Publications by authors named "Astrid Weyerbrock"

83 Publications

Assessment of the Minimum Clinically Important Difference in the Smartphone-based 6-minute Walking Test After Surgery for Lumbar Degenerative Disc Disease.

Spine (Phila Pa 1976) 2021 Sep;46(18):E959-E965

Department of Neurosurgery, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Study Design: Prospective cohort study.

Objective: The aim of this study was to determine the minimum clinically important difference (MCID) of the 6-minute walking test (6WT) after surgery for lumbar degenerative disc disease (DDD).

Summary Of Background Data: The smartphone-based 6WT is a valid and reliable tool to quantify objective functional impairment in patients with lumbar DDD. To date, the MCID of the 6WT has not been described in patients with DDD.

Methods: We assessed patients pre- and 6-weeks postoperatively, analyzing both raw 6-minute walking distances (6WD; in meters) and standardized 6WT z scores. Three methods were applied to compute MCID values using established patient-reported outcomes measures (PROMs) as anchors (VAS back/leg pain, Zurich Claudication Questionnaire [ZCQ], Core Outcome Measures Index [COMI]): average change, minimum detectable change, and the change difference approach.

Result: We studied 49 patients (59% male) with a mean age of 55.5 ± 15.8 years. The computation methods revealed MCID values ranging from 81 m (z score of 0.9) based on the VAS back pain to 99 m (z score of 1.0) based on the ZCQ physical function scale. The average MCID of the 6WT was 92 m (z score of 1.0). Based on the average MCID of raw 6WD values or standardized z scores, 53% or 49% of patients classified as 6-week responders to surgery for lumbar DDD, respectively.

Conclusion: The MCID for the 6WT in lumbar DDD patients is variable, depending on the calculation technique. We propose a MCID of 92m (z score of 1.0), based on the average of all three methods. Using a z score as MCID allows for the standardization of clinically meaningful change and attenuates age- and sex-related differences.Level of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000003991DOI Listing
September 2021

External Validation of the Minimum Clinically Important Difference in the Timed-Up-and-Go (TUG) Test after Surgery for Lumbar Degenerative Disc Disease.

Spine (Phila Pa 1976) 2021 May 24. Epub 2021 May 24.

Department of Neurosurgery, University Hospital Zurich and Clinical Neuroscience Center, University of Zurich, Zurich, Switzerland Department of Neurosurgery, Cantonal Hospital St.Gallen, St.Gallen, Switzerland Neuro- and Spine Center, Hirslanden Clinic St. Anna, Lucerne, Switzerland.

Study Design: Prospective observational cohort study.

Objective: To provide external validation of the minimum clinically important difference (MCID) of the Timed-Up-and-Go (TUG) test.

Summary Of Background Data: The TUG test is one of the best explored and most frequently applied objective task-based functional outcome measure in patients with lumbar degenerative disc disease (DDD). The increased use of the TUG test is based on its solid psychometric properties, however, an external validation of the originally determined MCID is lacking.

Methods: N = 49 patients with lumbar DDD, scheduled for elective spine surgery, were assessed pre- and 6-weeks (W6) postoperative. MCID values were calculate for raw TUG test times (in s) and standardized TUG z-scores using three different computation methods and the following established patient-reported outcome measures (PROMs) as anchors: Visual Analog Scales (VAS), Core Outcome Measures Index (COMI) Back, Zurich Claudication Questionnaire (ZCQ)).

Results: The three computation methods generated a range of MCID values, depending on the PROM used as anchor, from 0.9 s (z-score of 0.3) based on the VAS leg pain to 3.0 s (z-score of 2.7) based on the ZCQ physical function scale. The average MCID of the TUG test across all anchors and computation methods was 2.1 s (z-score of 1.5). According to the average MCID of raw TUG test values or TUG z-scores, 41% and 43% of patients classified as W6 responders to surgery, respectively.

Conclusion: This study confirms the ordinally reported TUG MCID values in patients undergoing surgery for lumbar. A TUG test time change of 2.1 s (or TUG z-score change of 1.5) indicates an objective and clinically meaningful change in functional status. This report facilitates the interpretation of TUG test results in clinical routine as well as in research.Level of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000004128DOI Listing
May 2021

Responsiveness of the self-measured 6-minute walking test and the Timed Up and Go test in patients with degenerative lumbar disorders.

J Neurosurg Spine 2021 May 7. Epub 2021 May 7.

Department of Neurosurgery, University Hospital Zurich and Clinical Neuroscience Center, University of Zurich.

Objective: The 6-minute walking test (6WT) and the Timed Up and Go (TUG) test are two of the most commonly applied standardized measures of objective functional impairment that help support clinical decision-making for patients undergoing surgery for degenerative lumbar disorders. This study correlates smartphone-app-based 6WT and TUG results to evaluate their responsiveness.

Methods: In a prospective study, 49 consecutive patients were assessed preoperatively and 6 weeks postoperatively using the 6WT, the TUG test, and commonly used patient-reported outcome measures. Raw values and standardized z-scores of both objective tests were correlated. An external criterion for treatment success was created based on the Zurich Claudication Questionnaire patient satisfaction subscale. Internal and external responsiveness for both functional tests was evaluated.

Results: The mean preoperative 6WT results improved from 401 m (SD 129 m), z-score -1.65 (SD 1.6) to 495 m (SD 129 m), z-score -0.71 (SD 1.6, p < 0.001). The mean preoperative TUG test results improved from 10.44 seconds (SD 4.37, z-score: -3.22) to 8.47 seconds (SD 3.38, z-score: -1.93, p < 0.001). The 6WT showed a strong negative correlation with TUG test results (r = -66, 95% CI 0.76-0.53, p < 0.001). The 6WT showed higher internal responsiveness (standardized responsive mean = 0.86) compared to the TUG test (standardized responsive mean = 0.67). Evaluation of external responsiveness revealed that the 6WT was capable of differentiating between patients who were satisfied and those who were unsatisfied with their treatment results (area under the curve = 0.70), whereas this was not evident for the TUG test ( area under the curve = 0.53).

