, Severity of Illness Index, Surveys and Questionnaires standards
- Abstract
Purpose: German pediatric guidelines for severe traumatic brain injury (TBI) management expired in 2011. Thus, divergent evidence-based institutional protocols are predominantly being followed. We performed a survey of current Pediatric Intensive Care Unit (PICU) management of isolated severe TBI in Germany to reveal potential varying practices., Methods: Seventy German PICUs were invited to join an anonymous online survey from February to May 2017. Twenty-nine participants (41.4%) successfully completed the survey (17 university hospitals and 12 district hospitals). The majority of items were polar (yes/no) or scaled (e.g., never - always). Main topics were imaging, neurosurgery, neuromonitoring, adjuvant therapy, and medication. Severity of TBI was defined via Glasgow Coma Scale., Results: The majority of respondents (93.1%) had internal TBI standards, and patients were mainly administered to interdisciplinary trauma units. The use of advanced neuromonitoring techniques, intracranial hypertension management, and drug treatment differed between PICUs. Routine administration of hypertonic saline in TBI-associated cerebral edema was performed by 3.4%, while it was never an option for 31.0% of the participants. Prophylactic anticonvulsive therapy was restrictively performed. If indicated, the main anticonvulsive drugs used were phenobarbital and levetiracetam. Neuroendocrine follow-up was recommended/performed by 58.6% of the PICUs., Conclusions: This survey provides an overview of the current PICU practices of isolated severe TBI management in Germany and demonstrates a wide instrumental and therapeutical range, revealing an unmet need for the revised national guideline and further (international) clinical trials for the treatment of severe TBI in pediatrics.
- Published
- 2019
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27. Neutrophil-to-lymphocyte ratio as an independent predictor for unfavorable functional outcome in aneurysmal subarachnoid hemorrhage.
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Giede-Jeppe A, Reichl J, Sprügel MI, Lücking H, Hoelter P, Eyüpoglu IY, Kuramatsu JB, Huttner HB, and Gerner ST
- Subjects
- Adult, Aged, Angiography, Digital Subtraction methods, Female, Humans, Longitudinal Studies, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Stroke blood, Stroke diagnostic imaging, Treatment Outcome, Lymphocytes metabolism, Neutrophils metabolism, Recovery of Function physiology, Subarachnoid Hemorrhage blood, Subarachnoid Hemorrhage diagnostic imaging
- Abstract
Objective: Stroke-associated immunosuppression and inflammation are increasingly recognized as factors triggering infections and thus potentially influencing outcome after stroke. Several studies have demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes for patients with ischemic stroke or intracerebral hemorrhage. Thus far, in patients with subarachnoid hemorrhage the association between NLR and outcome is insufficiently established. The authors sought to investigate the association between NLR on admission and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH)., Methods: This observational study included all consecutive aSAH patients admitted to a German tertiary center over a 5-year period (2008-2012). Data regarding patient demographics and clinical, laboratory, and in-hospital measures, as well as neuroradiological data, were retrieved from institutional databases. Functional outcome was assessed at 3 and 12 months using the modified Rankin Scale (mRS) score and categorized into favorable (mRS score 0-2) and unfavorable (mRS score 3-6). Patients' radiological and laboratory characteristics were compared between aSAH patients with favorable and those with unfavorable outcome at 3 months. In addition, multivariate analysis was conducted to investigate parameters independently associated with favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cutoff for NLR to discriminate between favorable and unfavorable outcome in these patients. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on outcome measures., Results: Overall, 319 patients with aSAH were included. Patients with unfavorable outcome at 3 months were older, had worse clinical status on admission (Glasgow Coma Scale score and Hunt and Hess grade), greater amount of subarachnoidal and intraventricular hemorrhage (modified Fisher Scale grade and Graeb score), and higher rates of infectious complications (pneumonia and sepsis). A significantly higher NLR on admission was observed in patients with unfavorable outcome according to mRS score (median [IQR] NLR 5.8 [3.0-10.0] for mRS score 0-2 vs NLR 8.3 [4.5-12.6] for mRS score 3-6; p < 0.001). After adjustments, NLR on admission remained a significant predictor for unfavorable outcome in SAH patients (OR [95% CI] 1.014 [1.001-1.027]; p = 0.028). In ROC analysis, an NLR of 7.05 was identified as the best cutoff value to discriminate between favorable and unfavorable outcome (area under the curve = 0.614, p < 0.001, Youden's index = 0.211; mRS score 3-6: 94/153 [61.4%] for NLR ≥ 7.05 vs 67/166 [40.4%] for NLR < 7.05; p < 0.001). Subanalysis of patients with NLR levels ≥ 7.05 vs < 7.05, performed using 2 propensity score-matched cohorts (n = 133 patients in each group), revealed an increased proportion of patients with unfavorable functional outcome at 3 months in patients with NLR ≥ 7.05 (mRS score 3-6 at 3 months: NLR ≥ 7.05 82/133 [61.7%] vs NLR < 7.05 62/133 [46.6%]; p = 0.014), yet without differences in mortality at 3 months (NLR ≥ 7.05 37/133 [27.8%] vs NLR < 7.05 27/133 [20.3%]; p = 0.131)., Conclusions: Among aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. Whether the impact of NLR on functional outcome is related to preexisting comorbidities or represents independent causal relationships in the context of stroke-associated immunosuppression should be investigated in future studies.
- Published
- 2019
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28. Initiating anticoagulant therapy after ICH is associated with patient characteristics and treatment recommendations.
