Publications by authors named "Gabriele Schackert"

225 Publications

GliPR1 knockdown by RNA interference exerts anti-glioma effects in vitro and in vivo.

J Neurooncol 2021 Apr 15. Epub 2021 Apr 15.

Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Introduction: In human glioblastomas, glioma pathogenesis-related protein1 (GliPR1) is overexpressed and appears to be an oncoprotein. We investigated whether GliPR1 knockdown in glioma cells by RNA interference exerts anti-glioma effects.

Methods: Experiments used human glioblastoma cell lines transduced with GliPR1 shRNA (sh#301, sh#258). Transduction produced stringent doxycycline-dependent GliPR1 knockdown in clones (via lentiviral "all-in-one" TetOn-shRNA vector) or stable GliPR1 knockdown in polyclonal cells (via constitutive retroviral-shRNA vector). In vitro assessments included cellular proliferation and clonogenic survival. In vivo assessments in tumor-bearing nude mice included tumor growth and survival.

Results: Using doxycycline-dependent GliPR1 knockdown, shGliPR1-transduced U87-MG clones demonstrated reductions in cellular proliferation in the presence versus absence of doxycycline. Using stable GliPR1 knockdown, polyclonal shGliPR1-transduced U87-MG, A172, and U343-MG cells consistently showed decreased clonogenic survival and induced apoptosis (higher proportion of early apoptotic cells) compared to control shLuc-transduced cells. In tumor-bearing nude mice, using doxycycline-dependent GliPR1 knockdown, subcutaneous and cranial transplantation of the U87-MG clone 980-5 (transduced with GliPR1 sh#301) resulted in reduced subcutaneous tumor volume and cerebral tumor area in doxycycline-treated mice versus those left untreated. Using stable GliPR1 knockdown, nude mice cranially transplanted with polyclonal U87-MG cells transduced with GliPR1 sh#258 had significantly prolonged survival compared to mice cranially transplanted with control shLuc-transduced cells (41 versus 26 days; P < 0.001).

Conclusion: GliPR1 knockdown in glioma cells decreased cellular proliferation, decreased clonogenic survival, and induced apoptosis in vitro, and reduced glioblastoma tumor growth and prolonged survival in vivo. These findings support that GliPR1 may have potential value as a therapeutic target.
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http://dx.doi.org/10.1007/s11060-021-03737-3DOI Listing
April 2021

Telomerase reverse transcriptase promoter mutation- and O-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Eur J Cancer 2021 Apr 22;147:84-94. Epub 2021 Feb 22.

Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany; German Cancer Consortium, Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Aim Of The Study: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.

Methods: MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).

Results: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.

Conclusions: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.
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http://dx.doi.org/10.1016/j.ejca.2021.01.014DOI Listing
April 2021

Long-term results following electrical stimulation of the peroneal nerve using the ActiGait® system in 33 patients with central drop foot.

Innov Surg Sci 2021 Jan 6;6(1):20191003. Epub 2021 Jan 6.

Department of Neurosurgery, Technische Universität Dresden, Dresden, Germany.

Objective: Direct electrical stimulation of the peroneal nerve, using the implantable ActiGait® system, enables a therapy of the centrally caused drop foot, to improve the gait of the patients. In this paper, we present long-term results at 36-month follow-up post implantation.

Method: A total of 33 patients, 27 stroke and six multiple sclerosis (MS) patients, suffering from spastic drop foot were implanted in our center and assessed in terms of gait endurance, speed, risk of fall, and life quality at baseline and 36 months following implantation.

Results: The six min gait endurance test increased significantly from 202 ± 41 m without walking aids to 380 ± 30 m (p=0.038), while using the implant. Moreover, the time in the gait speed measured over 20 m decreased from 31.8 ± 10.2 s without to 18.5 ± 4.6 s by using the ActiGait® system (p=0.039). Similarly, gait steadiness, measured by the Timed Up and Go (TUG) test improved by 36.6%, with patients demonstrating a reduced time from 18.6 ± 5.5 to 11.2 ±  3.8 s (p=0.041) upon implant activation. Most importantly, 31 of 33 patients reported remarkable improvements of their quality of life following direct electrical nerve stimulation.

Conclusion: Our findings confirm previously published efficacy data at 12 months after implantation and underline the long-lasting effect of the ActiGait® system.
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http://dx.doi.org/10.1515/iss-2019-1003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790182PMC
January 2021

Sporadic multiple meningiomas harbor distinct driver mutations.

Acta Neuropathol Commun 2021 01 6;9(1). Epub 2021 Jan 6.

Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

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http://dx.doi.org/10.1186/s40478-020-01113-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789520PMC
January 2021

Vestibular Schwannoma Surgery: Outcome and Complications in Lateral Decubitus Position versus Semi-sitting Position-A Personal Learning Curve in a Series of 544 Cases over 3 Decades.

World Neurosurg 2021 Apr 28;148:e182-e191. Epub 2020 Dec 28.

Department of Neurosurgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Objective: To retrospectively evaluate influence of intraoperative positioning (semisitting vs. lateral decubitus) and surgeon's learning curve with regard to functional outcome of patients with vestibular schwannoma.