Conclusions: Both tests adequately quantified functional impairment in surgical candidates with degenerative lumbar disorders. The 6WT demonstrated better internal and external responsiveness compared with the TUG test. Clinical trial registration no.: NCT03977961 (clinicaltrials.gov).

Abbreviations: AUC = area under the curve; COMI = Core Outcome Measures Index; DLDs = degenerative lumbar disorders; LDH = lumbar disc herniation; LSS = lumbar spinal stenosis; PROM = patient-reported outcome measure; ROC = receiver operating characteristic; SRM = standardized responsive mean; TUG = Timed Up and Go; VAS = visual analog scale; 6WD = 6-minute walking distance; 6WT = 6-minute walking test; ZCQ = Zurich Claudication Questionnaire.
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http://dx.doi.org/10.3171/2020.11.SPINE201621DOI Listing
May 2021

Patients undergoing surgery for lumbar degenerative spinal disorders favor smartphone-based objective self-assessment over paper-based patient-reported outcome measures.

Spine J 2021 04 17;21(4):610-617. Epub 2020 Dec 17.

Department of Neurosurgery, Kantonsspital St.Gallen, St. Gallen, Switzerland; Department of Neurosurgery, University Hospital Zurich & Clinical Neuroscience Center, University of Zurich, Zurich, Switzerland.

Background Context: Smartphone-based applications enable new prospects to monitor symptoms and assess functional outcome in patients with lumbar degenerative spinal disorders. However, little is known regarding patient acceptance and preference towards new modes of digital objective outcome assessment.

Purpose: To assess patient preference of an objective smartphone-based outcome measure compared to conventional paper-based subjective methods of outcome assessment.

Study Design: Prospective observational cohort study.

Patient Sample: Fourty-nine consecutive patients undergoing surgery for lumbar degenerative spinal disorder.

Outcome Measures: Patients completed a preference survey to assess different methods of outcome assessment. A 5-level Likert scale ranged from strong disagreement (2 points) over neutral (6 points) to strong agreement (10 points) was used.

Methods: Patients self-determined their objective functional impairment using the 6-minute Walking Test application (6WT-app) and completed a set of paper-based patient-reported outcome measures (PROMs) before and 6 weeks after surgery. Patients were then asked to rate the methods of outcome assessment in terms of suitability, convenience, and responsiveness to their symptoms.

Results: The majority of patients considered the 6WT-app a suitable instrument (median 8.0, interquartile range [IQR] 4.0). Patients found the 6WT more convenient (median 10.0, IQR 2.0) than the Zurich Claudication Questionnaire (ZCQ; median 8.0, IQR 4.0, p=.019) and Core Outcome Measure Index (COMI; median 8.0, IQR 4.0, p=.007). There was good agreement that the 6WT-app detects change in physical performance (8.0, IQR 4.0). 78 % of patients considered the 6WT superior in detecting differences in symptoms (vs. 22% for PROMs). Seventy-six percent of patients would select the 6WT over the other, 18% the ZCQ and 6% the COMI. Eighty-two percent of patients indicated their preference to use a smartphone app for the assessment and monitoring of their spine-related symptoms in the future.

Conclusions: Patients included in this study favored the smartphone-based evaluation of objective functional impairment over paper-based PROMs. Involving patients more actively by means of digital technology may increase patient compliance and satisfaction as well as diagnostic accuracy.
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http://dx.doi.org/10.1016/j.spinee.2020.11.013DOI Listing
April 2021

Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS).

Stroke 2021 01 4;52(1):344-347. Epub 2020 Dec 4.

Neuroradiology (L.R., M.D.), Kantonsspital Aarau Switzerland.

Background And Purpose: The purpose of this study was to assess nationwide incidence and outcomes of aneurysmal subarachnoid hemorrhage (aSAH). The Swiss SOS (Swiss Study on Subarachnoid Hemorrhage) was established in 2008 and offers the unique opportunity to provide this data from the point of care on a nationwide level.

Methods: All patients with confirmed aneurysmal subarachnoid hemorrhage admitted between January 1, 2009 and December 31, 2014, within Switzerland were recorded in a prospective registry. Incidence rates were calculated based on time-matched population data. Admission parameters and outcomes at discharge and at 1 year were recorded.

Results: We recorded data of 1787 consecutive patients. The incidence of aneurysmal subarachnoid hemorrhage in Switzerland was 3.7 per 100 000 persons/y. The number of female patients was 1170 (65.5%). With a follow-up rate of 91.3% at 1 year, 1042 patients (58.8%) led an independent life according to the modified Rankin Scale (0-2). About 1 in 10 patients survived in a dependent state (modified Rankin Scale, 3-5; n=185; 10.4%). Case fatality was 20.1% (n=356) at discharge and 22.1% (n=391) after 1 year.

Conclusions: The current incidence of aneurysmal subarachnoid hemorrhage in Switzerland is lower than expected and an indication of a global trend toward decreasing admissions for ruptured intracranial aneurysms. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03245866.
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http://dx.doi.org/10.1161/STROKEAHA.120.029538DOI Listing
January 2021

Surgery for IDH1/2 wild-type glioma invading the corpus callosum.

Acta Neurochir (Wien) 2021 04 23;163(4):937-945. Epub 2020 Oct 23.

Department of Neurosurgery, Medical Center - University of Freiburg, Breisacher Straße 64, 79106, Freiburg, BW, Germany.

Background: Glioblastoma of the corpus callosum (ccGBM) are rare tumors, with a dismal prognosis marked by a rapid clinical deterioration. For a long time, surgical treatment was not considered beneficial for most patients with such tumors. Recent studies claimed an improved survival for patients undergoing extensive resection, albeit without integration of the molecular profile of the lesions. The purpose of this study was to investigate the effect of biopsy and surgical resection on oncological and functional outcomes in patients with IDH wild-type ccGBM.