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Sembill JA, Wieser CY, Sprügel MI, Gerner ST, Giede-Jeppe A, Reindl C, Eyüpoglu IY, Hoelter P, Lücking H, Kuramatsu JB, and Huttner HB
- Subjects
- Administration, Oral, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Anticoagulants therapeutic use, Cerebral Hemorrhage drug therapy, Cerebral Hemorrhage epidemiology, Practice Guidelines as Topic, Practice Patterns, Physicians'
- Abstract
Background: The proportion of patients with intracerebral hemorrhage (ICH) and concomitant indication for oral anticoagulant (OAC) therapy is increasing. Although recent studies documented a favorable risk-benefit profile of OAC initiation, deciding whether, when, and which OAC should be started remains controversial. We investigated (1) OAC recommendations, its implementation, and adherence and (2) factors associated with OAC initiation after ICH., Methods: This prospective observational study analyzed consecutive ICH patients (n = 246) treated at the neurological and neurosurgical department of the University-Hospital Erlangen, Germany over a 21-month inclusion period (05/2013-01/2015). We analyzed the influence of patient characteristics, in-hospital measures, and functional status on treatment recommendations and on OAC initiation during 12-month follow-up., Results: In-hospital mortality of 24.8% (n = 61/246) left 185 patients discharged alive of which 34.1% (n = 63/185) had OAC indication. In these patients, OAC initiation was clearly recommended in only 49.2% (n = 31/63) and associated with favorable [modified Rankin Scale (mRS) = 0-3] functional discharge status [OR 7.18, CI (1.05-49.13), p = 0.04], less frequent heart failure [OR 0.19, CI (0.05-0.71), p = 0.01], and younger age [OR 0.95, CI (0.90-1.00), p = 0.05]. OAC was more often started if clearly recommended [n = 19/31 (61.3%) versus (no recommendation) n = 4/26 (15.4%), p < 0.001; (clearly not recommended, n = 6)] and associated with younger age [67 (58-74) versus 79 (73-83), p < 0.001], favorable functional outcome [n = 10/23 (43.5%) versus n = 5/40 (12.5%), p = 0.01], decreased mortality [n = 6/23 (26.1%) versus n = 19/40 (47.5%), p = 0.06], and functional improvement [n = 13/17 (76.5%) versus n = 7/21 (33.3%), p = 0.01]. We observed no differences in rates of intracranial complications [thromboembolism, n = 3/23 (13.0%) versus n = 4/40 (10.0%), p = 1.00; hemorrhage, n = 1/23 (4.3%) versus n = 3/40 (7.5%), p = 1.00]., Conclusions: Clear treatment recommendations by attending stroke physicians significantly influence OAC initiation after ICH. OAC were more frequently recommended and started in younger patients with better functional recovery independent from intracranial complications. This might represent an important determinant of observed beneficial associations, hinting towards an indication bias which might affect observational analyses.
- Published
- 2018
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29. Meningioma growth dynamics assessed by radiocarbon retrospective birth dating.
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Huttner HB, Bergmann O, Salehpour M, El Cheikh R, Nakamura M, Tortora A, Heinke P, Coras R, Englund E, Eyüpoglu IY, Kuramatsu JB, Roeder SS, Kloska SP, Muehlen I, Doerfler A, Schwab S, Possnert G, Bernard S, and Frisén J
- Subjects
- Cell Proliferation, Humans, Models, Biological, Carbon Radioisotopes chemistry, Cellular Senescence, Meningioma pathology, Radiopharmaceuticals chemistry
- Abstract
It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n=6 with meningothelial and n=6 with fibrous subtype, as well as n=2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived
14 C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1±6.5years, whereas atypical WHO grade II meningiomas originated 1.5±0.1years prior to surgery (p<0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2018
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30. MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis.
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Ghoochani A, Schwarz MA, Yakubov E, Engelhorn T, Doerfler A, Buchfelder M, Bucala R, Savaskan NE, and Eyüpoglu IY
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- Animals, Autocrine Communication, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Disease Models, Animal, Disease Progression, Gene Knockdown Techniques, Glioma diagnostic imaging, Glioma genetics, Glioma pathology, Heterografts, Humans, Interferon-gamma metabolism, Mice, Microglia immunology, Models, Biological, Phagocytosis, Rats, Antigens, Differentiation, B-Lymphocyte metabolism, Cell Transformation, Neoplastic metabolism, Glioma metabolism, Histocompatibility Antigens Class II metabolism, Macrophage Migration-Inhibitory Factors metabolism, Microglia metabolism, Signal Transduction
- Abstract
Microglial cells in the brain tumor microenvironment are associated with enhanced glioma malignancy. They persist in an immunosuppressive M2 state at the peritumoral site and promote the growth of gliomas. Here, we investigated the underlying factors contributing to the abolished immune surveillance. We show that brain tumors escape pro-inflammatory M1 conversion of microglia via CD74 activation through the secretion of the cytokine macrophage migration inhibitory factor (MIF), which results in a M2 shift of microglial cells. Interruption of this glioma-microglial interaction through an antibody-neutralizing approach or small interfering RNA (siRNA)-mediated inhibition prolongs survival time in glioma-implanted mice by reinstating the microglial pro-inflammatory M1 function. We show that MIF-CD74 signaling inhibits interferon (IFN)-γ secretion in microglia through phosphorylation of microglial ERK1/2 (extracellular signal-regulated protein kinases 1 and 2). The inhibition of MIF signaling or its receptor CD74 promotes IFN-γ release and amplifies tumor death either through pharmacological inhibition or through siRNA-mediated knockdown. The reinstated IFN-γ secretion leads both to direct inhibition of glioma growth as well as inducing a M2 to M1 shift in glioma-associated microglia. Our data reveal that interference with the MIF signaling pathway represents a viable therapeutic option for the restoration of IFN-γ-driven immune surveillance.
- Published
- 2016
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31. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis.