Methods: This study included 544 patients (median age 57 years) and spanned 3 decades: 1991-1999 (n = 103), 2000-2009 (n = 210), and 2010-2019 (n = 231). Surgery was performed in the lateral decubitus position in 318 patients and the semisitting position in 163 patients. Large T3 and T4 tumors were present in 77% of patients.

Results: Complete tumor removal was achieved in 94.3% of patients. A significant reduction in surgery duration and blood loss was observed over 3 decades for T3 (from 325 to 261 minutes, P < 0.001) and T4 (from 440 to 330 minutes, P < 0.001), but not for T1 and T2, tumors. The semisitting position diminished surgical time in T3 and T4 tumors by 1 more hour (P < 0.001). Over 3 decades, facial nerve outcome improved significantly from 59.8% House-Brackmann grade 1-2 in the first decade to 81.7% in the last decade (P < 0.001). Furthermore, hearing was preserved in 45.3%: 23.3% of patients in the first decade and 50.5% in the last decade (P = 0.03). However, neither facial nerve outcome nor hearing preservation significantly differed in patients operated on in the lateral decubitus versus the semisitting position. The most common complication was cerebrospinal fluid leak (6.1%) followed by hemorrhage (3.5%) and pulmonary embolism (2.2%).

Conclusions: Follow-up over 3 decades illustrates a learning curve with significantly improved results. While the semisitting position accelerates the procedure and is associated with reduced blood loss, it does not significantly influence functional outcome.
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http://dx.doi.org/10.1016/j.wneu.2020.12.107DOI Listing
April 2021

Exome sequencing identifies frequent genomic loss of TET1 in IDH-wild-type glioblastoma.

Neoplasia 2020 12 2;22(12):800-808. Epub 2020 Nov 2.

Department of Medicine I, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Genomic and epigenomic alterations of multiple cancer-driving genes are frequent in GBM. To identify molecular alterations associated with epigenetic aberrations, we performed whole exome sequencing-based analysis of DNA copy number variations in 55 adult patients with IDH-wild-type GBM. Beside mutations in common GBM driver genes such as TERTp (76%), TP53 (22%) and PTEN (20%), 67% of patients were affected by amplifications of genes associated with RTK/Rb/p53 cell signaling, including EGFR (45%), CDK4 (13%), and MDM2/4 (both 7%). The minimal deleted region at chromosome 10 was detected at the DNA demethylase TET1 (93%), mainly due to a loss-of-heterozygosity of complete chromosome 10 (53%) or by a mono-allelic microdeletion at 10q21.3 (7%). In addition, bi-allelic TET1 deletions, detected in 18 patients (33%), frequently co-occurred with EGFR amplification and were associated with low levels of TET1 mRNA expression, pointing at loss of TET1 activity. Bi-allelic TET1 loss was not associated with global concentrations of 5-hydroxymethylcytosine, indicating a site-specific effect of TET1 for DNA (de)methylation. Focal amplification of EGFR positively correlated with overall mutational burden, tumor size, and poor long-term survival. Bi-allelic TET1 loss was not an independent prognostic factor, but significantly associated with poor survival in patients with concomitant EGFR amplification. Rates of genomic TET1 deletion were significantly lower in a cohort of IDH1-mutated patients. Despite the relevance of TET1 for DNA demethylation and as potential therapeutic target, a frequent genomic loss of TET1 has not previously been reported in GBM.
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http://dx.doi.org/10.1016/j.neo.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642757PMC
December 2020

Twenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma.

Neurology 2020 12 28;95(23):e3138-e3144. Epub 2020 Sep 28.

From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.

Objective: To determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.

Methods: Sixty-five patients (median age 62 years, range 27-75; median Karnofsky performance score 70, range 20-90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.

Results: Median follow-up for surviving patients was 19.6 years (17.5-23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9-5.9); for patients ≤60 years, 11.0 years (95% CI 4.8-17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.

Conclusion: At a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.

Classification Of Evidence: This work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.
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http://dx.doi.org/10.1212/WNL.0000000000010949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734926PMC
December 2020

Parcellation of the Subthalamic Nucleus in Parkinson's Disease: A Retrospective Analysis of Atlas- and Diffusion-Based Methods.

Stereotact Funct Neurosurg 2020 23;98(6):416-423. Epub 2020 Sep 23.

Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.

Background: Deep brain stimulation (DBS) is an established method of treatment for Parkinson's disease (PD). A stimulation sweet spot at the interface between the motor and associative clusters of the subthalamic nucleus (STN) has recently been postulated. The aim of this study was to analyze the available clustering methods for the STN and their correlation to outcome.

Methods: This is a retrospective analysis of a group of 20 patients implanted with a DBS device for PD. Atlas-based and diffusion tractography-based parcellation of the STN was performed. The distances of the electrode to the obtained clusters were compared to each other and to outcome parameters, which included levodopa equivalent dose (LED) reduction, Unified Parkinson's Disease Rating Scale (UPDRS)-III scores, and reduction in scores for items 32 and 36 of the UPDRS-IV.

Results: The implanted electrodes were located nearest to the motor clusters of the STN. The following significant associations with postoperative LED reduction were found: (1) distance of the electrode to the motor cluster in the Accolla and DISTAL atlases (p < 0.01) and (2) distance of the electrode to the supplementary motor area cluster (p = 0.02). There was no association with either the UPDRS-III or the UPDRS-IV score.