Methods: We performed a retrospective analysis of our institution's database of patients having been treated for high-grade glioma between 2005 and 2017. Inclusion criteria were defined as follows: patients older than 18 years, histopathological, and molecularly defined IDH wild-type glioma, major tumor mass (at least 2/3) invading the corpus callosum in the sagittal plane with a uni- or bilateral infiltration of the adjacent lobules. Surgical therapy (resection vs. biopsy), extent of resection according to the remaining tumor volume and adjuvant treatment as well as overall survival and functional outcome using the Karnofsky Performance Score (KPS) were analyzed.

Results: Fifty-five patients were included in the study, from which the mean age was 64 years and men (n = 34, 61.8%) were more often affected than women (n = 21, 38.2%). Thirty (54.5%) patients were treated with stereotactic biopsy alone, while 25 patients received tumor resection resulting in 14.5% (n = 8) gross-total resections and 30.9% (n = 17) partial resections. The 2-year survival rate after resection was 30% compared to 7% after biopsy (p = 0.047). The major benefit was achieved in the group with gross-total resection, while partial resection failed to improve survival. Neurological outcome measured by KPS did not differ between both groups either pre- or postoperatively.

Conclusions: Our study suggests that in patients with corpus callosum glioblastoma, gross-total resection prolongs survival without negatively impacting neurological outcome as compared to biopsy.
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http://dx.doi.org/10.1007/s00701-020-04623-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966629PMC
April 2021

External Validation of the Timed Up and Go Test as Measure of Objective Functional Impairment in Patients With Lumbar Degenerative Disc Disease.

Neurosurgery 2021 01;88(2):E142-E149

Neuro- and Spine Center, Hirslanden Clinic St. Anna, Lucerne, Switzerland.

Background: The Timed Up and Go (TUG) test is the most commonly applied objective measure of functional impairment in patients with lumbar degenerative disc disease (DDD).

Objective: To demonstrate external content validity of the TUG test.

Methods: Consecutive adult patients, scheduled for elective lumbar spine surgery, were screened for enrollment into a prospective observational study. Disease severity was estimated by patient-reported outcome measures (PROMs; Visual Analog Scales [VAS], Core Outcome Measures Index [COMI] back, Zurich Claudication Questionnaire [ZCQ]) and the TUG test. Pearson correlation coefficients (PCCs) were used to describe the relationship between logarithmic TUG test raw values and PROMs.

Results: A total of 70 patients (mean age 55.9 ± 15.4 yr; 38.6% female; 27.1% previous spine surgery; 28.6% lower extremity motor deficits) with lumbar disc herniation (50%), lumbar spinal stenosis (34.3%), or instability requiring spinal fusion (15.7%) were included. The mean TUG test time was 10.8 ± 4.4 s; age- and sex-adjusted objective functional impairment (OFI) T-score was 134.2 ± 36.9. A total of 12 (17.1%) patients had mild, 14 (20%) moderate, and 9 (12.9%) severe OFI, while 35 (50%) had TUG test results within the normal population range (no OFI). PCCs between TUG test time and VAS back pain were r = 0.37 (P = .002), VAS leg pain r = 0.37 (P = .002), COMI back r = 0.50 (P < .001), ZCQ symptom severity r = 0.41 (P < .001), and ZCQ physical function r = 0.36 (P = .002).

Conclusion: This external validation demonstrated similar OFI rates and PCCs between logarithmic TUG test results and PROMs compared to the original article from 2016. These findings support the TUG test being a quick, easy-to-use objective test, which provides the physician with a robust estimate of pain and functional impairment.
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http://dx.doi.org/10.1093/neuros/nyaa441DOI Listing
January 2021

Development of a Complication- and Treatment-Aware Prediction Model for Favorable Functional Outcome in Aneurysmal Subarachnoid Hemorrhage Based on Machine Learning.

Neurosurgery 2021 01;88(2):E150-E157

Department of Neurosurgery, University Hospital Zurich & Clinical Neuroscience Center, University of Zurich, Zurich, Switzerland.

Background: Current prognostic tools in aneurysmal subarachnoid hemorrhage (aSAH) are constrained by being primarily based on patient and disease characteristics on admission.

Objective: To develop and validate a complication- and treatment-aware outcome prediction tool in aSAH.

Methods: This cohort study included data from an ongoing prospective nationwide multicenter registry on all aSAH patients in Switzerland (Swiss SOS [Swiss Study on aSAH]; 2009-2015). We trained supervised machine learning algorithms to predict a binary outcome at discharge (modified Rankin scale [mRS] ≤ 3: favorable; mRS 4-6: unfavorable). Clinical and radiological variables on admission ("Early" Model) as well as additional variables regarding secondary complications and disease management ("Late" Model) were used. Performance of both models was assessed by classification performance metrics on an out-of-sample test dataset.

Results: Favorable functional outcome at discharge was observed in 1156 (62.0%) of 1866 patients. Both models scored a high accuracy of 75% to 76% on the test set. The "Late" outcome model outperformed the "Early" model with an area under the receiver operator characteristics curve (AUC) of 0.85 vs 0.79, corresponding to a specificity of 0.81 vs 0.70 and a sensitivity of 0.71 vs 0.79, respectively.

Conclusion: Both machine learning models show good discrimination and calibration confirmed on application to an internal test dataset of patients with a wide range of disease severity treated in different institutions within a nationwide registry. Our study indicates that the inclusion of variables reflecting the clinical course of the patient may lead to outcome predictions with superior predictive power compared to a model based on admission data only.
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http://dx.doi.org/10.1093/neuros/nyaa401DOI Listing
January 2021

Cooled radiofrequency for the treatment of sacroiliac joint pain - impact on pain and psychometrics: a retrospective cohort study.

Scand J Pain 2020 Oct;20(4):737-745

Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.