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Sehm T, Rauh M, Wiendieck K, Buchfelder M, Eyüpoglu IY, and Savaskan NE
- Subjects
- Amino Acid Transport System y+ genetics, Animals, Apoptosis drug effects, Apoptosis genetics, Astrocytes metabolism, Autophagy drug effects, Autophagy genetics, Cell Cycle Checkpoints drug effects, Cell Cycle Checkpoints genetics, Cell Line, Tumor, Cell Survival genetics, Dacarbazine pharmacology, Drug Resistance, Neoplasm genetics, Drug Synergism, Gene Expression, Gene Knockdown Techniques, Glioma metabolism, Humans, Mice, Niacinamide analogs & derivatives, Niacinamide pharmacology, Phenylurea Compounds pharmacology, Piperazines pharmacology, Pyramidal Cells drug effects, Pyramidal Cells metabolism, Rats, Sorafenib, Temozolomide, Amino Acid Transport System y+ metabolism, Antineoplastic Agents, Alkylating pharmacology, Dacarbazine analogs & derivatives
- Abstract
The glutamate exchanger xCT (SLC7a11) is causally linked with the malignancy grade of brain tumors and represents a key player in glutamate, cystine and glutathione metabolism. Although blocking xCT is not cytotoxic for brain tumors, xCT inhibition disrupts the neurodegenerative and microenvironment-toxifying activity of gliomas. Here, we report on the use of various xCT inhibitors as single modal drugs and in combination with the autophagy-inducing standard chemotherapeutic agent temozolomide (Temodal/Temcad®, TMZ). xCT overexpressing cells (xCTOE) are more resistant to the FDA and EMA approved drug sulfasalazine (Azulfidine/Salazopyrin/Sulazine®, SAS) and RNAi-mediated xCT knock down (xCTKD) in gliomas increases the susceptibility towards SAS in rodent gliomas. In human gliomas, challenged xCT expression had no impact on SAS-induced cytotoxicity. Noteworthy, other xCT inhibitors such as erastin and sorafenib showed enhanced efficacy on xCTKD gliomas. In contrast, cytotoxic action of TMZ operates independently from xCT expression levels on rodent gliomas. Human glioma cells with silenced xCT expression display higher vulnerability towards TMZ alone as well as towards combined TMZ and SAS. Hence, we tested the partial xCT blockers and ferroptosis inducing agents erastin and sorafenib (Nexavar®, FDA and EMA-approved drug for lung cancer). Noteworthy, xCTOE gliomas withstand erastin and sorafenib-induced cell death in a concentration-dependent manner, whereas siRNA-mediated xCT knock down increased susceptibility towards erastin and sorafenib. TMZ efficacy can be potentiated when combined with erastin, however not by sorafenib. Moreover, gliomas with high xCT expression are more vulnerable towards combinatorial treatment with erastin-temozolomide. These results disclose that ferroptosis inducers are valid compounds for potentiating the frontline therapeutic agent temozolomide in a multitoxic approach.
- Published
- 2016
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32. Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency.
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Yakubov E, Ghoochani A, Buslei R, Buchfelder M, Eyüpoglu IY, and Savaskan N
- Abstract
Cowden syndrome (CS) is clinically presented by multiple hamartomas, often with mucocutaneous lesions, goiter, breast cancer and gastrointestinal polyps. CS is a genetic disorder of autosomal dominant inheritance and is one distinct syndrome of the phosphatase and tensin homolog on chromosome 10 (PTEN) hamartoma tumor spectrum. Noteworthy, PTEN germline mutations are related to a wide range of brain tumors. We performed a systematic analysis and review of the medical literature for Cowden syndrome and meningioma and additionally present the case of a 29-year- old CS patient diagnosed with multiple meningiomas. We found strong evidence for high incidence of brain tumors in CS patients. In particular meningiomas and gangliocytomas/Lhermitte-Duclos disease were often associated with 8% and 9% respectively in CS patients. Since aberrations in chromosome 10q are associated with meningiomas, it is likely that the underlying mutations in CS drive to a certain extent neoplastic meningioma growth. We propose to include meningiomas and brain tumors in the major criteria spectrum of CS-related disorders. This could warrant early diagnosis of brain lesions and close therapy, as well as better monitoring of patients with CS.
- Published
- 2016
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33. Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema.
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Sehm T, Fan Z, Ghoochani A, Rauh M, Engelhorn T, Minakaki G, Dörfler A, Klucken J, Buchfelder M, Eyüpoglu IY, and Savaskan N
- Subjects
- Amino Acid Transport System X-AG antagonists & inhibitors, Amino Acid Transport System X-AG metabolism, Animals, Animals, Newborn, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Brain Edema diagnostic imaging, Brain Edema etiology, Brain Neoplasms complications, Brain Neoplasms metabolism, Cell Death drug effects, Cell Line, Tumor, Cell Survival drug effects, Cells, Cultured, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Dose-Response Relationship, Drug, Drug Synergism, Glioma complications, Glioma metabolism, Humans, Magnetic Resonance Imaging, Rats, Wistar, Temozolomide, Brain Edema prevention & control, Brain Neoplasms drug therapy, Glioma drug therapy, Sulfasalazine pharmacology, Tumor Microenvironment drug effects
- Abstract
The glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 µM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor., Competing Interests: CONFLICTS OF INTERESTS The authors declare no competing financial conflict of interests.
- Published
- 2016
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34. Supra-complete surgery via dual intraoperative visualization approach (DiVA) prolongs patient survival in glioblastoma.