Conclusions: The results of this study suggest the possibility that atlas-based clustering, as well as diffusion tractography-based parcellation, can be useful in estimating the stimulation target ("sweet spot") for STN-DBS in PD patients. Atlas-based as well as diffusion-based clustering might become a useful tool in DBS trajectory planning.
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http://dx.doi.org/10.1159/000509780DOI Listing
September 2020

Author Correction: Label-Free Imaging of Tissue Architecture during Axolotl Peripheral Nerve Regeneration in Comparison to Functional Recovery.

Sci Rep 2020 09 15;10(1):15343. Epub 2020 Sep 15.

Neurosurgery, Carl Gustav Carus University Hospital, TU Dresden, Dresden, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-72252-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490685PMC
September 2020

Label-free multiphoton microscopy as a tool to investigate alterations of cerebral aneurysms.

Sci Rep 2020 07 23;10(1):12359. Epub 2020 Jul 23.

Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstraße 74, 01307, Dresden, Saxony, Germany.

Cerebral aneurysms are abnormal focal dilatations of arterial vessel walls with pathological vessel structure alterations. Sudden rupture can lead to a subarachnoid hemorrhage, which is associated with a high mortality. Therefore, the origin of cerebral aneurysms as well as the progression to the point of rupture needs to be further investigated. Label-free multimodal multiphoton microscopy (MPM) was performed on resected human aneurysm domes and integrated three modalities: coherent anti-Stokes Raman scattering, endogenous two-photon fluorescence and second harmonic generation. We showed that MPM is a completely label-free and real-time powerful tool to detect pathognomonic histopathological changes in aneurysms, e.g. thickening and thinning of vessel walls, intimal hyperplasia, intra-wall haemorrhage, calcification as well as atherosclerotic changes. In particular, the loss or fragmentation of elastin as well as fibromatous wall remodelling appeared very distinct. Remarkably, cholesterol and lipid deposits were clearly visible in the multiphoton images. MPM provides morphological and biochemical information that are crucial for understanding the mechanisms of aneurysm formation and progression.
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http://dx.doi.org/10.1038/s41598-020-69222-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378195PMC
July 2020

Label-free multiphoton imaging allows brain tumor recognition based on texture analysis-a study of 382 tumor patients.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa035. Epub 2020 Mar 12.

Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.

Background: Label-free multiphoton microscopy has been suggested for intraoperative recognition and delineation of brain tumors. For any future clinical application, appropriate approaches for image acquisition and analysis have to be developed. Moreover, an evaluation of the reliability of the approach, taking into account inter- and intrapatient variability, is needed.

Methods: Coherent anti-Stokes Raman scattering (CARS), two-photon excited fluorescence (TPEF), and second-harmonic generation were acquired on cryosections of brain tumors of 382 patients and 28 human nontumor brain samples. Texture parameters of those images were calculated and used as input for linear discriminant analysis.

Results: The combined analysis of texture parameters of the CARS and TPEF signal proved to be most suited for the discrimination of nontumor brain versus brain tumors (low- and high-grade astrocytoma, oligodendroglioma, glioblastoma, recurrent glioblastoma, brain metastases of lung, colon, renal, and breast cancer and of malignant melanoma) leading to a correct rate of 96% (sensitivity: 96%, specificity: 100%). To approximate the clinical setting, the results were validated on 42 fresh, unfixed tumor biopsies. 82% of the tumors and, most important, all of the nontumor samples were correctly recognized. An image resolution of 1 µm was sufficient to distinguish brain tumors and nontumor brain. Moreover, the vast majority of single fields of view of each patient's sample were correctly classified with high probabilities, which is important for clinical translation.

Conclusion: Label-free multiphoton imaging might allow fast and accurate intraoperative delineation of primary and secondary brain tumors in combination with endoscopic systems.
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http://dx.doi.org/10.1093/noajnl/vdaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212881PMC
March 2020

Isocitrate dehydrogenase 1 mutant glioblastomas demonstrate a decreased rate of pseudoprogression: a multi-institutional experience.

Neurooncol Pract 2020 Mar 10;7(2):185-195. Epub 2019 Oct 10.

Department of Radiation Oncology, Indiana University Simon Cancer Center, Indianapolis, USA.

Background: Pseudoprogression (psPD) represents false radiologic evidence of tumor progression and is observed in some glioblastoma (GBM) patients after postoperative chemoradiation (CRT) with temozolomide (TMZ). The ambiguity of the psPD diagnosis confounds identification of true progression and may lead to unnecessary interventions. The association between psPD and isocitrate dehydrogenase 1 () mutational (mut) status is understudied, and its incidence may alter clinical decision making.

Methods: We retrospectively evaluated 120 patients with -mut (n = 60) and -wild-type (IDH-WT; [n = 60]) GBMs who received postoperative CRT with TMZ at 4 academic institutions. Response Assessment in Neuro-Oncology criteria were used to identify psPD rates in routine brain MRIs performed up to 90 days after CRT completion.