Objectives Cooled radiofrequency (cRF) is an effective treatment for sacroiliac pain. In contrast to conventional radiofrequency denervation, this technique allows enlarging the area of denervation by cooling the radiofrequency probe. However, there is sparse knowledge about the impact of interventional procedures like cRF treatment of sacroiliac joint pain on psychological comorbidities. The aim of this retrospective study was to evaluate the outcome of cRF in chronic pain patients regarding the psychological outcomes anxiety, depression, sleep quality and pain related disability. Methods In this retrospective observational study 29 interventions were performed over a period of two years in 28 patients. Pre- and post-interventional pain levels, depression and anxiety scores, pain-related disability, treatment satisfaction and sleep quality were assessed by standardized and validated questionnaires. Pain medication was recorded prior to the intervention and at follow-up. Results Hospital Anxiety and Depression Scale (HADS-D) scores for depression showed a statistically significant reduction after therapy which did not remain significant after Bonferroni-Holm correction. Anxiety as measured by the HADS-A score did not show a statistically significant change. No statistically significant improvement was observed in the pain disability index. Patients reported fewer sleep disorders after treatment. Mean pain (NRS) was statistically significantly reduced 1 week post intervention and at time of follow-up. There was no clear reduction of analgesic medication. Conclusions Besides pain reduction, our data show a positive influence on sleep quality, possibly on depression, but not on anxiety and pain disability.
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http://dx.doi.org/10.1515/sjpain-2020-0011DOI Listing
October 2020

Evaluation of the 6-minute walking test as a smartphone app-based self-measurement of objective functional impairment in patients with lumbar degenerative disc disease.

J Neurosurg Spine 2020 08 7;33(6):779-788. Epub 2020 Aug 7.

1Department of Neurosurgery, University Hospital Zurich and Clinical Neuroscience Center, University of Zurich.

Objective: Digital transformation enables new possibilities to assess objective functional impairment (OFI) in patients with lumbar degenerative disc disease (DDD). This study examines the psychometric properties of an app-based 6-minute walking test (6WT) and determines OFI in patients with lumbar DDD.

Methods: The maximum 6-minute walking distance (6WD) was determined in patients with lumbar DDD. The results were expressed as raw 6WDs (in meters), as well as in standardized z-scores referenced to age- and sex-specific values of spine-healthy volunteers. The 6WT results were assessed for reliability and content validity using established disease-specific patient-reported outcome measures.

Results: Seventy consecutive patients and 330 volunteers were enrolled. The mean 6WD was 370 m (SD 137 m) in patients with lumbar DDD. Significant correlations between 6WD and the Core Outcome Measures Index for the back (r = -0.31), Zurich Claudication Questionnaire (ZCQ) symptom severity (r = -0.32), ZCQ physical function (r = -0.33), visual analog scale (VAS) for back pain (r = -0.42), and VAS for leg pain (r = -0.32) were observed (all p < 0.05). The 6WT revealed good test-retest reliability (intraclass correlation coefficient 0.82), and the standard error of measurement was 58.3 m. A 4-tier severity stratification classified patients with z-scores > -1 (no OFI), -1 to -1.9 (mild OFI), -2 to -2.9 (moderate OFI), and ≤ -3 (severe OFI).

Conclusions: The smartphone app-based self-measurement of the 6WT is a convenient, reliable, and valid way to determine OFI in patients with lumbar DDD. The 6WT app facilitates the digital evaluation and monitoring of patients with lumbar DDD.
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http://dx.doi.org/10.3171/2020.5.SPINE20547DOI Listing
August 2020

Longitudinal smartphone-based self-assessment of objective functional impairment in patients undergoing surgery for lumbar degenerative disc disease: initial experience.

Acta Neurochir (Wien) 2020 09 13;162(9):2061-2068. Epub 2020 May 13.

Department of Neurosurgery, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9001, St. Gallen, Switzerland.

Background: The worldwide spread of smartphone usage enables new possibilities for longitudinal monitoring of objective functional impairment (OFI) in patients undergoing surgery for lumbar degenerative disc disease (DDD).

Methods: Three patients, undergoing elective surgery for lumbar DDD, self-assessed OFI using a recently validated 6-min walking test (6WT) smartphone application. Results are presented as raw 6-min walking distance (6WD) as well as in reference to age- and sex-specific healthy population reference values using standardized z-scores (number of standard deviations). In parallel, patient-reported outcome measures (PROMs), including numeric rating scale (NRS) leg-pain and Core Outcome Measures Index (COMI) were obtained before (pre) and 6 weeks (6 W) as well as 3 months (3 M) after surgery. Descriptive analyses were used to compare PROMs with repeated 6WT measurements over time. The feasibility and benefits of the longitudinal OFI measurements using the 6WT app are discussed.

Results: One patient presented a favorable outcome, reflected by a clinically meaningful improvement in PROMs. Correspondingly, the 6WT distance gradually improved above the normal population values ((pre 399 m (z-score - 1.96) vs. 6 W 494 m (- 0.85) vs. 3 M 557 m (- 0.1)). One patient experienced initial improvement at 6 W, followed by a decline in 6WD at 3 M which promoted further interventions with subsequent recovery ((358 m (z-score - 3.29) vs 440 m (- 2.2) vs 431 m (- 2.32) vs 471 m (- 1.78)). The last patient showed a lack of improvement in PROMs as well as in OFI (360 m (z-score 0.0) vs 401 m (0.30) vs 345 m (- 0.11)) resulting in secondary surgery.

Conclusion: The longitudinal assessment of OFI using the 6WT app was feasible and provided the physician with a detailed history of patients' postoperative walking capacity complementing commonly used PROMs.
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http://dx.doi.org/10.1007/s00701-020-04377-8DOI Listing
September 2020

Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study.

J Neurooncol 2020 May 4;148(1):117-130. Epub 2020 May 4.

Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University of Regensburg, Regensburg, Germany.