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Eyüpoglu IY, Hore N, Merkel A, Buslei R, Buchfelder M, and Savaskan N
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms mortality, Female, Glioblastoma mortality, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Brain Neoplasms surgery, Glioblastoma surgery, Neuronavigation methods
- Abstract
Safe and complete resection represents the first step in the treatment of glioblastomas and is mandatory in increasing the effectiveness of adjuvant therapy to prolong overall survival. With gross total resection currently limited in extent to MRI contrast enhancing areas, the extent to which supra-complete resection beyond obvious contrast enhancement could have impact on overall survival remains unclear. DiVA (dual intraoperative visualization approach) redefines gross total resection as currently accepted by enabling for the first time supra-complete surgery without compromising patient safety. This approach exploits the advantages of two already accepted surgical techniques combining intraoperative MRI with integrated functional neuronavigation and 5-ALA by integrating them into a single surgical approach. We investigated whether this technique has impact on overall outcome in GBM patients. 105 patients with GBM were included. We achieved complete resection with intraoperative MRI alone according to current best-practice in glioma surgery in 75 patients. 30 patients received surgery with supra-complete resection. The control arm showed a median life expectancy of 14 months, reflecting current standards-of-care and outcome. In contrast, patients receiving supra-complete surgery displayed significant increase in median survival time to 18.5 months with overall survival time correlating directly with extent of supra-complete resection. This extension of overall survival did not come at the cost of neurological deterioration. We show for the first time that supra-complete glioma surgery leads to significant prolongation of overall survival time in GBM patients., Competing Interests: The authors declare no competing financial interests.
- Published
- 2016
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35. Adaptive Immune Response to and Survival Effect of Temozolomide- and Valproic Acid-induced Autophagy in Glioblastoma.
- Author
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Proske J, Walter L, Bumes E, Hutterer M, Vollmann-Zwerenz A, Eyüpoglu IY, Savaskan NE, Seliger C, Hau P, and Uhl M
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Autophagy drug effects, Brain Neoplasms immunology, Brain Neoplasms mortality, Cancer Vaccines administration & dosage, Cancer Vaccines pharmacology, Cell Line, Tumor, Dacarbazine administration & dosage, Dacarbazine pharmacology, Glioblastoma immunology, Glioblastoma mortality, Mice, Retrospective Studies, Survival Analysis, Temozolomide, Treatment Outcome, Valproic Acid pharmacology, Xenograft Model Antitumor Assays, Adaptive Immunity drug effects, Brain Neoplasms drug therapy, Dacarbazine analogs & derivatives, Glioblastoma drug therapy, Valproic Acid administration & dosage
- Abstract
Background/aim: The combination of radiotherapy, temozolomide and valproic acid (VPA) has shown some promise in retrospective analyses of patients with glioblastoma, although their mechanisms of action remain unknown., Materials and Methods: We investigated the in vitro and in vivo effects of pretreating glioma cells with temozolomide and VPA as an immunization strategy to boost an adaptive immune response in a syngeneic mouse model., Results: Temozolomide and VPA induced autophagy in GL261 glioma cells, and caused tumor antigen-specific T-cells to become activated effector T-cells. Mice with a pre-existing glioma showed no improvement in clinical outcome when immunized with temozolomide- and VPA-treated glioma cells., Conclusion: Although temozolomide and VPA treatment of glioma cells can boost the adaptive immune response, in the context of a vaccine therapy, additional factors are necessary to eradicate the tumor and improve survival., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2016
36. A versatile ex vivo technique for assaying tumor angiogenesis and microglia in the brain.
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Ghoochani A, Yakubov E, Sehm T, Fan Z, Hock S, Buchfelder M, Eyüpoglu IY, and Savaskan NE
- Subjects
- Animals, Antineoplastic Agents, Alkylating pharmacology, Brain Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Glioma pathology, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Humans, Mice, Transgenic, Microscopy, Confocal, Microscopy, Fluorescence, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Rats, Wistar, Reproducibility of Results, Temozolomide, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, Brain Neoplasms blood supply, Glioma blood supply, Microglia metabolism, Neovascularization, Pathologic diagnostic imaging, Organ Culture Techniques methods
- Abstract
Primary brain tumors are hallmarked for their destructive activity on the microenvironment and vasculature. However, solely few experimental techniques exist to access the tumor microenvironment under anatomical intact conditions with remaining cellular and extracellular composition. Here, we detail an ex vivo vascular glioma impact method (VOGIM) to investigate the influence of gliomas and chemotherapeutics on the tumor microenvironment and angiogenesis under conditions that closely resemble the in vivo situation. We generated organotypic brain slice cultures from rats and transgenic mice and implanted glioma cells expressing fluorescent reporter proteins. In the VOGIM, tumor-induced vessels presented the whole range of vascular pathologies and tumor zones as found in human primary brain tumor specimens. In contrast, non-transformed cells such as primary astrocytes do not alter the vessel architecture. Vascular characteristics with vessel branching, junctions and vessel meshes are quantitatively assessable as well as the peritumoral zone. In particular, the VOGIM resembles the brain tumor microenvironment with alterations of neurons, microglia and cell survival. Hence, this method allows live cell monitoring of virtually any fluorescence-reporter expressing cell. We further analyzed the vasculature and microglia under the influence of tumor cells and chemotherapeutics such as Temozolamide (Temodal/Temcad®). Noteworthy, temozolomide normalized vasculare junctions and branches as well as microglial distribution in tumor-implanted brains. Moreover, VOGIM can be facilitated for implementing the 3Rs in experimentations. In summary, the VOGIM represents a versatile and robust technique which allows the assessment of the brain tumor microenvironment with parameters such as angiogenesis, neuronal cell death and microglial activity at the morphological and quantitative level.
- Published
- 2016
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37. Epigenetics in Brain Tumors: HDACs Take Center Stage.