Results: Within 90 days of completing CRT, 9 GBM patients (1 [1.7%] -mut and 8 [13.3%] -WTs) demonstrated true progression, whereas 17 patients (3 [5%] -muts and 14 [23.3%] -WTs) demonstrated psPD ( =  .004). -mut GBMs had a lower probability of psPD (hazard ratio: 0.173, 95% CI, 0.047-0.638, = .008). Among the patients with radiologic signs suggestive of progression (n = 26), psPD was found to be the cause in 3 of 4 (75.0%) of the -mut GBMs and 14 of 22 (63.6%) of the -WT GBMs ( .496). Median overall survival for -mut and -WT GBM patients was 40.3 and 23.0 months, respectively ( < .001).

Conclusions: -mut GBM patients demonstrate lower absolute rates of psPD expression. Irrespective of GBM subtype, psPD expression was more likely than true progression within 90 days of completing CRT. Continuing adjuvant treatment for -mut GBMs is suggested if radiologic progression is suspected during this time interval.
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http://dx.doi.org/10.1093/nop/npz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318854PMC
March 2020

Molecular Characterization of Astrocytoma Progression Towards Secondary Glioblastomas Utilizing Patient-Matched Tumor Pairs.

Cancers (Basel) 2020 Jun 26;12(6). Epub 2020 Jun 26.

National Center for Tumor Diseases (NCT), Partner Site Dresden, D-01307 Dresden, Germany.

Astrocytomas are primary human brain tumors including diffuse or anaplastic astrocytomas that develop towards secondary glioblastomas over time. However, only little is known about molecular alterations that drive this progression. We measured multi-omics profiles of patient-matched astrocytoma pairs of initial and recurrent tumors from 22 patients to identify molecular alterations associated with tumor progression. Gene copy number profiles formed three major subcluters, but more than half of the patient-matched astrocytoma pairs differed in their gene copy number profiles like astrocytomas from different patients. Chromosome 10 deletions were not observed for diffuse astrocytomas, but occurred in corresponding recurrent tumors. Gene expression profiles formed three other major subclusters and patient-matched expression profiles were much more heterogeneous than their copy number profiles. Still, recurrent tumors showed a strong tendency to switch to the mesenchymal subtype. The direct progression of diffuse astrocytomas to secondary glioblastomas showed the largest number of transcriptional changes. Astrocytoma progression groups were further distinguished by signaling pathway expression signatures affecting cell division, interaction and differentiation. As expected, IDH1 was most frequently mutated closely followed by TP53, but also MUC4 involved in the regulation of apoptosis and proliferation was frequently mutated. Astrocytoma progression groups differed in their mutation frequencies of these three genes. Overall, patient-matched astrocytomas can differ substantially within and between patients, but still molecular signatures associated with the progression to secondary glioblastomas exist and should be analyzed for their potential clinical relevance in future studies.
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http://dx.doi.org/10.3390/cancers12061696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352509PMC
June 2020

Artificial feeder cells expressing ligands for killer cell immunoglobulin-like receptors and CD94/NKG2A for expansion of functional primary natural killer cells with tolerance to self.

Cytotherapy 2020 07 23;22(7):354-368. Epub 2020 May 23.

Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany. Electronic address:

Background Aims: Natural killer (NK) cells are promising cells for immunotherapy of cancer, and there are ongoing efforts to improve their ex vivo expansion to clinically relevant numbers. This study focused on the development of a C1-, C2-, Bw4 killer cell immunoglobulin-like receptor (KIR) ligand and NKG2A ligand-containing feeder cell line for autonomous expansion of functional NK cells.

Methods: PC3-derived feeder cells expressing IL-2, 4-1BBL and membrane-bound IL-15-mutDAP12 (mIL-15d) fusion protein in combinations or alone were generated and used for expansion. Expanded NK cells were analyzed with respect to subpopulations, expression of NK cell receptors and immune checkpoint molecules as well as their cytotoxicity against K562 cells, cetuximab-marked tumor cells and autologous B cells.

Results: Only combinatorial expression of IL-2 plus 4-1BBL or IL-2, 4-1BBL plus mIL-15d in feeder cells efficiently expanded NK cells and supported selective outgrowth of NK cells from peripheral blood mononuclear cell samples. Best expansion of NK cells was achieved using PC3-IL-2-4-1BBL-mIL-15d feeder cells. Such expanded NK cells exhibited upregulation of natural cytotoxicity receptors, DNAM-1 and NKG2C and induced expression of high affinity IL-2 receptor, which were paralleled by attenuated KIR and increased expression of NKG2A and ILT2. In addition, elevated TIM-3 levels were noted and PD-1 and T cell immunoreceptor with Ig and ITIM domain (TIGIT) levels remained low. Expanded NK cells were highly cytolytic when encountering K562 cells and cetuximab-marked target cells but remained unresponsive to autologous B cells and target cells with protective levels of human leukocyte antigen.

Conclusions: Collectively, the results demonstrate the feasibility of PC3-IL-2-4-1BBL-mIL-15d feeder cells for robust expansion of NK cells, which remain tolerant to self and could be used in the future for adoptive cell therapy of cancer.
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http://dx.doi.org/10.1016/j.jcyt.2020.02.004DOI Listing
July 2020

Improved efficiency of patient admission with electronic health records in neurosurgery.

Health Inf Manag 2020 May 20:1833358320920990. Epub 2020 May 20.

Technical University of Dresden, Germany.

