Publications by authors named "Christian Senft"

130 Publications

Cerebrospinal Fluid Concentrations of Meropenem and Vancomycin in Ventriculitis Patients Obtained by TDM-Guided Continuous Infusion.

Antibiotics (Basel) 2021 Nov 20;10(11). Epub 2021 Nov 20.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, 60590 Frankfurt am Main, Germany.

Effective antibiotic therapy of cerebral infections such as meningitis or ventriculitis is hindered by low penetration into the cerebrospinal fluid (CSF). Because continuous infusion of meropenem and vancomycin and routine therapeutic drug monitoring (TDM) have been proposed to optimize antimicrobial exposure in ventriculitis patients, an individualized dosing strategy was implemented in our department. We present a retrospective analysis of meropenem and vancomycin concentrations in serum and CSF in the first nine ventriculitis patients treated with continuous infusion and TDM-guided dose optimization aiming at 20-30 mg/L. Median initial dosing was 8.8 g/24 h meropenem and 4.25 g/24 h vancomycin, respectively, resulting in median serum concentrations of 21.3 mg/L for meropenem and 24.5 mg/L for vancomycin and CSF concentrations of 3.4 mg/L for meropenem and 1.7 mg/L for vancomycin. Median CSF penetration was 15% for meropenem and 7% for vancomycin. With initial dosing, all but one patient achieved CSF concentrations above 1 mg/L. Dose adjustment according to TDM ensured sufficient CSF concentrations in all patients within 48 h of treatment. Given the limited penetration, continuous infusion of meropenem and vancomycin based on renal function and TDM-guided dose optimization appears a reasonable approach to attain sufficient CSF concentrations in ventriculitis patients.
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http://dx.doi.org/10.3390/antibiotics10111421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614961PMC
November 2021

Short- and Long-Term Effects of Rehabilitation after Perimesencephalic Subarachnoid Hemorrhage.

Diseases 2021 Oct 7;9(4). Epub 2021 Oct 7.

Department of Neurosurgery, Goethe-University Hospital, 60528 Frankfurt am Main, Germany.

In about 25% of patients with spontaneous subarachnoid hemorrhage (SAH), a bleeding source cannot be identified during radiological diagnostics. Generally, the outcome of perimesencephalic or prepontine (PM) SAH is known to be significantly better than after non-PM SAH. Data about long-term follow-up concerning physical and mental health are scarce, so this study is reports on long-term results. We measured the influence of PM SAH on a quality-of-life modified Rankin (mRs) scale after six months. For long-term follow-up, a SF-36 questionnaire was used. Questionnaires were sent out between 18 and 168 months after ictus. In 37 patients, a long-term follow-up was available (up to 14 years after SAH). Data detected with the SF-36 questionnaire are compared to reference applicability to the standard population. In total, 37 patients were included for further analysis and divided in 2 subgroups; 13 patients (35%) received subsequent rehabilitation after clinical stay and 24 (65%) did not. In the short-term outcome, a significant improvement from discharge until follow-up was identified in patients with subsequent rehabilitation, but not in the matched pair group without rehabilitation. When PM SAH was compared to the standard population, a reduction in quality of life was identified in physical items (role limitations because of physical health problems, physical functioning) as well as in psychological items (role limitations because of emotional problems). Subsequent rehabilitation on PM SAH patients probably leads to an increase in independence and better mRs. While better mRs was shown at discharge in patients without subsequent rehabilitation, the mRs of rehabilitants was nearly identical after rehabilitation. Patients with good mRs also reached high levels of health-related quality of life (HRQoL) without rehabilitation. Thus, subsequent rehabilitation needs to be encouraged on an individual basis. Indication criteria for subsequent rehabilitation should be defined in further studies to improve patient treatment and efficiency in health care.
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http://dx.doi.org/10.3390/diseases9040069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544554PMC
October 2021

Correlation of quantitative computed tomography derived bone density values with Hounsfield units of a contrast medium computed tomography in 98 thoraco-lumbar vertebral bodies.

