Publications by authors named "Marco Stein"

46 Publications

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated.

J Clin Oncol 2021 Dec 7;39(34):3839-3852. Epub 2021 Oct 7.

Department of Neurosurgery, NYU Langone Hospital, New York, NY.

Purpose: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established ( and ), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma.

Methods: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases.

Results: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively).

Conclusion: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
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http://dx.doi.org/10.1200/JCO.21.00784DOI Listing
December 2021

Serum biomarkers for risk assessment of intra-hospital transports in neurosurgical intensive care unit patients.

J Neurosurg Sci 2021 Aug 3. Epub 2021 Aug 3.

Department of Neurosurgery, Justus-Liebig-University Giessen, Giessen, Germany.

Background: Intra-hospital transport (IHT) of neurosurgical intensive care (NICU) patients for cranial computed tomography (CCT) scans is associated with a high rate of complications. The potential of serum biomarkers to estimate the risk for complications associated with IHT and improve their safety remains underexplored. The present study investigated the influence of several serum biomarkers on IHT-associated complications in brain-injured NICU patients.

Methods: A total of 523 IHTs in 223 NICU patients were prospectively analysed (05/2019-05/2020). Haemoglobin, haematocrit, serum sodium, and albumin levels were evaluated as serum biomarkers. Each patient's demographic data, cranial computed tomography (CCT) scan, NICU parameters and modified Rankin Scale at discharge as well as indications, consequences, and complications of IHTs were analysed.

Results: In 58.7% of all IHTs, at least one IHT-associated complication was observed with 60.1% of all IHTs having no therapeutic consequence. Significantly lower rates of increased intracranial pressure (ICP; p<0.0001), decreased cerebral perfusion pressure (CPP; p=0.03) as well as hemodynamic (p<0.0001) and pulmonary events (p=0.01) were observed in patients with higher haemoglobin levels prior to IHT. Additionally, higher haematocrit levels before IHT were associated with a fewer rate of hemodynamic (p<0.0001), pulmonary (p=0.006), ICP (p<0.0001), and CPP (p=0.01) events.

Conclusions: Higher levels of haemoglobin and haematocrit are associated with less complications with respect to ICP, CPP, hemodynamic and pulmonary events during IHT in NICU patients. Therefore, these biomarkers may be helpful for risk assessment of potential complications prior to IHT.
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http://dx.doi.org/10.23736/S0390-5616.21.05409-6DOI Listing
August 2021

Proposed definition of competencies for surgical neuro-oncology training.

J Neurooncol 2021 May 21;153(1):121-131. Epub 2021 Apr 21.

Department of Neurosurgery, Justus-Liebig University Giessen, Giessen, Germany.

Objective: The aim of this work is to define competencies and entrustable professional activities (EPAs) to be imparted within the framework of surgical neuro-oncological residency and fellowship training as well as the education of medical students. Improved and specific training in surgical neuro-oncology promotes neuro-oncological expertise, quality of surgical neuro-oncological treatment and may also contribute to further development of neuro-oncological techniques and treatment protocols. Specific curricula for a surgical neuro-oncologic education have not yet been established.

Methods: We used a consensus-building approach to propose skills, competencies and EPAs to be imparted within the framework of surgical neuro-oncological training. We developed competencies and EPAs suitable for training in surgical neuro-oncology.

Result: In total, 70 competencies and 8 EPAs for training in surgical neuro-oncology were proposed. EPAs were defined for the management of the deteriorating patient, the management of patients with the diagnosis of a brain tumour, tumour-based resections, function-based surgical resections of brain tumours, the postoperative management of patients, the collaboration as a member of an interdisciplinary and/or -professional team and finally for the care of palliative and dying patients and their families.

Conclusions And Relevance: The present work should subsequently initiate a discussion about the proposed competencies and EPAs and, together with the following discussion, contribute to the creation of new training concepts in surgical neuro-oncology.
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http://dx.doi.org/10.1007/s11060-021-03750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131302PMC
May 2021

Preoperative Elevated Levels for Depression, Anxiety, and Subjective Mental Stress Have No Influence on Outcome Measures of Peripheral Nerve Field Stimulation for Chronic Low Back Pain-A Prospective Study.

Neuromodulation 2021 Aug 1;24(6):1042-1050. Epub 2021 Feb 1.

Department of Neurosurgery, Justus-Liebig-University Giessen, Giessen, Germany.

Objective: Peripheral nerve field stimulation (PNFS) is an effective alternative treatment for patients with chronic low back pain. The treatment of low back pain strongly depends on psychological factors like anxiety, depression, and mental stress. The aim of this study was to evaluate the impact of such factors on outcome measures after lead- and implantable pulse generator-implantation.

Materials And Methods: Between 2014 and 2019, a prospective cohort study of 39 patients with chronic lumbar pain was conducted. Hospital Anxiety and Depression Scale (HADS) score was assessed at baseline to measure symptoms of anxiety and depression. Symptom checklist-90 (SCL-90) was used to measure subjective psychopathology. Pain intensity (numeric pain rating scale [NRS]), SF12v2 with Physical Component Summary and Mental Component Summary (MCS) scores, and Oswestry Disability Index (ODI) were assessed pre- and postoperatively as well as three and six months after PNFS implantation. Outcome values were compared to baseline data. Statistical analysis was performed using depending t-test and analysis of variance (ANOVA). A p value <0.05 was considered significant.

Results: The cohort consisted of 39 patients (18 females, 21 males) with a median age of 61 years (IQR  = 52-67 years). NRS, ODI, and SF12v2 showed significant improvement in the whole follow-up period compared to baseline values (p < 0.05). Elevated HADS scores for anxiety were seen in 64.1%, for depression in 76.9% of the patients at baseline. SCL-90 was pathologic in 71.8% of the cases. A one-way ANOVA revealed no differences between elevated HADS- and SCL-90 values and all outcome measures after PNFS implantation in the whole follow-up period (p > 0.05).

Conclusion: Chronic low back pain is often associated with psychological distress. Our study showed highly elevated levels for anxiety and depression as well as subjective mental stress in patients with chronic low back pain without negative impact on NRS, ODI, and SF12v2 in the whole follow-up after PNFS implantation.
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http://dx.doi.org/10.1111/ner.13368DOI Listing
August 2021

Early Serum Biomarkers for Intensive Care Unit Treatment within the First 24 Hours in Patients with Intracerebral Hemorrhage.

J Neurol Surg A Cent Eur Neurosurg 2021 Mar 8;82(2):138-146. Epub 2020 Dec 8.

Department of Neurosurgery, Universitätsklinikum Giessen und Marburg Standort Giessen, Giessen, Germany.

Background:  The prognostic significance of serum biomarkers in patients with intracerebral hemorrhage (ICH) is not well investigated concerning inhospital mortality (IHM) and cardiopulmonary events within the first 24 hours of intensive care unit (ICU) treatment. The influence of troponin I (TNI) value and cortisol value (CV) on cardiopulmonary events within the first 24 hours of ICU treatment was reported in subarachnoid hemorrhage patients, but not in ICH patients up to now. The aim of this study was to investigate the role of early serum biomarkers on IHM and TNI value and CV on cardiopulmonary events within the first 24 hours of ICU treatment.