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Eyüpoglu IY and Savaskan NE
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, DNA Methylation drug effects, DNA Methylation genetics, Epigenesis, Genetic drug effects, Humans, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, Brain Neoplasms genetics, Brain Neoplasms metabolism, Epigenesis, Genetic genetics, Histone Deacetylases genetics, Histone Deacetylases metabolism
- Abstract
Primary tumors of the brain account for 2 % of all cancers with malignant gliomas taking the lion's share with 70 %. Malignant gliomas (high grade gliomas WHO° III and °IV) belong to one of the most threatening tumor entities known with their disappointingly short median survival time of just 14 months despite maximum therapy according to current gold standards. Malignant gliomas secrete various factors, through which they adapt and manipulate the tumor microenvironment to their advantage. Epigenetic mechanisms operate on the tumor microenvironment by de- and methylation processes and imbalances between the histone deacetylases (HDAC) and histone acetylases (HAT). Many compounds have been discovered modulating epigenetically controlled signals. Recent studies indicate that xCT (system xc-, SLC7a11) and CD44 (H-CAM,ECM-III, HUTCH-1) functions as a bridge between these epigenetic regulatory mechanisms and the malignant glioma progression. The question that ensues is the extent to which therapeutic intervention on these signaling pathways would exert influence on the treatment of malignant gliomas as well as the extent to which manipulation of HDAC activity can sensitize tumor cells for chemotherapeutics through 'epigenetic priming'. Considering the current stagnation in the development of therapeutic options the need for new strategies in the treatment of gliomas has never been so urgent. Here, the possibility of pharmacological intervention on tumor-associated genes by epigenetic priming opens a novel path in combating primary brain tumors.
- Published
- 2016
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38. Comparison of the Ramirez technique for the closure of large open myelomeningocele defects with alternative methods.
- Author
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Kneser U, Bigdeli AK, Himmler JP, Eyüpoglu IY, Ganslandt O, Hirsch A, Schmidt VJ, Beier JP, and Horch RE
- Subjects
- Female, Humans, Infant, Newborn, Male, Retrospective Studies, Treatment Outcome, Meningomyelocele surgery, Neurosurgical Procedures methods, Plastic Surgery Procedures methods
- Abstract
Background: To compare the Ramirez technique for the operative closure of large open myelomeningocele defects with conventional closure techniques in newborns. We hypothesized that the immediate surgical treatment with the Ramirez technique is superior to prior used operative techniques., Methods: From 2003 to 2010, 23 children (8 female, 15 male) underwent closure of large open myelomeningocele defects using the Ramirez technique (group A), while from 1993 to 2002, 23 children (6 female, 17 male) underwent conventional closure techniques (group B). All children were included in the retrospective analysis with a mean follow-up period of 3.4 years., Results: Perioperative variables were similar in both groups (P = ns). There were no hospital deaths in both groups. The operation time was significantly higher in group A (228.7 ± 76.8 versus 157.8 ± 70.3 min, P = 0.003). Mean length of hospital stay was significantly lower in group A (30.7 ± 16.4 days versus 52.0 ± 38.5; P = 0.02). Postoperative complication rate was significantly lower in group A (P = 0.01). Beyond postoperative day 10, liquor fluid leakage was significantly lower in group A (P = 0.05). During follow-up, there were no complications in group A. In group B, 2 children developed liquor fistulas., Conclusions: The Ramirez technique allows efficient and safe closure of large open myelomeningocele defects and reduces incidence of postoperative liquor fistulae. The increased operation time and surgical efforts seem to be justified. Treatment of large myelomeningocele defects requires an interdisciplinary team including paediatrician-neonatologists, neurosurgeons and plastic surgeons., (Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)
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- 2015
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39. A new functional classification system (FGA/B) with prognostic value for glioma patients.
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Friedlein K, Bozhkov Y, Hore N, Merkel A, Sommer B, Brandner S, Buchfelder M, Savaskan NE, and Eyüpoglu IY
- Subjects
- Adolescent, Adult, Brain Neoplasms therapy, Child, Combined Modality Therapy methods, Female, Glioma therapy, Humans, Male, Middle Aged, Prognosis, Young Adult, Brain Neoplasms pathology, Glioma pathology
- Abstract
Despite advances in multimodal treatments, malignant gliomas remain characterized by a short survival time. Surgical treatment is accepted to be the first line of therapy, with recent studies revealing that maximal possible tumor reduction exerts significant impact on patient outcome. Consideration of tumor localization in relation to functionally eloquent brain areas has been gaining increasing importance. Despite existing assessment methods, the availability of a simple but reliable preoperative grading based on functional data would therefore prove to be indispensable for the prediction of postoperative outcome and hence for overall survival in glioma patients. We performed a clinical investigation comprising 322 patients with gliomas and developed a novel classification system of preoperative tumor status, which considers tumor operability based on two graduations (Friedlein Grading - FG): FGA with lesions at safe distance to eloquent regions which can be completely resected, and FGB referring to tumors which can only be partially resected or biopsied. Investigation of outcome revealed that FGA were characterized by a significantly longer overall survival time compared to FGB. We offer the opportunity to classify brain tumors in a dependable and reproducible manner. The FGA/B grading method provides high prognostic value with respect to overall survival time in relation to the extent of location-dependent tumor resection.
- Published
- 2015
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40. Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment.
- Author
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Hatipoglu G, Hock SW, Weiss R, Fan Z, Sehm T, Ghoochani A, Buchfelder M, Savaskan NE, and Eyüpoglu IY
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Apoptosis drug effects, Astrocytes drug effects, Astrocytes metabolism, Brain Neoplasms metabolism, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Disease Progression, Endothelial Cells drug effects, Endothelial Cells metabolism, Glioma metabolism, Humans, Mice, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Neurodegenerative Diseases drug therapy, Neurons drug effects, Neurons metabolism, Rats, Rodentia, Sunitinib, Vascular Endothelial Growth Factor Receptor-2 metabolism, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Glioma drug therapy, Indoles pharmacology, Neuroprotective Agents pharmacology, Pyrroles pharmacology, Tumor Microenvironment drug effects
- Abstract
Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)
- Published
- 2015
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41. Intraoperative vascular DIVA surgery reveals angiogenic hotspots in tumor zones of malignant gliomas.