Background: Electronic health records (EHRs) may be controversial but they have the potential to improve patient care. We investigated whether the introduction of an electronic template-based admission form for the collection of information about the patient's medical history and neurological and clinical state at admission in the neurosurgical unit might have an impact on the quality of documentation in a discharge record and the amount of time taken to produce this documentation.

Method: A new digital template-based admission form (EHR) was developed and assessed with QNOTE, an assessment tool of medical notes with standardised criteria and the possibility to benchmark the quality of documentations. This was compared to 30 prior paper-based handwritten documentations (HWD) regarding the utilisation of these medical notes for dictation of medical discharge records.

Results: Implementation of the EHR significantly improved the quality of patient admission documentation with a QNOTE mean grand score of 87 ± 22 ( < 0.0001) compared to prior HWD with 44 ± 30. The mean documentation time for HWD was 8.1 min ± 4.1 min and the dictation time for discharge records was 10.6 min ± 3.5 min. After implementation of EHR, the documentation time increased slightly to 9.6 min ± 2.3 min (n.s.), while the time for dictation of discharge records was reduced to 5.1 min ± 1.2 min ( < 0.0001). There was a clear correlation between a higher quality of documentation and a higher needed documentation time as well as higher quality of documentation and lower dictation times of discharge records.

Conclusion: Implementation of the EHR improved the quality of patient admission documentation and reduced the dictation time of discharge records.

Implications: It is crucial to involve stakeholders and users of EHRs in a timely manner during the stage of development and implementation phase to ensure optimal results and better usability.
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http://dx.doi.org/10.1177/1833358320920990DOI Listing
May 2020

Sigma-1 Receptor Positron Emission Tomography: A New Molecular Imaging Approach Using ()-(-)-[F]Fluspidine in Glioblastoma.

Molecules 2020 May 6;25(9). Epub 2020 May 6.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research site Leipzig, 04318 Leipzig, Germany.

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand ()-(-)-[F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical K values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology.
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http://dx.doi.org/10.3390/molecules25092170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248975PMC
May 2020

Comparison of Automatic Segmentation Algorithms for the Subthalamic Nucleus.

Stereotact Funct Neurosurg 2020 5;98(4):256-262. Epub 2020 May 5.

Department of Neurosurgery, University Hospital Carl-Gustav-Carus, Technical University of Dresden, Dresden, Germany.

Introduction: Various automatic segmentation algorithms for the subthalamic nucleus (STN) have been published recently. However, most of the available software tools are not approved for clinical use.

Objective: The aim of this study is to evaluate a clinically available automatic segmentation tool of the navigation planning software Brainlab Elements (BL-E) by comparing the output to manual segmentation and a nonclinically approved research method using the DISTAL atlas (DA) and the Horn electrophysiological atlas (HEA).

Methods: Preoperative MRI data of 30 patients with idiopathic Parkinson's disease were used, resulting in 60 STN segmentations. The segmentations were created manually by two clinical experts. Automatic segmentations of the STN were obtained from BL-E and Advanced Normalization Tools using DA and HEA. Differences between manual and automatic segmentations were quantified by Dice and Jaccard coefficient, target overlap, and false negative/positive value (FNV/FPV) measurements. Statistical differences between similarity measures were assessed using the Wilcoxon signed-rank test with continuity correction, and comparison with interrater results was performed using the Mann-Whitney U test.

Results: For manual segmentation, the mean size of the segmented STN was 133 ± 24 mm3. The mean size of the STN was 121 ± 18 mm3 for BL-E, 162 ± 21 mm3 for DA, and 130 ± 17 mm3 for HEA. The Dice coefficient for the interrater comparison was 0.63 and 0.54 ± 0.12, 0.59 ± 0.13, and 0.52 ± 0.14 for BL-E, DA, and HEA, respectively. Significant differences between similarity measures were found for Dice and Jaccard coefficient, target overlap and FNV between BL-E and DA; and FPV between BL-E and HEA. However, none of the differences were significant compared to interrater variability. The analysis of the center of gravity of the segmentations revealed that the BL-E STN ROI was located more medially, superior and posterior compared to other segmentations. Regarding the target overlap for beta power within the STN ROI included with the HEA, the BL-E segmentation showed a significantly higher value compared to manual segmentation.

Conclusion: Automatic image segmentation by means of the clinically approved software BL-E provides STN segmentations with similar accuracy like research tools, and differences are in the range of observed interrater variability. Further studies are required to investigate the clinical validity, for example, by comparing segmentation results of BL-E with electrophysiological data.
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http://dx.doi.org/10.1159/000507028DOI Listing
May 2020

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma.

Cancers (Basel) 2020 Apr 3;12(4). Epub 2020 Apr 3.

OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz- Zentrum Dresden-Rossendorf, 01307 Dresden, Germany.

Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients' samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2 cells ( = 0.49, = 0.016) and nestin cells ( = 0.55, = 0.007). Our results show that many PDXs maintain key features of the patients' samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers.
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http://dx.doi.org/10.3390/cancers12040871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226316PMC
April 2020

Peripheral nerve field stimulation in medically refractory trigeminal neuralgia attributed to multiple sclerosis.

J Neurosurg 2020 Mar 20:1-7. Epub 2020 Mar 20.