Patients And Methods:  A total of 329 patients with spontaneous ICH were retrospectively analyzed. Blood samples were taken on admission to measure serum biomarkers. The TNI value and CV were defined as biomarkers for cardiopulmonary stress. Demographic data, cardiopulmonary parameters, including norepinephrine application rate (NAR) in microgram per kilogram per minute and inspiratory oxygen fraction (FiO) within the first 24 hours, and treatment regime were analyzed concerning their impact on ICU treatment and in hospital outcome. Binary logistic analysis was used to identify independent prognostic factors for IHM.

Results:  Patients with initially nonelevated CVs required higher NAR ( = 0.01) and FiO ( = 0.046) within the first 24 hours of ICU treatment. Lower cholinesterase level ( = 0.004), higher NAR ( = 0.002), advanced age ( < 0.0001), larger ICH volume ( < 0.0001), presence of intraventricular hemorrhage ( = 0.007) and hydrocephalus ( = 0.009), raised level of C-reactive protein ( = 0.024), serum lactate ( = 0.003), and blood glucose ( = 0.05) on admission were significantly associated with IHM. In a multivariate model, age (odds ratio [OR]: 1.055; 95% confidence interval [CI]: 1.026-1.085;  < 0.0001), ICH volume (OR: 1.016; CI: 1.008-1.025;  < 0.0001), and Glasgow Coma Scale (GCS) score (OR: 0.680; CI: 0.605-0.764;  < 0.0001) on admission as well as requiring NAR (OR: 1.171; CI: 1.026-1.337;  = 0.02) and FiO (OR: 0.951; CI: 0.921-0.983,  = 0.003) within the first 24 hours were independent predictors of IHM.

Conclusion:  Higher levels of C-reactive protein, serum lactate, blood glucose, and lower cholinesterase level on admission were significantly associated with IHM. Patients with initially nonelevated CVs required higher NAR and FiO within the first 24 hours of ICU treatment. Furthermore, requiring an NAR > 0.5 µg/kg/min or an FiO > 0.21 were identified as additional independent predictors for IHM. These results could be helpful to improve ICU treatment in ICH patients.
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http://dx.doi.org/10.1055/s-0040-1716516DOI Listing
March 2021

The Predictive Value of Transcutaneous Electrical Nerve Stimulation for Patient Selection in Peripheral Nerve Field Stimulation for Chronic Low Back Pain: A Prospective Study.

Neuromodulation 2021 Aug 5;24(6):1051-1058. Epub 2020 Aug 5.

Department of Neurosurgery, Justus-Liebig-University Giessen, Giessen, Germany.

Objective: Peripheral nerve field stimulation (PNFS) is an effective alternative treatment for patients with chronic low back pain. Transcutaneous electrical nerve stimulation (TENS) is frequently used in pain therapy. Aim of this prospective study was to examine the predictive value of TENS for later PNFS treatment.

Materials And Methods: Between 2014 and 2019, a prospective cohort study of 41 patients with chronic lumbar pain was conducted. Pain intensity (NRS) was assessed before and after TENS use, preoperatively/postoperatively and in the follow-up after three and six months, SF12v2 questionnaires with physical (PCS) and mental component summary (MCS) scores, and Oswestry disability index (ODI) questionnaire at baseline as well as three and six months after PNFS implantation. Implantation of the PNFS-system with two percutaneous leads was performed after four to seven days of positive testing. Statistical analysis was performed using depending t-test, ANOVA, and Spearman correlation.

Results: The cohort consisted of 41 patients (19 females, 22 males) with a median age of 60.5 years (IQR 52-67). Two patients were lost to follow-up. After positive PNFS testing a pulse generator (IPG) was implanted in 15 patients with positive TENS effect and 15 patients without TENS effect. Leads were explanted in nine patients after negative PNFS trial phase. TENS positive patients showed significant correlation to a positive effect in the PNFS trial phase in NRS reduction (p = 0.042) indicating that TENS responders will also respond to PNFS (94% patients). After three and six months follow-up median NRS and SF12v2 (PCS) improved significantly in both cohorts, SF12v2 (MCS) and ODI only in the TENS positive cohort, respectively.

Conclusion: TENS can be predictive for patient selection in PNFS, as TENS positive patients showed significant correlation with a positive PNFS trial period. Therefore, TENS positive patients might be justifiable to be directly implanted with leads and IPG. TENS positive patients further tend to show a better improvement in the follow-up.
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http://dx.doi.org/10.1111/ner.13244DOI Listing
August 2021

Case Report of Complete Radiological Response of a Thalamic Glioblastoma After Treatment With Proton Therapy Followed by Temozolomide and Tumor-Treating Fields.

Front Oncol 2020 21;10:477. Epub 2020 Apr 21.

Department of Radiation Oncology, UKGM Giessen, Giessen, Germany.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. We present a case of a 42-year-old male patient presenting with headache and vomiting. Imaging demonstrated obstructive hydrocephalus and a ring-enhancing lesion in the right posterior thalamus. After endoscopic third ventriculostomy and stereotactic biopsy, the histopathologic diagnosis of a malignant glioma was confirmed by DNA methylation array as GBM isocitrate dehydrogenase wild type. The patient was treated with combined treatment of chemoradiation with temozolomide (TMZ) including proton boost, TMZ maintenance, and tumor-treating fields. In this case report, complete radiological response was observed 1 year after the end of radiation therapy.
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http://dx.doi.org/10.3389/fonc.2020.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186451PMC
April 2020

Impact of Early C-Reactive Protein/Albumin Ratio on Intra-Hospital Mortality Among Patients with Spontaneous Intracerebral Hemorrhage.

J Clin Med 2020 Apr 24;9(4). Epub 2020 Apr 24.

Department of Neurosurgery, Justus-Liebig-University Gießen, Klinikstraße 33, 35392 Gießen, Germany.

Objective: The impact of increased C-reactive protein (CRP)/albumin ratio on intra-hospital mortality has been investigated among patients admitted to general intensive care units (ICU). However, it was not investigated among patients with spontaneous intracerebral hemorrhage (ICH). This study aimed to investigate the impact of CRP/albumin ratio on intra-hospital mortality in patients with ICH.

Patients And Methods: This retrospective study was conducted on 379 ICH patients admitted between 02/2008 and 12/2017. Blood samples were drawn upon admission and the patients' demographic, medical, and radiological data were collected. The identification of the independent prognostic factors for intra-hospital mortality was calculated using binary logistic regression and COX regression analysis.

Results: Multivariate regression analysis shows that higher CRP/albumin ratio (odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.193-2.317, = 0.003) upon admission is an independent predictor of intra-hospital mortality. Multivariate Cox regression analysis indicated that an increase of 1 in the CRP/albumin ratio was associated with a 15.3% increase in the risk of intra-hospital mortality (hazard ratio = 1.153, 95% CI = 1.005-1.322, = 0.42). Furthermore, a CRP/albumin ratio cut-off value greater than 1.22 was associated with increased intra-hospital mortality (Youden's Index = 0.19, sensitivity = 28.8, specificity = 89.9, = 0.007).