Background: Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL).

Methods: Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL.

Results: 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range.

Conclusions: This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.
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http://dx.doi.org/10.1007/s11060-020-03502-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280359PMC
May 2020

Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma.

Neuro Oncol 2020 08;22(8):1162-1172

Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.

Background: O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups.

Methods: This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg.

Results: In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0-10.0] months for TMZ treatment versus 9.4 [8.1-10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76-1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2-4.1) months vs 4.6 (4.2-5.0) months] did not differ, with HR = 1.02 (0.83-1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] mo and 8.5 [6.9-13.3] mo) versus RT (9.6 [6.4-13.7] mo and 4.8 [4.3-6.2] mo, HR 0.44 [0.27-0.70], P < 0.001 for OS and 0.46 [0.29-0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts.

Conclusion: MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.
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http://dx.doi.org/10.1093/neuonc/noaa033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594575PMC
August 2020

Digital transformation in spine research and outcome assessment.

Spine J 2020 02;20(2):310-311

Department of Neurosurgery, Stanford University Hospital and Clinics, Stanford, CA; Department of Neurosurgery, University Hospital Zurich & Clinical Neuroscience Center, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1016/j.spinee.2019.06.027DOI Listing
February 2020

Molecular Evolution of Wild-Type Glioblastomas Treated With Standard of Care Affects Survival and Design of Precision Medicine Trials: A Report From the EORTC 1542 Study.

J Clin Oncol 2020 01 19;38(1):81-99. Epub 2019 Nov 19.

Erasmus University Medical Center, Rotterdam, the Netherlands.

Purpose: Precision medicine trials in glioblastoma (GBM) are often conducted at tumor recurrence. However, second surgeries for recurrent GBM are not routinely performed, and therefore, molecular data for trial inclusion are predominantly derived from the primary sample. This study aims to establish whether molecular targets change during tumor progression and, if so, whether this affects precision medicine trial design.

Materials And Methods: We collected 186 pairs of primary-recurrent GBM samples from patients receiving chemoradiotherapy with temozolomide and sequenced approximately 300 cancer genes. , , and status was individually determined.

Results: The molecular profile of our cohort was identical to that of other GBM cohorts ( wild-type [WT], 95%; amplified, approximately 50%), indicating that patients amenable to second surgery do not represent a specific molecular subtype. Molecular events in WT GBMs were stable in approximately 80% of events, but changes in mutation status were observed for all examined genes (range, approximately 90% and 60% for and mutations, respectively), and such changes strongly affected targeted trial size and design. A similar pattern of GBM driver instability was observed within promoter-methylated tumors. promoter methylation status remained prognostic at tumor recurrence. The observation that hypermutation at GBM recurrence was rare (8%) and not correlated with outcome was relevant for immunotherapy-based treatments.

Conclusion: This large cohort of matched primary and recurrent WT tumors establishes the frequency of GBM driver instability after chemoradiotherapy with temozolomide. This allows per gene or pathway calculation of trial size at tumor recurrence, using molecular data of the primary tumor only. We also identify genes for which repeat surgery is necessary because of low mutation retention rate.
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http://dx.doi.org/10.1200/JCO.19.00367DOI Listing
January 2020

Patterns of care for ruptured aneurysms of the middle cerebral artery: analysis of a Swiss national database (Swiss SOS).

J Neurosurg 2019 Nov 15:1-10. Epub 2019 Nov 15.

11Department of Neurosurgery, University Hospital Zurich.

Objective: The objective of this study was to determine patterns of care and outcomes in ruptured intracranial aneurysms (IAs) of the middle cerebral artery (MCA) in a contemporary national cohort.

Methods: The authors conducted a retrospective analysis of prospective data from a nationwide multicenter registry of all aneurysmal subarachnoid hemorrhage (aSAH) cases admitted to a tertiary care neurosurgical department in Switzerland in the years 2009-2015 (Swiss Study on Aneurysmal Subarachnoid Hemorrhage [Swiss SOS]). Patterns of care and outcomes at discharge and the 1-year follow-up in MCA aneurysm (MCAA) patients were analyzed and compared with those in a control group of patients with IAs in locations other than the MCA (non-MCAA patients). Independent predictors of a favorable outcome (modified Rankin Scale score ≤ 3) were identified, and their effect size was determined.

Results: Among 1866 consecutive aSAH patients, 413 (22.1%) harbored an MCAA. These MCAA patients presented with higher World Federation of Neurosurgical Societies grades (p = 0.007), showed a higher rate of concomitant intracerebral hemorrhage (ICH; 41.9% vs 16.7%, p < 0.001), and experienced delayed cerebral ischemia (DCI) more frequently (38.9% vs 29.4%, p = 0.001) than non-MCAA patients. After adjustment for confounders, patients with MCAA were as likely as non-MCAA patients to experience DCI (aOR 1.04, 95% CI 0.74-1.45, p = 0.830). Surgical treatment was the dominant treatment modality in MCAA patients and at a significantly higher rate than in non-MCAA patients (81.7% vs 36.7%, p < 0.001). An MCAA location was a strong independent predictor of surgical treatment (aOR 8.49, 95% CI 5.89-12.25, p < 0.001), despite statistical adjustment for variables traditionally associated with surgical treatment, such as (space-occupying) ICH (aOR 1.73, 95% CI 1.23-2.45, p = 0.002). Even though MCAA patients were less likely to die during the acute hospitalization (aOR 0.52, 0.30-0.91, p = 0.022), their rate of a favorable outcome was lower at discharge than that in non-MCAA patients (55.7% vs 63.7%, p = 0.003). At the 1-year follow-up, 68.5% and 69.6% of MCAA and non-MCAA patients, respectively, had a favorable outcome (p = 0.676).