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Eyüpoglu IY, Hore N, Fan Z, Buslei R, Merkel A, Buchfelder M, and Savaskan NE
- Subjects
- Antigens, CD34 metabolism, Cell Count, Fluorescein Angiography, Humans, Indocyanine Green metabolism, Microtubule-Associated Proteins metabolism, Brain Neoplasms blood supply, Brain Neoplasms surgery, Glioma blood supply, Glioma surgery, Intraoperative Care methods, Neovascularization, Pathologic surgery, Vascular Surgical Procedures methods
- Abstract
Malignant gliomas belong to the most threatening tumor entities and are hallmarked by rapid proliferation, hypervascularization and an invasive growth pattern. The primary obstacle in surgical treatment lies in differentiation between healthy and pathological tissue at the tumor margins, where current visualization methods reach their limits. Here, we report on a novel technique (vascular dual intraoperative visualization approach - vDIVA) enabling visualization of different tumor zones (TZ I-III) on the basis of angiogenic hotspots. We investigated glioblastoma patients who underwent 5-ALA fluorescence-guided surgery with simultaneous intraoperative ICG fluorescence angiography. This vDIVA technique revealed hypervascularized areas which were further histologically investigated. Neuropathological assessments revealed tissue areas at the resection margins corresponding to TZ II, and postoperative CD34- and Map2 immunostaining confirmed these angiogenic hotspots to be occupied by glioma cells. Hence, the vascular architecture in this transitional zone could be well differentiated from both primary tumor bulk and healthy brain parenchyma. These data demonstrate that ICG fluorescence angiography improves state-of-the-art glioma surgery techniques and facilitates the future characterization of polyclonal attributes of malignant gliomas.
- Published
- 2015
- Full Text
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42. Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia.
- Author
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Kuramatsu JB, Kollmar R, Gerner ST, Madžar D, Pisarčíková A, Staykov D, Kloska SP, Doerfler A, Eyüpoglu IY, Schwab S, and Huttner HB
- Subjects
- Adult, Brain Damage, Chronic etiology, Brain Damage, Chronic prevention & control, Case-Control Studies, Cerebral Angiography, Cerebral Infarction diagnostic imaging, Cerebral Infarction prevention & control, Cerebral Infarction therapy, Critical Care methods, Databases, Factual, Endovascular Procedures, Female, Hospital Mortality, Humans, Hydrocephalus etiology, Hydrocephalus prevention & control, Hydrocephalus surgery, Hypnotics and Sedatives therapeutic use, Length of Stay statistics & numerical data, Male, Middle Aged, Neuromuscular Agents therapeutic use, Perfusion Imaging, Pilot Projects, Prospective Studies, Recovery of Function, Risk, Subarachnoid Hemorrhage complications, Tomography, X-Ray Computed, Treatment Outcome, Ultrasonography, Doppler, Transcranial, Vasospasm, Intracranial diagnostic imaging, Vasospasm, Intracranial prevention & control, Vasospasm, Intracranial therapy, Ventriculoperitoneal Shunt, Cerebral Infarction etiology, Hypothermia, Induced adverse effects, Hypothermia, Induced methods, Subarachnoid Hemorrhage therapy, Vasospasm, Intracranial etiology
- Abstract
Background: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated., Methods: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome., Results: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06)., Conclusion: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact., (© 2015 S. Karger AG, Basel.)
- Published
- 2015
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43. Neurodegeneration and the Brain Tumor Microenvironment. [corrected].
- Author
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Savaskan NE, Fan Z, Broggini T, Buchfelder M, and Eyüpoglu IY
- Subjects
- Amino Acid Transport Systems drug effects, Animals, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Brain Neoplasms drug therapy, Glutamic Acid metabolism, Humans, Models, Molecular, Nerve Degeneration drug therapy, Nerve Degeneration metabolism, Reactive Oxygen Species metabolism, Sulfasalazine therapeutic use, Transient Receptor Potential Channels metabolism, Amino Acid Transport Systems metabolism, Brain Neoplasms complications, Brain Neoplasms pathology, Nerve Degeneration etiology
- Abstract
Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.
- Published
- 2015
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44. Selenium action in neuro-oncology.
- Author
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Yakubov E, Buchfelder M, Eyüpoglu IY, and Savaskan NE
- Subjects
- Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brain Neoplasms metabolism, Brain Neoplasms pathology, Glioblastoma metabolism, Glioblastoma pathology, Humans, Selenium administration & dosage, Selenium adverse effects, Selenium deficiency, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Selenium therapeutic use, Selenoproteins metabolism
- Abstract
The trace element selenium and selenocysteine-carrying selenoproteins play a pivotal role in the brain. Beside the essential function during development and maintenance of brain action, selenium has also been associated with several neurological and neuro-oncological conditions. Reliable supply of selenium is important since selenium compounds can affect tumor microenvironment and neoangiogenesis in malignant gliomas (WHO grade III and IV [glioblastoma, GBM]) via induction of apoptosis and alteration of matrix metalloproteinases expression. Here, we summarize recent findings focusing on the anti-toxicity and cancer-preventive properties of selenium and their implication in current multimodal therapies including temozolomide (Temodal), cyclophosphamide (Endoxan), and cisplatin (DDP, Platiblastin, and Platinol). We shed light on unintended side effects in chemotherapy and the developments of novel combinatorial chemotherapeutics with selenium compounds. We found that selenium and selenium compounds have dual action profiles with direct anti-cancer and chemotherapy-intensifier effects as well as neuroprotective and cytoprotective agents. Current selenium trials and selenium supplementation with focus on neuro-oncology will be discussed with regard to low-adequate-to-high/toxic selenium status.