Conclusions: A CRP/albumin ratio greater than 1.22 upon admission was significantly associated with intra-hospital mortality in the ICH patients.
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http://dx.doi.org/10.3390/jcm9041236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230407PMC
April 2020

Transcranial Doppler Sonography Defined Vasospasm, Ischemic Brain Lesions, and Delayed Ischemic Neurological Deficit in Younger and Elderly Patients after Aneurysmal Subarachnoid Hemorrhage.

World Neurosurg 2020 06 17;138:e718-e724. Epub 2020 Mar 17.

Department of Neurosurgery, Justus-Liebig-University Gießen, Gießen, Germany.

Background: Vasospasm, delayed ischemic neurologic deficit (DIND), and ischemic brain lesions after acute subarachnoid hemorrhage (SAH) are associated with increased morbidity and mortality. The purpose of this study was to analyze age cutoffs for vasospasm, DIND, and ischemic brain lesions after SAH.

Methods: This study included 292 aneurysmal SAH patients from January 2005 to December 2015. Patients' data were extracted from a prospective database with measurements of transcranial Doppler sonography. Any vasospasm was defined as a maximum mean flow velocity (MMFV) >120 cm/sec. Severe vasospasms were defined as at least 2 measurements of MMFVs >200 cm/sec or an increase of MMFV >50 cm/sec/24 hours over 2 consecutive days or a new neurologic deficit. All MMFVs >120 cm/sec in absence of severe vasospasm criteria were defined as mild vasospasm. Age-related cutoff values were calculated using receiver operating curve analysis.

Results: Any vasospasms occurred in 142 patients and thereof mild vasospasm in 86/142 (60.6%) patients and severe vasospasm in 56/142 patients (39.4%). Significantly higher incidences of any vasospasm (P = 0.005), severe vasospasm (P = 0.003), DIND (P = 0.031), and ischemic brain lesions (P = 0.04) were observed in patients aged <50 years. According to receiver operating curve analysis, the optimal age cutoff was 50 years for the presence of overall vasospasms, severe vasospasms, DIND, and ischemic brain lesions and 65 years for mild vasospasms.

Conclusions: Higher incidences of any vasospasms, severe vasospasms, DIND, and ischemic brain lesions were observed in younger SAH patients.
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http://dx.doi.org/10.1016/j.wneu.2020.03.051DOI Listing
June 2020

National Institutes of Health Stroke Scale (NIHSS) on admission predicts acute symptomatic seizure risk in ischemic stroke: a population-based study involving 135,117 cases.

Sci Rep 2020 03 2;10(1):3779. Epub 2020 Mar 2.

Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Frankfurt am Main, Germany.

The National Institutes of Health Stroke Scale (NIHSS) score is the most frequently used score worldwide for assessing the clinical severity of a stroke. Prior research suggested an association between acute symptomatic seizures after stroke and poorer outcome. We determined the frequency of acute seizures after ischemic stroke in a large population-based registry in a central European region between 2004 and 2016 and identified risk factors for acute seizures in univariate and multivariate analyses. Additionally, we determined the influence of seizures on morbidity and mortality in a matched case-control design. Our analysis of 135,117 cases demonstrated a seizure frequency of 1.3%. Seizure risk was 0.6% with an NIHSS score at admission <3 points and increased up to 7.0% with >31 score points. Seizure risk was significantly higher in the presence of acute non-neurological infections (odds ratio: 3.4; 95% confidence interval: 2.8-4.1). A lower premorbid functional level also significantly increased seizure risk (OR: 1.7; 95%CI: 1.4-2.0). Mortality in patients with acute symptomatic seizures was almost doubled when compared to controls matched for age, gender, and stroke severity. Acute symptomatic seizures increase morbidity and mortality in ischemic stroke. Their odds increase with a higher NIHSS score at admission.
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http://dx.doi.org/10.1038/s41598-020-60628-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051974PMC
March 2020

Carbon Ion Beam Reirradiation in Recurrent High-Grade Glioma.

Cancer Manag Res 2020 28;12:633-639. Epub 2020 Jan 28.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Background: Patients with recurrent glioma after prior radiotherapy have a poor prognosis. Carbon ion beam radiotherapy offers highly conformal dose distributions and more complex biological radiation effects eventually resulting in optimized normal tissue sparing and improved outcome. The aim of this study was to analyze toxicity, local control and overall survival after reirradiation of recurrent high-grade glioma with carbon ion radiotherapy.

Methods: Between 10/2015 and 12/2018, 30 patients (median age: 59 years) with recurrent high-grade glioma were reirradiated with carbon ion beams and retrospectively analyzed. Diagnosis of recurrent glioma was based on magnetic resonance imaging. Thirteen patients had repeated resection prior to reirradiation and 24 patients underwent additional chemotherapy. The median initial radiation dose was 60 Gy and the median time interval between the initial and repeated radiotherapy was 10 months. The reirradiation dose was 45 Gy (relative biological effectiveness) applied in 15 fractions. All patients received regular follow-up imaging after reirradiation. Kaplan-Meier estimation, log rank test and Cox regression analysis were used for statistical assessment.

Results: Applying common toxicity criteria, there were no grade 5 or 4 adverse events, while 8 patients showed grade 3 adverse events. The median follow-up after reirradiation was 11 months and the median overall survival after diagnosis of recurrent high-grade glioma was 13 months. The 6-, 12- and 24-month overall survival rates after diagnosis of recurrent high-grade glioma were 76%, 50% and 19%, respectively. Upon multivariate Cox regression analysis, a Ki67 score of the initial tumor histology of less than 20% was prognostic. Repeated resection or chemotherapy for the recurrent disease did not result in significantly prolonged survival.

Conclusion: Carbon ion reirradiation in recurrent high-grade glioma is safe and feasible. No radiation-associated grade 4 toxicities were documented and treatment was tolerated well.
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http://dx.doi.org/10.2147/CMAR.S217824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995286PMC
January 2020

Programmable valve breakage in shunt systems of children with posthemorrhagic hydrocephalus after minor head trauma-a case series.

Childs Nerv Syst 2020 09 20;36(9):2027-2031. Epub 2020 Feb 20.

Department of Neurosurgery, Justus-Liebig-University Giessen, Klinikstrasse 33, 35392, Giessen, Germany.

Purpose: We report five rare cases of programmable valve breakage (Codman Hakim-Medos valve) in shunt systems of children with posthemorrhagic hydrocephalus. Only four similar studies have been published in the current literature.

Methods: Between 2013 and 2018, five children with posthemorrhagic hydrocephalus were admitted to the pediatric department. All patients had a history of slight blows to the head in a minor trauma and follow up MRI scans. After initial clinical examination, cranial computed tomography (CT) and X-ray were conducted.