Conclusions: Microsurgical occlusion remains the predominant treatment choice for about 80% of ruptured MCAAs in a European industrialized country. Although patients with MCAAs presented with worse admission grades and greater rates of concomitant ICH, in-hospital mortality was lower and long-term disability was comparable to those in patients with non-MCAA.
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http://dx.doi.org/10.3171/2019.9.JNS192055DOI Listing
November 2019

Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF.

Cancer Immunol Res 2019 Dec 9;7(12):1910-1927. Epub 2019 Oct 9.

Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.

Glioblastoma (GBM) is a non-T-cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0865DOI Listing
December 2019

[Intracranial Meningiomas: A Neurosurgical Disease? Possibilities and Limitations of Surgery].

Praxis (Bern 1994) 2019 Sep;108(12):787-792

Klinik für Neurochirurgie, Kantonsspital St. Gallen.

Intracranial Meningiomas: A Neurosurgical Disease? Possibilities and Limitations of Surgery Meningiomas are the most common intracranial tumors. According to the WHO classification they are categorized as WHO I-III. Most meningiomas are WHO I and can be treated by complete microsurgical resection and thus cured. Imaging and controls should be performed using MRI. Asymptomatic meningiomas can be observed. Symptomatic meningiomas and meningiomas in proximity to neural and vascular structures should be resected microsurgically using modern techniques such as neuromonitoring, neuronavigation and minimally invasive techniques. The recurrence rate is determined by the extent of resection according to the Simpson classification and the histological grading of the tumor. With subtotal resection, complex tumors, recurrences and higher grade meningiomas the use of radiotherapy or radiosurgical treatment should be discussed in a tumor board.
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http://dx.doi.org/10.1024/1661-8157/a003297DOI Listing
September 2019

Baseline T1 hyperintense and diffusion-restricted lesions are not linked to prolonged survival in bevacizumab-treated glioblastoma patients of the GLARIUS trial.

J Neurooncol 2019 Sep 19;144(3):501-509. Epub 2019 Jul 19.

Division of Clinical Neurooncology, Department of Neurology, University of Bonn Medical Center, Bonn, Germany.

Purpose: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase promoter non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). To identify subpopulations with a particularly favorable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers before treatment onset.

Methods: MRIs at baseline (before treatment onset) were analyzed for T1-hyperintense and diffusion-restricted lesions; as well as the presence of both hyperintense and diffusion-restricted (double positive) lesions. The MRI findings were correlated with overall and progression-free survival.

Results: MRI scans were evaluable in 71% of the GLARIUS modified intention-to-treat population (n = 121 of 170; 88 patients in the BEV/IRI arm, and 33 patients in the TMZ control arm). Diffusion-restricted and T1 hyperintense lesions were present in 60% and 65% of patients in BEV/IRI arm, while 57% and 63% were found in the TMZ arm, respectively. Double positive lesions were found in 37% of BEV/IRI patients and in 39% of TMZ patients. Neither the presence of T1-hyperintense, diffusion-restricted lesions, nor double positive lesions were associated with improved survival.

Conclusions: Baseline T1-hyperintense and diffusion-restricted lesions are not suitable to predict progression-free or overall survival of patients treated with bevacizumab/irinotecan or temozolomide.
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http://dx.doi.org/10.1007/s11060-019-03246-4DOI Listing
September 2019

Intradural non-calcified thoracic disc herniation causing spontaneous intracranial hypotension: a case report.

BMC Surg 2019 Jun 21;19(1):66. Epub 2019 Jun 21.

Department of Neurosurgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Background: Spontaneous intracranial hypotension (SIH) is a rare pathology caused by a cerebrospinal fluid (CSF) leak. If intractable by conventional methods (i.e. bedrest, analgesics, or epidural blood patching) it may lead to the inability of the patient to cope with daily life and eventually to life-threatening complications. Recently, calcified discogenic microspurs or dorsal osteophytes were identified as a major cause for ventral CSF loss through vertical longitudinal dural slits. We report a rare case of intractable SIH due to an intradural disc herniation at the thoracolumbar junction (without signs of calcification) and its management.

Case Presentation: A 46-year old woman suffered from orthostatic headache (sudden onset, no history of trauma) due to intractable SIH for over 2 month (without neurologic deficits). There was no clinical amelioration by conservative measures (analgesics, bedrest) and serial unspecific epidural blood patches (repeated for 3 times). She was diagnosed with an intradural disc herniation at the thoracolumbar junction causing a CSF leak. Surgical exploration by a translaminar and transdural approach with removal of the disc herniation and closure of the CSF leak was performed with immediate cessation of orthostatic symptoms. Histological workup revealed non-calcified intervertebral disc material. After 3 months of follow-up and no evidence for clinical relapse the patient returned to work.

Conclusions: We report the rare phenomenon of an intradural non-calcified disc sequester at the thoracolumbar junction as the cause of a ventral dural tear leading to a CSF leak with intractable SIH. This is of particular interest as the major cause of ventral dural leakage is thought to arise from calcified discogenic microspurs or dorsal osteophytes. Furthermore, we comprehensively describe a short and reasonable diagnostic and surgical approach of this rare pathology, which may particularly be of use in daily clinical routine in neurological wards and general surgical spine centers not facing such pathologies on a regular basis.
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http://dx.doi.org/10.1186/s12893-019-0527-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588915PMC
June 2019

Conscious Experience and Psychological Consequences of Awake Craniotomy.

World Neurosurg 2019 Sep 25;129:e381-e386. Epub 2019 May 25.

Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland. Electronic address:

Background: Experiencing cranial surgery under awake conditions may expose patients to considerable psychological strain.

Methods: This study aimed to investigate the occurrence and course of psychological sequelae following awake craniotomy (AC) for brain tumors in a series of 20 patients using a broad, validated psychological assessment preoperatively, intraoperatively, postoperatively and a standardized follow-up of 3 months. In addition, the association of the preoperative psychological condition (including, but not limited to, anxiety and fear) with perioperative pain perception and interference was assessed.