1Department of Neurosurgery, University Hospital Carl Gustav Carus.

Objective: Case reports and small patient series have suggested peripheral nerve field stimulation (PNFS) as a treatment for refractory trigeminal neuralgia attributed to multiple sclerosis (MS). Here, the authors aimed to assess the effects of this technique on long-term pain severity.

Methods: Data were prospectively collected on patients with refractory trigeminal neuralgia attributed to MS who underwent PNFS between July 2013 and August 2017 at the authors' neurosurgical department. Patients were evaluated before and after the first treatment as well as at follow-up at least twice a year. Patients underwent assessment of their pain severity using the Barrow Neurological Institute (BNI) Scale before treatment and at follow-up and were questioned about adverse events following cranial MRI performed after implantation of a permanent PNFS system.

Results: Eight patients (3 women) underwent PNFS trials and their median age was 61 years (IQR 73.75 - 46.5 years). Seven patients proceeded to permanent implantation of the stimulation system. At a median follow-up of 33 months (IQR 42 - 24 months), pain severity decreased from baseline to the last follow-up (BNI score decrease from V [IQR V - V] to III [IQR V - III], p = 0.054). Four patients experienced long-lasting benefit (at 48, 33, 24, and 15 months' follow-up, respectively), while in 3 patients the treatment eventually failed after an initially successful period. One patient had an infection, requiring system removal and subsequent reimplantation. No other complications occurred. No adverse events were noted in the patients undergoing MRI postimplantation.

Conclusions: This analysis indicates a possibly beneficial long-term effect of PNFS on refractory trigeminal neuralgia attributed to MS in some patients.
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http://dx.doi.org/10.3171/2019.12.JNS192261DOI Listing
March 2020

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers.

Neurol Sci 2020 Jul 3;41(7):1685-1696. Epub 2020 Mar 3.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson's disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.
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http://dx.doi.org/10.1007/s10072-020-04293-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359149PMC
July 2020

Mapping of language and motor function during awake neurosurgery with intraoperative optical imaging.

Neurosurg Focus 2020 02;48(2):E3

6Department of Neurosurgery, Carl Gustav Carus University Hospital, Technische Universität Dresden, Saxony, Germany.

Intraoperative optical imaging (IOI) is a marker-free, contactless, and noninvasive imaging technique that is able to visualize metabolic changes of the brain surface following neuronal activation. Although it has been used in the past mainly for the identification of functional brain areas under general anesthesia, the authors investigated the potential of the method during awake surgery. Measurements were performed in 10 patients who underwent resection of lesions within or adjacent to cortical language or motor sites. IOI was applied in 3 different scenarios: identification of motor areas by using finger-tapping tasks, identification of language areas by using speech tasks (overt and silent speech), and a novel approach-the application of IOI as a feedback tool during direct electrical stimulation (DES) mapping of language. The functional maps, which were calculated from the IOI data (activity maps), were qualitatively compared with the functional MRI (fMRI) and the electrophysiological testing results during the surgical procedure to assess their potential benefit for surgical decision-making.The results reveal that the intraoperative identification of motor sites with IOI in good agreement with the preoperatively acquired fMRI and the intraoperative electrophysiological measurements is possible. Because IOI provides spatially highly resolved maps with minimal additional hardware effort, the application of the technique for motor site identification seems to be beneficial in awake procedures. The identification of language processing sites with IOI was also possible, but in the majority of cases significant differences between fMRI, IOI, and DES were visible, and therefore according to the authors' findings the IOI results are too unspecific to be useful for intraoperative decision-making with respect to exact language localization. For this purpose, DES mapping will remain the method of choice.Nevertheless, the IOI technique can provide additional value during the language mapping procedure with DES. Using a simple difference imaging approach, the authors were able to visualize and calculate the spatial extent of activation for each stimulation. This might enable surgeons in the future to optimize the mapping process. Additionally, differences between tumor and nontumor stimulation sites were observed with respect to the spatial extent of the changes in cortical optical properties. These findings provide further evidence that the method allows the assessment of the functional state of neurovascular coupling and is therefore suited for the delineation of pathologically altered tissue.
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http://dx.doi.org/10.3171/2019.11.FOCUS19759DOI Listing
February 2020

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

Int J Stroke 2020 Aug 19;15(6):609-618. Epub 2020 Jan 19.

Department for Neurology, Klinikum rechts der Isar, TU München, München, Germany.

Background: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth.

Aims: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage.

Methods: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used.

Results: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in  = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay.

Conclusion: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.
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http://dx.doi.org/10.1177/1747493019895654DOI Listing
August 2020

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin.

Cancers (Basel) 2019 Dec 16;11(12). Epub 2019 Dec 16.

Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.

IDH1 (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1 converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP), whereas IDH1 uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1 are still ambiguous. The present study demonstrates that IDH1 expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD levels upon IDH1 transduction. However, in astrocytes IDH1 led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1 cells utilize NAD to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.
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http://dx.doi.org/10.3390/cancers11122028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966450PMC
December 2019

Olfactory bulb volume changes associated with trans-sphenoidal pituitary surgery.

PLoS One 2019 18;14(12):e0224594. Epub 2019 Dec 18.

Interdisciplinary Smell & Taste Clinic, Department of Otorhinolaryngology, Dresden University of Technology, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.