Results: In all cases, pumping the reservoir resulted in very slow refilling. The cranial CT in one patient showed slit ventricles confirming the suspicion of overdrainage, the other cases a slight enhancement of the hydrocephalus. In lateral X-rays of the skull in comparison to the first X-ray control of the shunt valve, the pressure control chamber could be seen dislocated in the inferior part of the reservoir in all cases. Surgery revealed that the shunt valve was broken. The pressure control chamber had dropped to the bottom of the reservoir. After implantation of a new shunt valve, the symptoms resolved completely in all five children. Overall this complication occurred in 4.3% (5 of 85 implanted Codman Hakim-Medos valve) of all children necessitating ventriculoperitoneal shunt implantation between January 2013 and December 2018.

Conclusion: The well-accepted Codman Hakim-Medos programmable valve is part of a tube-system, which is designed to offer the possibility of a reliable and precise treatment of hydrocephalus. Various mechanical and non-mechanical complications of shunt systems have been reported. Valve breakage is a very rare condition, often missed, and must be kept in mind when trauma and prior MRI scan are reported.
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http://dx.doi.org/10.1007/s00381-020-04541-6DOI Listing
September 2020

Acute symptomatic seizures in intracerebral and subarachnoid hemorrhage: A population study of 19,331 patients.

Epilepsy Res 2020 03 5;161:106286. Epub 2020 Feb 5.

Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, Goethe University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany; Department of Neurology and Epilepsy Center Hessen, Philipps University Marburg, Marburg (Lahn), Germany.

Background: Risk factors for acute symptomatic seizures after stroke demonstrated in retrospective analyses should be confirmed in large population studies. While seizures following ischemic stroke have been studied intensively, less is known about seizure predictors in hemorrhagic stroke. This study sought to identify risk factors of acute symptomatic seizures and to elucidate associated short-term (in-hospital) morbidity and mortality rates in primary intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH).

Methods: We determined the frequency of all acute symptomatic seizures perceived by clinical staff after hemorrhagic stroke in a large population-based registry in a central European region between 2004 and 2016. Further, we analyzed risk factors for seizure occurrence, morbidity, and mortality in univariate and multivariate analyses.

Results: Of 297,120 stroke patients, 19,331 experienced a hemorrhagic stroke. Frequency of acute seizures (without semiological differentiation) in this subpopulation was 4% (4.0% in ICH and 3.6% in SAH). The risk for acute symptomatic seizures was significantly increased in both stroke types in the presence of an acute non-neurological infection (odds ratio: 2.0 for ICH and 4.2 for SAH). A lower premorbid functional level also significantly increased the seizure risk (odds ratio: 2.0 for ICH and 3.1 for SAH). The odds of in-hospital mortality in the presence of acute seizures were significantly reduced in ICH patients (odds ratio: 0.7) but not in SAH patients.

Conclusion: Acute symptomatic seizures are equally common in ICH and SAH patients in this registry. Seizure risk is invariably increased in the presence of acute non-neurological infection. Mortality is reduced in ICH patients with seizures, but the exact reason for this relationship is not clear and might represent a biased finding.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106286DOI Listing
March 2020

Troponin I as an early biomarker of cardiopulmonary parameters during the first 24 h of intensive care unit treatment in isolated traumatic brain injury patients.

Injury 2020 May 7;51(5):1189-1195. Epub 2020 Jan 7.

Department of Neurosurgery, Justus-Liebig-University Giessen, Klinikstrasse 33, Giessen 35392, Germany.

Objective: Cardiopulmonary (CP) complications are well-known phenomena after an isolated traumatic brain injury (iTBI) and they may be associated with an elevated serum troponin I (TnI) value. However, the influence of an elevated TnI level on CP parameters within the first 24 h after an iTBI is still unknown. The current study was conducted to assess the associations between the initial TnI value on admission and CP parameters during the first 24 h of intensive care unit (ICU) treatment in iTBI patients.

Patients And Methods: A total of 288 patients with iTBIs, who were admitted to our emergency department between January 2010 and November 2016 were retrospectively analyzed. Blood samples were taken on admission to determine TnI value. Each patient's demographic data, treatment regime, computed tomography results, and intra-hospital outcomes were evaluated, as well as several CP parameters, within the first 24 h of ICU treatment. The entire study population was stratified into patients with an initial TnI elevation (TnI positive) and without an initial TnI elevation (TnI negative).

Results: Increased TnI values on admission were found in 59 (20.5%) patients. There were significant correlations between an initially elevated TnI value and a lower Glasgow Coma Scale score (p = 0.003), higher head Abbreviated Injury Scale score (p<0.0001), and higher Acute Physiology and Chronic Health Evaluation II score (p = 0.005) on admission, as well as a lower Glasgow Outcome Scale score (p = 0.0002) and higher modified Rankin Scale score (p = 0.0001) at discharge. In addition, a significantly higher norepinephrine application rate (NAR) (p<0.0001) and inspiratory oxygen fraction (FiO2) (p = 0.028) were needed in the TnI positive group.

Conclusion: Patients with elevated TnI values on admission require more circulation support (NAR and FiO2) within the first 24 h of ICU treatment after an iTBI. Therefore, the TnI may be a useful biomarker to improve ICU treatment of these patients.
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http://dx.doi.org/10.1016/j.injury.2020.01.002DOI Listing
May 2020

Serum Biomarkers for Risk Assessment of Intrahospital Transports in Mechanically Ventilated Neurosurgical Intensive Care Unit Patients.

J Intensive Care Med 2021 Apr 28;36(4):419-427. Epub 2019 Nov 28.

Department of Neurosurgery, 9175Justus-Liebig-University Gießen, Germany.

Objective: Intrahospital transports (IHTs) of neurosurgical intensive care unit (NICU) patients can be hazardous. Increasing intracranial pressure (ICP) and/or decreasing cerebral perfusion pressure (CPP) as well as cardiopulmonary alterations are common complications of an IHTs, which can lead to secondary brain injury. This study was performed to assess several serum biomarkers concerning their potential to improve safety of IHTs in mechanically ventilated NICU patients.

Methods: All IHTs of mechanically ventilated and sedated NICU patients from 03/2017 to 01/2018 were retrospectively analyzed. Intracranial pressure and CPP measurements were performed in all patients. Serum hemoglobin, hematocrit, and serum sodium were defined as serum biomarkers. Demographic data, computed tomography scan on admission, Simplified Acute Physiology Score and Acute Physiology and Chronic Health Evaluation II, modified Rankin Scale, indication and consequence of IHTs were analyzed. Alteration of ICP/CPP, hemodynamic and pulmonary events were defined as complications. The study population was stratified into patients with the occurrence of a complication and absence of a complication.

Results: We analyzed a total number of 184 IHTs in 70 NICU patients with an overall complication rate of 57.6%. Of all, 32.1% IHTs had no direct therapeutic consequence. In patients with higher hemoglobin values prior to IHT less complications occurred, concerning ICP ( = .001), CPP ( = .001), hemodynamic ( = .005), and pulmonary ( < .0001) events. In addition, complications concerning ICP ( = .001), CPP ( = .001), hemodynamic ( = .005), and pulmonary problems ( = .002) were significantly lower in patients with higher hematocrit values before IHT.