Results: AC did not induce any shift in the median levels of anxiety, depression, and stress symptoms already present prior to the procedure. Furthermore, anxiety and depression were all moderately to strongly associated over time (all P < 0.05). Stress symptoms also correlated positively over all times of measurement. Stress 3 days after surgery was strongly associated with stress 3 months after surgery (P < 0.001), whereas the correlation between preoperative and immediate postoperative stress showed a statistical trend (P = 0.07). Preoperative fear was not related to intraoperative pain, but to pain and its interference with daily activity on the third postoperative day (P < 0.001 and P < 0.01, respectively).

Conclusions: Postoperative psychological symptoms clearly correlated with their corresponding preoperative symptoms. Thus, mental health was not negatively affected by the AC experience in our series. Intraoperative fear and pain were not related to the preoperative psychological condition. However, preoperative fear and anxiety were positively related with pain and its interference with daily activity in the immediate postoperative period.
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http://dx.doi.org/10.1016/j.wneu.2019.05.156DOI Listing
September 2019

Objective functional assessment using the "Timed Up and Go" test in patients with lumbar spinal stenosis.

Neurosurg Focus 2019 05;46(5):E4

3Department of Clinical Neuroscience, Division of Neurosurgery, Geneva University Hospitals and Faculty of Medicine, Geneva; and.

OBJECTIVEPatient-reported outcome measures (PROMs) are standard of care for the assessment of functional impairment. Subjective outcome measures are increasingly complemented by objective ones, such as the "Timed Up and Go" (TUG) test. Currently, only a few studies report pre- and postoperative TUG test assessments in patients with lumbar spinal stenosis (LSS).METHODSA prospective two-center database was reviewed to identify patients with LSS who underwent lumbar decompression with or without fusion. The subjective functional status was estimated using PROMs for pain (visual analog scale [VAS]), disability (Roland-Morris Disability Index [RMDI] and Oswestry Disability Index [ODI]), and health-related quality of life (HRQoL; 12-Item Short-Form Physical Component Summary [SF-12 PCS] and the EQ-5D) preoperatively, as well as on postoperative day 3 (D3) and week 6 (W6). Objective functional impairment (OFI) was measured using age- and sex-standardized TUG test results.RESULTSSixty-four patients (n = 32 [50%] male, mean age 66.8 ± 11.7 years) were included. Preoperatively, they reported a mean VAS back pain score of 4.1 ± 2.7, VAS leg pain score of 5.4 ± 2.7, RMDI of 10.4 ± 5.3, ODI of 41.9 ± 16.2, SF-12 PCS score of 32.7 ± 8.3, and an EQ-5D index of 0.517 ± 0.226. The preoperative rates of severe, moderate, and mild OFI were 4.7% (n = 3), 12.5% (n = 8), and 7.8% (n = 5), respectively, and the mean OFI T-score was 116.3 ± 23.7. At W6, 60 (93.8%) of 64 patients had a TUG test result within the normal population range (no OFI); 3 patients (4.7%) had mild and 1 patient (1.6%) severe OFI. The mean W6 OFI T-score was significantly decreased (103.1 ± 13.6; p < 0.001). Correspondingly, the PROMs showed a decrease in subjective VAS back pain (1.6 ± 1.7, p < 0.001) and leg pain (1.0 ± 1.8, p < 0.001) scores, disability (RMDI 5.3 ± 4.7, p < 0.001; ODI 21.3 ± 16.1, p < 0.001), and increase in HRQoL (SF-12 PCS 40.1 ± 8.3, p < 0.001; EQ-5D 0.737 ± 0.192, p < 0.001) at W6. The W6 responder status (clinically meaningful improvement) ranged between 81.3% (VAS leg pain) and 29.7% (EQ-5D index) of patients.CONCLUSIONSThe TUG test is a quick and easily applicable tool that reliably measures OFI in patients with LSS. Objective tests incorporating longer walking time should be considered if OFI is suspected but fails to be proven by the TUG test, taking into account that neurogenic claudication may not clinically manifest during the brief TUG examination. Objective tests do not replace the subjective PROM-based assessment, but add valuable information to a comprehensive patient evaluation.
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http://dx.doi.org/10.3171/2019.2.FOCUS18618DOI Listing
May 2019

Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.

Lancet 2019 02 14;393(10172):678-688. Epub 2019 Feb 14.

Division of Clinical Neurooncology, Department of Neurology and Centre of Integrated Oncology, University Hospital Bonn, Bonn, Germany.

Background: There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial.

Methods: In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m on day 1) plus temozolomide (100-200 mg/m per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109.

Findings: Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths.

Interpretation: Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial.

Funding: German Federal Ministry of Education and Research.
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http://dx.doi.org/10.1016/S0140-6736(18)31791-4DOI Listing
February 2019

Cyclooxygenase (COX) Inhibition by Acetyl Salicylic Acid (ASA) Enhances Antitumor Effects of Nitric Oxide in Glioblastoma In Vitro.

Mol Neurobiol 2019 Sep 4;56(9):6046-6055. Epub 2019 Feb 4.

Department of Neurosurgery, Medical Center, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with a high recurrence rate and a median survival of about 16 months even with multimodal therapy. Novel experimental strategies against malignant gliomas include cyclooxygenase (COX) inhibition and nitric oxide (NO)-based therapies. Therapeutic doses of NO can be delivered to tumor cells by NO donors such as JS-K (O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) which releases NO upon enzymatic activation by glutathione S-transferase. COX-2 is frequently overexpressed in tumors and increases tumor invasiveness and angiogenesis. In this study, we show that pretreatment with acetyl salicylic acid (ASA) enhanced the cytotoxic antitumor effect of NO in vitro. Combination of low doses of JS-K and ASA revealed a dose-dependent synergistic increase of necrotic cell death under circumvention of classical apoptosis and alteration of the metabolic calcium level. These findings provide an opportunity to improve currently used therapeutic strategies in the treatment of gliomas with a well-established remedy.
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http://dx.doi.org/10.1007/s12035-019-1513-6DOI Listing
September 2019

Multifocal lumbar disc herniation at a single level: a potential pitfall for wrong side surgery.