- Published
- 2014
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45. Intraventricular fibrinolysis has no effects on shunt dependency and functional outcome in endovascular-treated aneurysmal SAH.
- Author
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Gerner ST, Kuramatsu JB, Abel H, Kloska SP, Lücking H, Eyüpoglu IY, Doerfler A, Schwab S, and Huttner HB
- Subjects
- Adult, Aged, Cohort Studies, Drainage, Endovascular Procedures, Female, Humans, Hydrocephalus etiology, Injections, Intraventricular, Male, Middle Aged, Retrospective Studies, Subarachnoid Hemorrhage complications, Treatment Outcome, Cerebral Ventricles, Cerebrospinal Fluid Shunts statistics & numerical data, Fibrinolytic Agents therapeutic use, Hydrocephalus therapy, Subarachnoid Hemorrhage therapy, Thrombolytic Therapy methods, Tissue Plasminogen Activator therapeutic use
- Abstract
Background: Intraventricular fibrinolysis (IVF) in subarachnoid hemorrhage (SAH) is an emerging strategy aiming to hasten clot lysis, treat hydrocephalus, and reduce permanent shunt rates. Because of clinical heterogeneity of investigated patient effects of IVF on permanent shunt incidence and functional outcome are widely debated. The present study is the first to investigate solely endovascular-treated SAH patients., Methods: Overall, 88 consecutive patients with aneurysmal SAH requiring external ventricular drain placement and endovascular aneurysm closure were included. Functional outcome and shunt dependency were assessed 90 days after event. A matched controlled sub-analysis was carried out to investigate the effects of IVF treatment (n = 14; matching criteria: age, neuro-status and imaging). Multivariate modeling was performed to identify independent predictors for permanent shunt dependency., Results: In IVF-patients neurological status was significantly poorer [Hunt&Hess: IVF = 4(3-5) vs. non-IVF = 3(1-5); p = 0.035] and the extent of ventricular hemorrhage was increased [Graeb Score: IVF = 7(6-8) vs. non-IVF = 3(1-4); p ≤ 0.001]. Consecutive matched controlled sub-analysis revealed no significant therapeutic effect of IVF with respect to shunt dependency rate and functional outcome. Multivariate analysis revealed Graeb score [OR = 1.34(1.02-1.76); p = 0.035] and sepsis [OR = 11.23(2.28-55.27); p = 0.003] as independent predictors for shunt dependency, whereas IVF did not exert significant effects (p = 0.820)., Conclusions: In endovascular-treated SAH patients IVF neither reduced permanent shunt dependency nor influenced functional outcome. Despite established effects on intraventricular clot resolution IVF appears less powerful in SAH as compared to ICH. Given the reported positive effects of lumbar drainage (LD) in SAH, a prospective analysis of a combined treatment approach of IVF and subsequent lumbar drain sOeems warranted aiming to reduce permanent shunting and improve functional outcome.
- Published
- 2014
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46. Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration.
- Author
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Wolf IM, Fan Z, Rauh M, Seufert S, Hore N, Buchfelder M, Savaskan NE, and Eyüpoglu IY
- Subjects
- Amino Acid Transport System y+ genetics, Apoptosis drug effects, Blotting, Western, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Adhesion drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Glioma metabolism, Glioma pathology, Humans, Immunoenzyme Techniques, RNA, Messenger genetics, Reactive Oxygen Species metabolism, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Vorinostat, Amino Acid Transport System y+ metabolism, Glioma drug therapy, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases chemistry, Hydroxamic Acids pharmacology, Tumor Microenvironment drug effects
- Abstract
Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter--i.e. in non-cancerously transformed cells too--as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.
- Published
- 2014
- Full Text
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47. The impact of dietary isoflavonoids on malignant brain tumors.
- Author
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Sehm T, Fan Z, Weiss R, Schwarz M, Engelhorn T, Hore N, Doerfler A, Buchfelder M, Eyüpoglu IY, and Savaskan NE
- Subjects
- Administration, Oral, Angiogenesis Inhibitors pharmacology, Animals, Astrocytes drug effects, Astrocytes physiology, Cell Line, Tumor, Cell Proliferation, Cell Survival drug effects, Diet, Drug Screening Assays, Antitumor, Genistein pharmacology, Humans, Male, Neoplasm Transplantation, Rats, Inbred F344, Rats, Wistar, Angiogenesis Inhibitors administration & dosage, Brain Neoplasms drug therapy, Genistein administration & dosage, Glioma drug therapy
- Abstract
Poor prognosis and limited therapeutic options render malignant brain tumors one of the most devastating diseases in clinical medicine. Current treatment strategies attempt to expand the therapeutic repertoire through the use of multimodal treatment regimens. It is here that dietary fibers have been recently recognized as a supportive natural therapy in augmenting the body's response to tumor growth. Here, we investigated the impact of isoflavonoids on primary brain tumor cells. First, we treated glioma cell lines and primary astrocytes with various isoflavonoids and phytoestrogens. Cell viability in a dose-dependent manner was measured for biochanin A (BCA), genistein (GST), and secoisolariciresinol diglucoside (SDG). Dose-response action for the different isoflavonoids showed that BCA is highly effective on glioma cells and nontoxic for normal differentiated brain tissues. We further investigated BCA in ex vivo and in vivo experimentations. Organotypic brain slice cultures were performed and treated with BCA. For in vivo experiments, BCA was intraperitoneal injected in tumor-implanted Fisher rats. Tumor size and edema were measured and quantified by magnetic resonance imaging (MRI) scans. In vascular organotypic glioma brain slice cultures (VOGIM) we found that BCA operates antiangiogenic and neuroprotective. In vivo MRI scans demonstrated that administered BCA as a monotherapy was effective in reducing significantly tumor-induced brain edema and showed a trend for prolonged survival. Our results revealed that dietary isoflavonoids, in particular BCA, execute toxicity toward glioma cells, antiangiogenic, and coevally neuroprotective properties, and therefore augment the range of state-of-the-art multimodal treatment approach., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2014
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48. Ultrasound-guided neuronavigation improves safety of ventricular catheter insertion in preterm infants.