Conclusion: Intrahospital transports of mechanically ventilated NICU patients carry a high risk of increased ICP and hemodynamic complications and should be performed restrictively. Higher values of hemoglobin and hematocrit prior to IHT were associated with less complications with regard to ICP, CPP as well as hemodynamic and pulmonary events and could be helpful to assess the potential risk of complications prior to IHTs.
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http://dx.doi.org/10.1177/0885066619891063DOI Listing
April 2021

Spinal cord stimulation for the treatment of complex regional pain syndrome leads to improvement of quality of life, reduction of pain and psychological distress: a retrospective case series with 24 months follow up.

Scand J Pain 2020 04;20(2):253-259

Department of Neurosurgery, Justus-Liebig-University Giessen, Giessen, Germany.

Background and aims Complex regional pain syndrome (CRPS) is a common pain condition which is characterized by pain, functional impairment, and trophic changes. Neurosurgical treatment is not widely offered. In this study the treatment with spinal cord stimulation (SCS) was evaluated over 24 months follow up. Methods A retrospective case analysis of six patients with severe CRPS was performed. Pain chronicity was recorded with the Mainz Pain Staging System (MPSS). Pain intensity (NRS), activity level and health-related quality of life (EQ-5D-5L), the actual mood state (ASTS), and treatment satisfaction (CSQ-8) were assessed. All patients received conventional pharmacological treatments including multimodal pain therapy through their local pain therapist or in specialized centers as well as physical therapy. A SCS electrode was implanted for trial stimulation. After successful trial a neurostimulator was implanted and connected to the electrode. Patients were retrospectively analyzed before implantation and 6, 12 and 24 months postoperatively. Statistical analysis was performed using Mann-Whitney U and Wilcoxon rank-sum test. Results Patients median age was 43 years (IQR25-75 37-43 years). The median MPSS Score was 3 of 3 indicating a high pain chronicity. Median NRS before implantation of the neurostimulator was 8.8 (IQR25-75 7.6-9.3). A reduction to 7.8 (IQR25-75 4.8-8.1; p = 0.14) after 6 months, 6.5 (IQR25-75 3.8-8.1; p = 0.08) after 1 year, and 6.8 (IQR25-75 3.8-8.5; p = 0.15) after 2 years was achieved. Median EQ-5D-5L index value before treatment was 0.27 (IQR25-75 0.25-0.41) indicating a severely lowered quality of life. A significant improvement to 0.53 (IQR25-75 0.26-0.65; p = 0.03) after 6 months, 0.58 (IQR25-75 0.26-0.84; p = 0.03) after 1 year as well as after 2 years was seen. ASTS scale showed an increase of values for positive mood, and a reduction in values for sorrow, fatigue, anger and desperation during the whole follow up period. The treatment satisfaction in the whole cohort with a median CSQ-8 value of 29.5 of 32 was very high. Conclusion The results of this small case series showed a significant improvement of the EQ-5D-5L after implantation of a neurostimulator. NRS reduction was not significant but a clear tendency towards reduced values was observed. We therefore conclude that SCS is an alternative option to relieve chronic pain and psychological distress originating from CRPS if non-invasive managements of severe CRPS failed. The preoperative selection plays a crucial role for good results. Implications CRPS is difficult to treat. SCS is an alternative option to improve the quality of life and relieve chronic pain originating from severe CRPS if conservative treatment modalities fail. Further psychological distress is reduced in long-term follow up. SCS should be kept in mind for therapy refractory cases.
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http://dx.doi.org/10.1515/sjpain-2019-0081DOI Listing
April 2020

Placement of External Ventricular Drain: Comparison of Two Methods.

J Neurol Surg A Cent Eur Neurosurg 2019 Mar 1;80(2):116-121. Epub 2019 Feb 1.

Department of Neurosurgery, Bremen-Mitte Hospital, Bremen, Germany.

Background:  Insertion of a frontal external ventricular drain (EVD) is a common emergency procedure in neurosurgery. Malpositioning of the EVD and/or triggering a new intracerebral or intraventricular hemorrhage (nICVH) are typical complications. The standard procedure (SP) uses a tape measure to identify the Kocher's point for placement of a frontal burr hole. A faster alternative to determine the correct position is the freehand technique (FHT). This study compared both techniques with regard to the correct positioning of the EVD tip and the induction catheter-induced nICVH.

Methods:  We performed a retrospective analysis of patients who required an EVD for acute or chronic hydrocephalus between January 2013 and March 2014. The study consisted of two groups. In the first group, EVDs were placed with the FHT. In the second group the SP was used. Postoperative computed tomography scans were analyzed regarding correct positioning of the ventricular catheter, malpositioning of the tip of the EVD using a 4-point-scale, and evidence for catheter-induced nICVH.

Results:  A total of 95 patients could be included. The FHT was performed in 43 cases and the SP in 52 cases. No significant differences between the two groups were found regarding the correct position of the EVD tip ( = 0.38) and nICVH ( = 0.12). There was no significant difference in malpositioning of the EVD tip between the groups ( = 0.34).

Conclusion:  Our results show no significant differences between the two methods with regard to correct position, malpositioning, and nICVH. Thus we conclude that the FHT is a fast, safe, and effective alternative to the SP.
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http://dx.doi.org/10.1055/s-0038-1676576DOI Listing
March 2019

Troponin I as an Early Biomarker of Cardiopulmonary Parameters Within the First 24 Hours After Nontraumatic Subarachnoid Hemorrhage in Intensive Care Unit Patients.

J Intensive Care Med 2020 Dec 8;35(12):1368-1373. Epub 2019 Jan 8.

Department of Neurosurgery, Bremen-Mitte Hospital, Bremen, Germany.

Objective: The elevation of serum cardiac troponin I (TNI) in patients with nontraumatic subarachnoid hemorrhage (ntSAH) is a well-known phenomenon. However, the relation between elevated TNI and different cardiopulmonary parameters (CPs) within the first 24 hours after ntSAH is unknown. The present study was conducted to investigate the association between TNI and different CP in patients with ntSAH within the first 24 hours of intensive care unit (ICU) treatment.

Patients And Methods: We retrospectively analyzed a consecutive group of 117 patients with ntSAH admitted to our emergency department between January 2008 and February 2017. Blood samples were taken to determine TNI values on admission. Demographic data, baseline Glasgow Coma Scale (GCS) score, World Federation of Neurosurgical Societies (WFNS) score, baseline Fisher grade (FG), norepinephrine application rate (NAR) in µg/kg/min, and inspiratory oxygen fraction (OF) were recorded within the first 24 hours.

Results: An increased TNI value was found in 32 (27.4%) of 117 patients. There was a significant correlation between initial elevated TNI and a low WFNS score ( = .007), a low GCS score ( = .003) as well as a high OF ( = <.001). The FG ( = .27) and NAR ( = .08) within the first 24 hours of ICU treatment did not show any significant correlation.

Conclusions: In the present study, an increased TNI value was significantly associated with a low WFNS score and GCS score on admission. The TNI was a predictor of the need for a higher OF within the first 24 hours after ntSAH so that TNI could be an informative biomarker to improve ICU therapy.
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http://dx.doi.org/10.1177/0885066618824568DOI Listing
December 2020

A Retrospective Analysis of 25 Cases With Peripheral Nerve Field Stimulation for Chronic Low Back Pain and the Predictive Value of Transcutaneous Electrical Nerve Stimulation for Patient Selection.