Br J Neurosurg 2021 02 10;35(1):120-121. Epub 2018 Aug 10.

Department of Neurosurgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

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http://dx.doi.org/10.1080/02688697.2018.1497774DOI Listing
February 2021

Different but similar: personality traits of​ surgeons and internists-results of a cross-sectional observational study.

BMJ Open 2018 07 7;8(7):e021310. Epub 2018 Jul 7.

Department of Neurosurgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Objectives: Medical practice may attract and possibly enhance distinct personality profiles. We set out to describe the personality profiles of surgical and medical specialties focusing on board-certified physicians.

Design: Prospective, observational.

Setting: Online survey containing the Ten-Item Personality Inventory (TIPI), an internationally validated measure of the Five Factor Model of personality dimensions, distributed to board-certified physicians, residents and medical students in several European countries and Canada. Differences in personality profiles were analysed using multivariate analysis of variance and Canonical Linear Discriminant Analysis on age-standardised and sex-standardised z-scores of the personality traits. Single personality traits were analysed using robust t-tests.

Participants: The TIPI was completed by 2345 board-certified physicians, 1453 residents and 1350 medical students, who also provided demographic information.

Results: Normal population and board-certified physicians' personality profiles differed (p<0.001). The latter scored higher on conscientiousness, extraversion and agreeableness, but lower on neuroticism (all p<0.001). There was no difference in openness to experience. Board-certified surgical and medical doctors' personality profiles were also different (p<0.001). Surgeons scored higher on extraversion (p=0.003) and openness to experience (p=0.002), but lower on neuroticism (p<0.001). There was no difference in agreeableness and conscientiousness. These differences in personality profiles were reproduced at other levels of training, that is, in students and training physicians engaging in surgical versus medical practice.

Conclusion: These results indicate the existence of a distinct and consistent average 'physician personality'. Despite high variability within disciplines, there are moderate but solid and reproducible differences between surgical and medical specialties.
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http://dx.doi.org/10.1136/bmjopen-2017-021310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045716PMC
July 2018

Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial.

J Cancer Res Clin Oncol 2018 Aug 28;144(8):1581-1589. Epub 2018 May 28.

Division of Clinical Neurooncology, Department of Neurology, University of Bonn Medical Center, Bonn, Germany.

Background: We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial.

Methods: In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test.

Results: At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42).

Conclusions: The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.
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http://dx.doi.org/10.1007/s00432-018-2671-zDOI Listing
August 2018

Quality of life in the GLARIUS trial randomizing bevacizumab/irinotecan versus temozolomide in newly diagnosed, MGMT-nonmethylated glioblastoma.

Neuro Oncol 2018 06;20(7):975-985

Division of Clinical Neuro-oncology, Department of Neurology, University of Bonn, Bonn, Germany.

Background: The GLARIUS trial, which investigated the efficacy of bevacizumab (BEV)/irinotecan (IRI) compared with standard temozolomide in the first-line therapy of O6-methylguanine-DNA methyltransferase (MGMT)-nonmethylated glioblastoma, showed that progression-free survival was significantly prolonged by BEV/IRI, while overall survival was similar in both arms. The present report focuses on quality of life (QoL) and Karnofsky performance score (KPS) during the whole course of the disease.

Methods: Patients (n = 170) received standard radiotherapy and were randomized (2:1) for BEV/IRI or standard temozolomide. At least every 3 months KPS was determined and QoL was measured using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life and 20-item Brain Neoplasm questionnaires. A generalized estimating equation (GEE) model evaluated differences in the course of QoL and KPS over time. Also, the time to first deterioration and the time to postprogression deterioration were analyzed separately.

Results: In all dimensions of QoL and KPS, GEE analyses and time to first deterioration analyses did not detect significant differences between the treatment arms. At progression, 82% of patients receiving second-line therapy in the standard arm received BEV second-line therapy. For the dimensions of motor dysfunction and headaches, time to postprogression deterioration was prolonged in the standard arm receiving crossover second-line BEV in the vast majority of patients at the time of evaluation.

Conclusions: GLARIUS did not find indications for a BEV-induced detrimental effect on QoL in first-line therapy of MGMT-nonmethylated GBM patients. Moreover, GLARIUS provided some indirect corroborative data supporting the notion that BEV may have beneficial effects upon QoL in relapsed GBM.
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http://dx.doi.org/10.1093/neuonc/nox204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007398PMC
June 2018

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07).

Neuro Oncol 2018 02;20(3):400-410

Department of Neurology, University Hospital Heidelberg, and Neuro-oncology Program at the National Center for Tumor Diseases, Heidelberg, Germany.

Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy.

Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy.

Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock.

Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.
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http://dx.doi.org/10.1093/neuonc/nox155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817955PMC
February 2018

The nitric oxide donor JS-K sensitizes U87 glioma cells to repetitive irradiation.

Tumour Biol 2017 Jun;39(6):1010428317703922

1 Department of Neurosurgery, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S-transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death. In vivo efficacy of JS-K and repetitive irradiation were investigated in an orthotopic U87 xenograft model in mice. For the first time, we could show that JS-K acts as a potent cytotoxic and radiosensitizing agent in U87 cells in vitro. This dose- and time-dependent effect is due to an enhanced induction of DNA double-strand breaks leading to mitotic catastrophe as the dominant form of cell death. However, this potent cytotoxic and radiosensitizing effect could not be confirmed in an intracranial U87 xenograft model, possibly due to insufficient delivery into the brain. Although NO donor treatment was well tolerated, neither a retardation of tumor growth nor an extended survival could be observed after JS-K and/or radiotherapy.
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http://dx.doi.org/10.1177/1010428317703922DOI Listing
June 2017
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