Objective: The trans-sphenoidal approach is most frequently used for pituitary adenoma (PA) enucleation. However, effects of this surgery on neighboring structures have received little attention so far. In particular, no investigations on olfactory bulb (OB) anatomy after trans-sphenoidal surgery have been reported. Because impairment of olfaction has been shown in small groups following trans-sphenoidal surgery we hypothesized that the transnasal approach is likely to alter OB volume which is associated with changes of olfactory function.

Methods: The study comprised 33 patients with pituitary adenoma (14 women and 19 men, mean age 50 years). Comprehensive assessment of olfactory function was conducted with the "Sniffin' Sticks" test kit. Based on magnetic resonance imaging scans OBs were measured before and approximately one year after trans-sphenoidal PA enucleation.

Results: Owing to postoperative non-compliance and MRI artifacts partly due to drill friction complete evaluation of "Sniffin' Sticks" in term of obtaining the TDI score was possible pre- and postoperatively in 21 patients whereas OB volumes were available in 32 patients. Approximately one year after surgery olfactory function was not significantly different from baseline. However, left- and right-sided OB volume in patients treated via trans-sphenoidal surgery decreased (p = 0.001). The side of the surgical approach did not affect OB volume in a side-specific manner. Changes in odor threshold were significantly correlated to changes in right-sided OB volume (r = 0.45, p = 0.024).

Conclusion: Overall olfactory performance one year after surgery was not significantly different from baseline. However, changes in OB volume are associated with changes in olfactory performance and OB volumes decreased in patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919594PMC
March 2020

Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma.

J Cancer Res Clin Oncol 2020 Mar 21;146(3):659-670. Epub 2019 Nov 21.

Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

Background: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O-methylguanine DNA methyltransferase (MGMT) promoter methylation status.

Methods: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression.

Results: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002).

Conclusions: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.
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http://dx.doi.org/10.1007/s00432-019-03086-9DOI Listing
March 2020

Rapid Label-Free Analysis of Brain Tumor Biopsies by Near Infrared Raman and Fluorescence Spectroscopy-A Study of 209 Patients.

Front Oncol 2019 5;9:1165. Epub 2019 Nov 5.

Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

In brain surgery, novel technologies are continuously developed to achieve better tumor delineation and maximize the extent of resection. Raman spectroscopy is an optical method that enables to retrieve a molecular signature of tissue biochemical composition in order to identify tumor and normal tissue. Here, the translation of Raman spectroscopy to the surgical practice for discerning a variety of different tumor entities from non-neoplastic brain parenchyma was investigated. Fresh unprocessed biopsies obtained from brain tumor surgery were analyzed over 1.5 years including all patients that gave consent. Measurements were performed with a Raman microscope by medical personnel as routine activity. The Raman and fluorescence signals of the acquired spectra were analyzed by principal component analysis, followed by supervised classification to discriminate non-tumor tissue vs. tumor and distinguish tumor entities. Histopathology of the measured biopsies was performed as reference. Classification led to the correct recognition of all non-neoplastic biopsies (7/7) and of 97% of the investigated tumor biopsies (195/202). For instance, GBM was recognized as tumor with a correct rate of 94% if primary, and of 100% if recurrent. Astrocytoma and oligodendroglioma were recognized as tumor with correct rates of 86 and 90%, respectively. All brain metastases, meningioma and schwannoma were correctly recognized as tumor and distinguished from non-neoplastic brain tissue. Furthermore, metastases were discerned from glioma with correct rate of 90%. Oligodendroglioma and astrocytoma -mutant, which differ in the presence of 1p/19q codeletion, were discerned with a correct rate of 81%. These results demonstrate the feasibility of rapid brain tumors recognition and extraction of diagnostic information by Raman spectroscopy, using a protocol that can be easily included in the routine surgical workflow.
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http://dx.doi.org/10.3389/fonc.2019.01165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848276PMC
November 2019

[Accreditation and digitization - just a load of crap? Systematic risk analysis among medical employees - today and 12 years ago].

Z Evid Fortbild Qual Gesundhwes 2019 Nov 11;147-148:67-72. Epub 2019 Nov 11.

Klinik und Poliklinik für Neurochirurgie des Uniklinikums DresdenDresden, Deutschland.

Background: The aim of this study was to elucidate whether measures of quality management and digitization have the potential to reduce treatment risks in patients of a surgical clinic.

Methods: All health professional involved in the treatment of patients were asked to participate in a systematic, process-orientated and anonymous survey to assess the probability of occurrence of 69 treatment risks in stationary patients. The surveys were conducted in 2006 before establishing quality management (QM) and digitization, and recently after various certification activities have been performed and the digitization has been completed.

Results: According to the survey respondents, QM measures and digitization have led to a significant reduction of the probability of occurrence of 20 treatment risks, although the number of surgeries performed rose 1.8-fold while the number of employees increased by just 1.2-fold to 1.4-fold. The risk reduction was most pronounced regarding mistaken patient identity errors, while complex process risks like insufficient postoperative aftercare or patient dissatisfaction with ineffective communication remained unchanged.

Discussion: An increase in process risks that may be due to an increased workload can be mitigated by QM and digitization measures. This requires a quality and risk management system that is organized by the administration, supported by responsible and risk-aware employees and not imposed.