Neuromodulation 2019 Jul 7;22(5):607-614. Epub 2018 Dec 7.

Department of Neurosurgery, Justus-Liebig-University Giessen, Giessen, Germany.

Objective: Transcutaneous electrical nerve stimulation (TENS) and peripheral nerve field stimulation (PNFS) may be proposed to patients with chronic lumbar pain refractory to conventional treatment. Aim of this study was to assess the importance of preoperatively treatment with TENS as a predictive value for later successful PNFS and impact of PNFS in follow-up of 12 months.

Methods: Between 2012 and 2016, a retrospective analysis of 25 patients with chronic lumbar pain and implantation of a PNFS-system was performed. Pain intensity (NRS), health-related quality of life (EQ-5D-5L), Oswestry disability index (ODI), actual mood state scale (ASTS), and treatment satisfaction (CSQ-8) were assessed pre/postoperatively, after 6 and 12 months. TENS use before surgery was assessed.

Results: The cohort consisted of 25 patients with a median age of 56 years (IQR 51-63). In a subgroup analysis, 18 patients used TENS before surgery, 7 did not use TENS and were excluded. No pain relief was observed in 14 patients. Ten of these patients showed later positive effect in PNFS trial stimulation. In four patients, pain relief with TENS was seen. One patient later on had no benefit after PNFS trial, three had sufficient pain relief. In the whole cohort, five patients had no benefit after PNFS trial, in 20 patients a neurostimulator was implanted. NRS, EQ-5D-5L, and ODI measures showed significant improvement in the whole follow-up after PNFS implantation. ASTS scale showed an increase of values for positive mood and a reduction in values for sorrow, fatigue, and anger. In 55%, a sustained reduction in demand for analgesics was seen after 6 months, 50% after 12 months, respectively.

Conclusion: In this retrospective analysis, TENS has no predictive value in the selection of patients with low back pain for the PFNS treatment. PNFS is effective and safe to relieve significantly symptoms of chronic low back pain.
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http://dx.doi.org/10.1111/ner.12890DOI Listing
July 2019

One decade of oral anticoagulation in stroke patients: Results from a large country-wide hospital-based registry.

Int J Stroke 2018 04 27;13(3):308-312. Epub 2017 Sep 27.

5 Institute of quality assurance Hesse, Eschborn/Frankfurt, Germany.

Background New evidence regarding stroke prevention in atrial fibrillation has been published. Implementing knowledge into clinical practice remains challenging. Aims To investigate oral anticoagulants in stroke patients documented in a nationwide registry. Methods The database is an obligatory federal-state-wide hospital-based registry that covers more than 95% of all ischemic strokes, transient ischemic attacks and intracerebral hemorrhages in a community of more than six million inhabitants (Hesse/Germany). We analyzed oral anticoagulants prescribed on discharge in patients with stroke or transient ischemic attack during 2006-2015. Results From 2006 to 2015, we annually selected median 20,895 patients. From 2006 to 2015, the proportion of patients treated with oral anticoagulants increased (9.8% to 24%). The annual proportion of patients with atrial fibrillation remained constant (median: 23%). In atrial fibrillation patients treated with oral anticoagulants, the age increased (median 2008/2009: 76.9 years vs. 2014/2015 79.4 years). The percentage of treated individuals in atrial fibrillation increased dramatically (2006: 30.1% to 2015: 74.5%); in 2015, 30.8% of these patients received vitamin K antagonists and 70.2% new oral anticoagulants. Independent factors associated with new oral anticoagulants therapy were a previous medication with new oral anticoagulants and a treatment on stroke unit. Between new oral anticoagulants- and vitamin K antagonists-treated patients (2015), no differences in age were noted (both mean: 79.4 years). Conclusions The new oral anticoagulants availability enhanced a general trend treating more target patients with oral anticoagulants.
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http://dx.doi.org/10.1177/1747493017733928DOI Listing
April 2018

Photopharmacological control of bipolar cells restores visual function in blind mice.

J Clin Invest 2017 Jun 5;127(7):2598-2611. Epub 2017 Jun 5.

Department of Ophthalmology, University of Washington School of Medicine, Seattle, Washington, USA.

Photopharmacological control of neuronal activity using synthetic photochromic ligands, or photoswitches, is a promising approach for restoring visual function in patients suffering from degenerative retinal diseases. Azobenzene photoswitches, such as AAQ and DENAQ, have been shown to restore the responses of retinal ganglion cells to light in mouse models of retinal degeneration but do not recapitulate native retinal signal processing. Here, we describe diethylamino-azo-diethylamino (DAD), a third-generation photoswitch that is capable of restoring retinal ganglion cell light responses to blue or white light. In acute brain slices of murine layer 2/3 cortical neurons, we determined that the photoswitch quickly relaxes to its inactive form in the dark. DAD is not permanently charged, and the uncharged form enables the photoswitch to rapidly and effectively cross biological barriers and thereby access and photosensitize retinal neurons. Intravitreal injection of DAD restored retinal light responses and light-driven behavior to blind mice. Unlike DENAQ, DAD acts upstream of retinal ganglion cells, primarily conferring light sensitivity to bipolar cells. Moreover, DAD was capable of generating ON and OFF visual responses in the blind retina by utilizing intrinsic retinal circuitry, which may be advantageous for restoring visual function.
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http://dx.doi.org/10.1172/JCI92156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490774PMC
June 2017

Defining Prolonged Length of Acute Care Stay for Surgically and Conservatively Treated Patients with Spontaneous Intracerebral Hemorrhage: A Population-Based Analysis.

Biomed Res Int 2016 27;2016:9095263. Epub 2016 Mar 27.

Department of Neurosurgery, Justus-Liebig University Giessen, Klinikstrasse 33, 35392 Giessen, Germany.

Background: The definition of prolonged length of stay (LOS) during acute care remains unclear among surgically and conservatively treated patients with intracerebral hemorrhage (ICH).

Methods: Using a population-based quality assessment registry, we calculated change points in LOS for surgically and conservatively treated patients with ICH. The influence of comorbidities, baseline characteristics at admission, and in-hospital complications on prolonged LOS was evaluated in a multivariate model.

Results: Overall, 13272 patients with ICH were included in the analysis. Surgical therapy of the hematoma was documented in 1405 (10.6%) patients. Change points for LOS were 22 days (CI: 8, 22; CL 98%) for surgically treated patients and 16 days (CI: 16, 16; CL: 99%) for conservatively treated patients. Ventilation therapy was related to prolonged LOS in surgically (OR: 2.2, 95% CI: 1.5-3.1; P < 0.001) and conservatively treated patients (OR: 2.5, 95% CI: 2.2-2.9; P < 0.001). Two or more in-hospital complications in surgical patients (OR: 2.7, 95% CI: 2.1-3.5) and ≥1 in conservative patients (OR: 3.0, 95% CI: 2.7-3.3) were predictors of prolonged LOS.