- Author
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Heussinger N, Eyüpoglu IY, Ganslandt O, Finzel S, Trollmann R, and Jüngert J
- Subjects
- Cerebral Hemorrhage complications, Cerebral Ventricles diagnostic imaging, Female, Humans, Hydrocephalus diagnostic imaging, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases diagnostic imaging, Male, Retrospective Studies, Ventriculoperitoneal Shunt, Catheterization methods, Cerebral Ventricles surgery, Hydrocephalus surgery, Infant, Premature, Diseases surgery, Neuronavigation methods, Ultrasonography, Interventional methods
- Abstract
Background: Intra-ventricular hemorrhage (IVH) is a frequent cause of shunt-dependent hydrocephalus. The management of IVH in preterm babies remains a challenge both for neonatologists and pediatric neurosurgeons, compounded by the lack of low-risk, validated therapy techniques., Objective: The aim of this study was to evaluate the feasibility and safety of a novel technique involving the ultrasound-guided placement of a central catheter connected with a Rickham-Capsule in a cohort of preterm, low-birth-weight babies with post-hemorrhagic hydrocephalus (PHH)., Methods: Eight preterm infants with PHH in which a Rickham-Capsule was placed from 2008-2012 were included. Conventional surgical techniques were used in four preterm infants; whereas in the other four preterm babies ultrasound guided catheter placement was performed with an 8 MegaHertz (MHz) micro convex transducer from LOGIQ 9, GE Healthcare; whereby the anterior fontanel was used as an acoustic window., Results: Overall gestational age was 24-31 weeks, mean age at operation was 20.1 (7-36) days, mean birth weight 972.5±370 g, mean weight at first surgical intervention 1023.75±400.4 g. Six patients had bilateral IVH II-III°, two patients had parenchymal involvement. Using the conventional approach, incorrect catheter placement occurred in one of four patients below 1000 g, whereas none of the ultrasound guided cases needed correction., Conclusions: Ultrasound-guided neuronavigation represents a relevant tool in the treatment of hydrocephalus in preterm infants through increased accuracy in placement of a central catheter connected to a Rickham-Capsule. The benefit of utilizing this form of neuronavigation needs to be assessed through corresponding standardized studies., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
49. Surgical resection of malignant gliomas-role in optimizing patient outcome.
- Author
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Eyüpoglu IY, Buchfelder M, and Savaskan NE
- Subjects
- Brain Neoplasms mortality, Glioma mortality, Humans, Karnofsky Performance Status, Brain Neoplasms surgery, Glioma surgery, Neurosurgical Procedures methods, Treatment Outcome
- Abstract
Malignant gliomas represent one of the most devastating human diseases. Primary treatment of these tumours involves surgery to achieve tumour debulking, followed by a multimodal regimen of radiotherapy and chemotherapy. Survival time in patients with malignant glioma has modestly increased in recent years owing to advances in surgical and intraoperative imaging techniques, as well as the systematic implementation of randomized trial-based protocols and biomarker-based stratification of patients. The role and importance of several clinical and molecular factors-such as age, Karnofsky score, and genetic and epigenetic status-that have predictive value with regard to postsurgical outcome has also been identified. By contrast, the effect of the extent of glioma resection on patient outcome has received little attention, with an 'all or nothing' approach to tumour removal still taken in surgical practice. Recent studies, however, reveal that maximal possible cytoreduction without incurring neurological deficits has critical prognostic value for patient outcome and survival. Here, we evaluate state-of-the-art surgical procedures that are used in management of malignant glioma, with a focus on assessment criteria and value of tumour reduction. We highlight key surgical factors that enable optimization of adjuvant treatment to enhance patient quality of life and improve life expectancy.
- Published
- 2013
- Full Text
- View/download PDF
50. Myocutaneous propeller flap based on the superior gluteal artery (SGA) for closure of large lumbosacral meningomyelocoele defects: a case report.
- Author
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Schmidt VJ, Horch RE, Dragu A, Beier JP, Eyüpoglu IY, Hirsch A, and Kneser U
- Subjects
- Arteries, Child, Preschool, Humans, Infant, Newborn, Lumbosacral Region, Male, Meningomyelocele surgery, Plastic Surgery Procedures methods, Surgical Flaps blood supply
- Abstract
Early and reliable closure of large meningomyelocoele defects in newborns is critical to prevent severe infectious complications and neurologic deterioration. Here, we introduce a new surgical method for the reconstruction of large horizontal meningomyelocoele defects, in which we use unilateral myocutaneous tissue based on the superior gluteal artery (SGA) as a propellar flap. This procedure permits a tension-free and durable multilayer closure of difficult, large-scale horizontal defects that cannot adequately be treated by conventional myocutaneous advancement flaps. The technique is reliable and straightforward and requires no skin grafts or relaxing incisions. The SGA-based myocutaneous propeller flap might be a promising alternative for complex meningomyelocoele reconstructions in the future., (Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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