Conclusion: Health professionals estimate that digitization and QM measures have the potential to reduce patients' treatment risks and help offset the increased workload. In particular, accreditations can help implement and maintain quality management measures.
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http://dx.doi.org/10.1016/j.zefq.2019.09.006DOI Listing
November 2019

Somatosensory functional MRI tractography for individualized targeting of deep brain stimulation in patients with chronic pain after brachial plexus injury.

Acta Neurochir (Wien) 2019 12 7;161(12):2485-2490. Epub 2019 Oct 7.

Department of Neurosurgery, University Hospital CarlGustavCarus, Technical University of Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Background: The optimal targets for deep brain stimulation (DBS) in patients with refractory chronic pain are not clearly defined. We applied sensory functional MRI (fMRI)- and diffusion tensor imaging (DTI)-based DBS in chronic pain patients into 3 different targets to ascertain the most beneficial individual stimulation site.

Methods: Three patients with incapacitating chronic pain underwent DBS into 3 targets (periventricular gray (PVG), ventroposterolateral thalamus (VPL), and posterior limb of the internal capsule according to fMRI and DTI (PLIC). The electrodes were externalized and double-blinded tested for several days. Finally, the two electrodes with the best pain reduction were kept for permanent stimulation. The patients were then followed up for 12 months. Outcome measures comprised the numerical rating scale (NRS), short-form McGill's score (SF-MPQ), and health-related quality of life (SF-36).

Results: Continuous pain (mean NRS 6.6) was reduced to NRS 3.6 after 12 months. Only with stimulation of the PLIC pain attacks, that occurred at least 3 times a week (mean NRS 9.6) resolved in 2 patients and improved in one patient concerning both intensity (NRS 5) and frequency (twice a month). The mean SF-MPQ decreased from 92.7 to 50. The health-related quality of life improved considerably.

Conclusion: fMRI- and DTI-based DBS to the PLIC was the only target with a significant effect on pain attacks and seems to be the most promising target in chronic pain patients after brachial plexus injury. The combination with PVG or VPL can further improve patients' outcome especially in terms of reducing the continuous pain.
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http://dx.doi.org/10.1007/s00701-019-04065-2DOI Listing
December 2019

Clinical Validation of Quality Improvements Using the Six Sigma Concept: A Case Study for Deep Brain Stimulation in Parkinson's Disease.

Stereotact Funct Neurosurg 2019 25;97(3):195-201. Epub 2019 Sep 25.

Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.

Background: The Six Sigma concept allows for the evaluation of quality changes after the implementation of new technical equipment or adjustment of perioperative procedures. Exemplarily, we applied this method for quality assessment in deep brain stimulation surgery (DBS) for Parkinson's disease.

Methods: The medical procedure and possible errors were registered. Then, 6 critical-to-quality characteristics regarding clinical outcome, surgical precision, and the surgical process were measured. The surgical procedure was then optimized in 2 steps, and its measurement, along with the analysis, was repeated twice.

Results: By optimizing perioperative settings, the operation time could be reduced, and the precision of the lead placement could be increased. Clinical outcome, as measured by improvement in UPDRS-III, IV, and reduction of medication could also be improved with smaller required stimulation voltage. With directional leads considerable reduction of medication was achieved in 97% of patients (σ-value 3.39) compared to 83.7% (σ-value 2.53) with nondirectional leads.

Conclusion: This study shows that the Six Sigma concept is a suitable quality tool to analyze and improve treatment quality of complex medical procedures such as lead positioning in DBS surgery in clinical routine. Our results suggest that directional leads in subthalamic nucleus DBS may have a favorable impact on patients' outcome.
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http://dx.doi.org/10.1159/000502654DOI Listing
February 2020

Label-free Imaging of Tissue Architecture during Axolotl Peripheral Nerve Regeneration in Comparison to Functional Recovery.

Sci Rep 2019 09 2;9(1):12641. Epub 2019 Sep 2.

Neurosurgery, Carl Gustav Carus University Hospital, TU Dresden, Dresden, Germany.

Human peripheral nerves hold the potential to regenerate after injuries; however, whether a successful axonal regrowth was achieved can be elucidated only months after injury by assessing function. The axolotl salamander is a regenerative model where nerves always regenerate quickly and fully after all types of injury. Here, de- and regeneration of the axolotl sciatic nerve were investigated in a single and double injury model by label-free multiphoton imaging in comparison to functional recovery. We used coherent anti-Stokes Raman scattering to visualize myelin fragmentation and axonal regeneration. The presence of axons at the lesion site corresponded to onset of functional recovery in both lesion models. In addition, we detected axonal regrowth later in the double injury model in agreement with a higher severity of injury. Moreover, endogenous two-photon excited fluorescence visualized macrophages and revealed a similar timecourse of inflammation in both injury models, which did not correlate with functional recovery. Finally, using the same techniques, axonal structure and status of myelin were visualized in vivo after sciatic nerve injury. Label-free imaging is a new experimental approach that provides mechanistic insights in animal models, with the potential to be used in the future for investigation of regeneration after nerve injuries in humans.
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http://dx.doi.org/10.1038/s41598-019-49067-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718386PMC
September 2019