Conclusion: The definition of prolonged LOS after ICH could be useful for several aspects of quality management and research. Preventing in-hospital complications could decrease the number of patients with prolonged LOS.
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http://dx.doi.org/10.1155/2016/9095263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826712PMC
December 2016

Microsurgical unilateral laminotomy for decompression of lumbar spinal stenosis: long-term results and predictive factors.

Acta Neurochir (Wien) 2016 06 15;158(6):1103-13. Epub 2016 Apr 15.

Department of Neurosurgery, Justus-Liebig-University Giessen, Klinikstr. 33, 35392, Giessen, Germany.

Background: The microsurgical unilateral laminotomy (MUL) technique for bilateral decompression of lumbar spinal stenosis (LSS) is a less destabilizing alternative to laminectomy and leads to good short-term outcomes. However, little is known about the long-term results including predictive factors.

Methods: Medical records of patients who underwent MUL for LSS decompression between 2005 and 2010 were reviewed, and a questionnaire was distributed to complement the long-term outcome data. The study population consisted of 176 patients including 17 patients with stable grade I spondylolisthesis. Complications and reoperations were meticulously analyzed. Clinical outcome was measured using a modified Prolo scale and was further dichotomized in good vs. poor outcome. Predictive factors were obtained from uni- and multivariate analyses.

Results: The median age of the cohort was 70.0 years and the follow-up 71.7 months. Complications occurred in 5.1 % of the patients. The overall reoperation rate was 17.0 %, including surgery, which was exclusively performed at other levels in 4.0 %. The reoperation rate for fusion was 4.5 %. Good neurogenic claudication outcome faded from 98.3 % at hospital discharge to 47.2 % at 6 years. Multivariate analysis identified previous lumbar operation as a potential independent predictor of a reoperation; potential independent predictors of poor long-term claudication outcome were older age, female gender, higher body mass index (BMI) and tobacco smoking.

Conclusions: In our experience, the long-term reoperation rate after MUL for LSS is not negligible and higher in previously operated patients. It seems like the good initial clinical results after MUL may fade over time, and several patient-related predictive factors including potentially modifiable obesity and tobacco smoking seem to play an important role.
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http://dx.doi.org/10.1007/s00701-016-2804-6DOI Listing
June 2016

NDRG2 and NDRG4 Expression Is Altered in Glioblastoma and Influences Survival in Patients with MGMT-methylated Tumors.

Anticancer Res 2016 Mar;36(3):887-97

Department of Neurosurgery, Justus Liebig University, Giessen, Germany.

Aim: The N-myc down-regulated gene (NDRG) family is a group of genes that have predominantly tumor-suppressive effects. The goal of this study was to investigate the expression of NDRG2 and NDRG4 in surgical specimens of human glioblastoma and in normal brain tissue, and to search for correlations with overall (OS) and progression-free survival (PFS).

Materials And Methods: Samples from 44 patients (31 males, 13 females; mean age±SD=57.4±15.7 years) with primary (n=40) or recurrent glioblastoma (n=4) were analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry, with dimensionless semiquantitative immunoreactivity score (IRS), ranging from 0-30] for expression of NDRG2 and NDRG4. Five non-tumorous autopsy brain specimens were used as controls.

Results: On the protein level, expression of NDRG2 was significantly down-regulated in glioblastoma (IRS=3.5±3.0 vs. 8.8±3.3; p=0.001), while expression of NDRG4 was significantly up-regulated (IRS=5.4±3.7 vs. 0.75±0.4 vs, p<0.001). There was no statistically significant difference in PFS between a group of 15 patients with glioblastoma with MGMT methylation and enhanced expression of NDRG4 mRNA who were treated with adjuvant radiochemotherapy (temozolomide and 60 Gy) and a group of patients with low expression of NDRG4 mRNA [10 (range=5.5-14.2) months vs. 21 (range=10.7-31.3) months] (p=0.13).

Conclusion: Expression of both NDRG2 and NDRG4 genes is significantly altered in glioblastomas. PFS among the patients with glioblastoma with MGMT methylation treated with radiochemotherapy differed significantly in high-expression groups compared to patients without MGMT methlation and without radiochemotherapy (p<0.05).
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March 2016

High-mobility group AT-hook protein 2 expression and its prognostic significance in MGMT methylated and unmethylated glioblastoma.

Int J Oncol 2016 Apr 17;48(4):1485-92. Epub 2016 Feb 17.

Department of Neurosurgery, Justus-Liebig University Giessen, Giessen, Germany.

High-mobility group AT-hook protein 2 (HMGA 2) is a transcription factor associated with malignancy and poor prognosis in a variety of human cancers. We correlated HMGA 2 expression with clinical parameters, survival, and O-6-methylguanine-DNA methyltransferase methylation status (MGMT) in glioblastoma patients. HMGA 2 expression was determined by performing quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry (IHC) in 44 glioblastoma patients and 5 non-tumorous brain specimens as controls. Gene expression levels of MGMT methylated vs. unmethylated patients, and gene expression levels between patient groups, both for qPCR and IHC data were compared using the Mann-Whitney U test. The relationship between HMGA 2 expression, progression-free survival and overall survival was analyzed using the Kaplan-Meier method and the log-rank test. P-values of <0.05 were considered statistically significant throughout the analyses. The mean age of patients at diagnosis was 57.4 ± 15.7 years, and the median survival was 16 months (SE 2.8; 95% CI, 10.6-21.4). HMGA 2 gene expression was significantly higher in glioblastoma compared to normal brain tissue on qPCR (mean, 0.35; SD, 0.27 vs. 0.03, SD, 0.05) and IHC levels (IRS mean, 17.21; SD, 7.43 vs. 3.20; SD, 1.68) (p=0.001). Survival analysis revealed that HMGA 2 overexpression was associated with a shorter progression-free and overall survival time in patients with methylation (n=24). The present study shows a tendency that HMGA 2 overexpression correlates with a poor prognosis of glioblastoma patients independent of MGMT methylation status. The results suggest that HMGA 2 could play an important role in the treatment of glioblastoma and could have a function in prognosis of this type of cancer.
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http://dx.doi.org/10.3892/ijo.2016.3397DOI Listing
April 2016

In-Hospital Mortality and Complication Rates in Surgically and Conservatively Treated Patients with Spontaneous Intracerebral Hemorrhage in Central Europe: A Population-Based Study.

World Neurosurg 2016 Apr 29;88:306-310. Epub 2015 Dec 29.

Department of Neurosurgery, Justus Liebig University Giessen, Giessen, Germany.

Objective: Secondary complications (SC) after intracerebral hemorrhage (ICH) can worsen outcome and are associated with early death. The purpose of the present study was to determine in-hospital mortality rates and SC after spontaneous ICH during acute care stay in a population-based cohort in central Europe.

Methods: A prospective database of the State of Hesse, Germany, was screened for all patients with the primary diagnosis of spontaneous ICH (International statistical classification-10: I61.0-I61.9) between January 2007 and December 2012.

Results: In the examined time period 10,029 patients with spontaneous ICH were identified. The cumulative rate of SC was 39.9% (1, 2, or ≥3 SC were documented in 25.0%, 10.1%, and 4.7%, respectively). The most common SC were pneumonia (15.1%), brain edema (6.5%), cardiac decompensation (5.9%), urogenital infection (5.5%), hydrocephalus (4.6%), epilepsy (3.4%), and rebleeding (3.4%). One, 2, or ≥3 SC were found in 2512 patients (25.0%), 1012 (10.1%), 473 (4.7%) patients, respectively. One SC was only a predictor of in-hospital mortality in conservatively treated patients (odds ratio [OR], 1.3; 95% confidence interval [CI] 1.2-1.5, P< 0.001). With an accumulation of SC to ≥3 the chance of in-hospital death increases for surgically (OR, 3.7, 95% CI 2.3-5.9; P< 0.001) and conservatively (OR, 3.0, 95% CI 2.3-3.9; P< 0.001) treated patients.

Conclusions: Surgical treatment of hematomas is associated with an increased rate of SC, but not with higher mortality rates compared with conservatively treated patients. The prevention of an accumulation of SC could lead to a decrease of in-hospital mortality after spontaneous ICH.
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http://dx.doi.org/10.1016/j.wneu.2015.11.075DOI Listing
April 2016

In-hospital mortality after pre-treatment with antiplatelet agents or oral anticoagulants and hematoma evacuation of intracerebral hematomas.

J Clin Neurosci 2016 Apr 11;26:42-5. Epub 2015 Dec 11.

Department of Neurosurgery, Justus-Liebig University, Klinikstrasse 33, 35392 Giessen, Germany.

Pre-treatment with antiplatelet agents is described to be a risk factor for mortality after spontaneous intracerebral hemorrhage (ICH). However, the impact of antithrombotic agents on mortality in patients who undergo hematoma evacuation compared to conservatively treated patients with ICH remains controversial. This analysis is based on a prospective registry for quality assurance in stroke care in the State of Hesse, Germany. Patients' data were collected between January 2008 and December 2012. Only patients with the diagnosis of spontaneous ICH were included (International Classification of Diseases 10th Revision codes I61.0-I61.9). Predictors of in-hospital mortality were determined by univariate analysis. Predictors with P<0.1 were included in a binary logistic regression model. The binary logistic regression model was adjusted for age, initial Glasgow Coma Score (GCS), the presence of intraventricular hemorrhage (IVH), and pre-ICH disability prior to ictus. In 8,421 patients with spontaneous ICH, pre-treatment with oral anticoagulants or antiplatelet agents was documented in 16.3% and 25.1%, respectively. Overall in-hospital mortality was 23.2%. In-hospital mortality was decreased in operatively treated patients compared to conservatively treated patients (11.6% versus 24.0%; P<0.001). Patients with antiplatelet pre-treatment had a significantly higher risk of death during the hospital stay after hematoma evacuation (odds ratio [OR]: 2.5; 95% confidence interval [CI]: 1.24-4.97; P=0.010) compared to patients without antiplatelet pre-treatment treatment (OR: 0.9; 95% CI: 0.79-1.09; P=0.376). In conclusion a higher rate of in-hospital mortality after pre-treatment with antiplatelet agents in combination with hematoma evacuation after spontaneous ICH was observed in the presented cohort.
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http://dx.doi.org/10.1016/j.jocn.2015.05.069DOI Listing
April 2016

Mean hemoglobin concentration after acute subarachnoid hemorrhage and the relation to outcome, mortality, vasospasm, and brain infarction.

J Clin Neurosci 2015 Mar 18;22(3):530-4. Epub 2014 Dec 18.

Department of Neurosurgery, HELIOS Vogtland Klinikum Plauen, Germany.

Lower mean hemoglobin (HGB) levels are associated with unfavorable outcome after spontaneous subarachnoid hemorrhage (SAH). Currently, there is no cutoff level for mean HGB levels associated with unfavorable outcome. This study was conducted to evaluate a threshold for mean HGB concentrations after SAH, and to observe the relation to outcome. The medical records of 702 patients with spontaneous SAH were reviewed. Predictors of outcome were proved by univariate analysis. Predictors with p<0.1 were included in a multivariate binary logistic regression model. Cutoff points for mean HGB levels were calculated by receiver operating characteristic curve analysis. Mean HGB was 11.9 g/dl (±standard deviation [SD] 1.7 g/dl) in patients with favorable outcome compared to 10.8 g/dl (±SD 1.1g/dl) in patients with unfavorable outcome (p<0.001). The highest Youden's index value was found for a HGB cutoff at 11.1 g/dl. In a binary logistic regression model, predictors of unfavorable outcome were identified as an initially high Hunt-Hess grade (odds ratio [OR]: 7.7; 95% confidence interval [CI]: 4.4-13.4; p<0.001), cerebral infarction on a CT scan during hospital stay (OR: 3.8; 95% CI: 2.0-7.3; p<0.001), rebleeding during the hospital stay (OR: 3.5; 95% CI: 1.6-8.0; p=0.002), mean HGB concentration <11.1g/dl (OR: 3.3; 95% CI: 2.0-5.3; p<0.001), and hydrocephalus (OR: 2.3; 95% CI: 1.4-3.7; p=0.001). In conclusion, a mean HGB concentration <11.1 g/dl during the hospital stay was associated with unfavorable outcome after acute SAH.
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http://dx.doi.org/10.1016/j.jocn.2014.08.026DOI Listing
March 2015

Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey.

Acta Neurochir (Wien) 2014 Dec 24;156(12):2315-24. Epub 2014 Sep 24.

Department of Neurosurgery, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany,

Background: Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children.

Methods: Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was "useful", i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence.

Results: Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %).

Conclusions: Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.
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http://dx.doi.org/10.1007/s00701-014-2234-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232748PMC
December 2014

Relative positioning of classical benzodiazepines to the γ2-subunit of GABAA receptors.

ACS Chem Biol 2014 Aug 1;9(8):1846-53. Epub 2014 Jul 1.

Institute of Biochemistry and Molecular Medicine, University of Bern , CH-3012 Bern, Switzerland.

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain. Benzodiazepine exert their action via a high affinity-binding site at the α/γ subunit interface on some of these receptors. Diazepam has sedative, hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. It acts by potentiating the current evoked by the agonist GABA. Understanding specific interaction of benzodiazepines in the binding pocket of different GABAA receptor isoforms might help to separate these divergent effects. As a first step, we characterized the interaction between diazepam and the major GABAA receptor isoform α1β2γ2. We mutated several amino acid residues on the γ2-subunit assumed to be located near or in the benzodiazepine binding pocket individually to cysteine and studied the interaction with three ligands that are modified with a cysteine-reactive isothiocyanate group (-NCS). When the reactive NCS group is in apposition to the cysteine residue this leads to a covalent reaction. In this way, three amino acid residues, γ2Tyr58, γ2Asn60, and γ2Val190 were located relative to classical benzodiazepines in their binding pocket on GABAA receptors.
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http://dx.doi.org/10.1021/cb500186aDOI Listing
August 2014
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