Arch Orthop Trauma Surg 2021 Sep 25. Epub 2021 Sep 25.

Department of Neurosurgery, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany.

Introduction: Vertebral fractures in patients with bone density reduction are often a major challenge for the surgeon, as reduced bone density can lead to screw loosening. Several options are available to determine bone density preoperatively. In our study, we investigated the correlation of Hounsfield units (HU) of a contrast medium computed tomography (CT) to the bone density values of a quantitative computed tomography (QCT) and computed a formula to estimate bone density values using HU.

Materials And Methods: In our retrospective data analysis, we examine 98 vertebral bodies from 35 patients who received a contrast medium CT of the spine and a QCT, performed no longer than 1 month apart. The determined HU from the contrast medium CT were compared with the bone density values of the QCT and examined for correlations. Linear logistic regression was used to estimate bone density values base on HU.

Results: A strong correlation was found between the HU measured in the CT and the bone density values (r = 0.894, p < 0.001), irrespective of patients' gender. We also found no correlation differences when the HU were measured at different levels. Bland-Altman plot demonstrated good agreement between the two measurements. The following formula was developed to estimate bone density values using HU: QCT-value = 0.71 × HU + 13.82.

Conclusions: Bone density values correlate well to HU measured in contrast medium CT. Using simple formula, the bone density of a contrast medium CT of vertebral bodies can be estimated based on HU without additional examinations and unnecessary costs.
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http://dx.doi.org/10.1007/s00402-021-04184-5DOI Listing
September 2021

Dexamethasone Treatment Limits Efficacy of Radiation, but Does Not Interfere With Glioma Cell Death Induced by Tumor Treating Fields.

Front Oncol 2021 30;11:715031. Epub 2021 Jul 30.

Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt, Germany.

Purpose: Dexamethasone (Dex) is the most common corticosteroid to treat edema in glioblastoma (GBM) patients. Recent studies identified the addition of Dex to radiation therapy (RT) to be associated with poor survival. Independently, Tumor Treating Fields (TTFields) provides a novel anti-cancer modality for patients with primary and recurrent GBM. Whether Dex influences the efficacy of TTFields, however, remains elusive.

Methods: Human GBM cell lines MZ54 and U251 were treated with RT or TTFields in combination with Dex and the effects on cell counts and cell death were determined flow cytometry. We further performed a retrospective analysis of GBM patients with TTFields treatment +/- concomitant Dex and analysed its impact on progression-free (PFS) and overall survival (OS).

Results: The addition of Dex significantly reduced the efficacy of RT in U251, but not in MZ54 cells. TTFields (200 kHz/250 kHz) induced massive cell death in both cell lines. Concomitant treatment of TTFields and Dex did not reduce the overall efficacy of TTFields. Further, in our retrospective clinical analysis, we found that the addition of Dex to TTFields therapy did not influence PFS nor OS.

Conclusion: Our translational investigation indicates that the efficacy of TTFields therapy in patients with GBM and GBM cell lines is not affected by the addition of Dex.
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http://dx.doi.org/10.3389/fonc.2021.715031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361446PMC
July 2021

Two-step staged resection of giant olfactory groove meningiomas.

Acta Neurochir (Wien) 2021 12 10;163(12):3425-3431. Epub 2021 Aug 10.

Department of Neurosurgery, Goethe - University, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany.

Background: The surgical treatment of giant olfactory groove meningiomas (OGMs) with marked perilesional brain oedema is still a surgical challenge. After tumour resection, increase of brain oedema may occur causing dramatic neurological deterioration and even death of the patient. The objective of this paper is to describe surgical features of a two-step staged resection of these tumours performed to counter increase of postoperative brain oedema.

Methods: This two-step staged resection procedure was carried out in a consecutive series of 19 patients harbouring giant OGMs. As first step, a bifrontal craniectomy was performed followed by a right-sided interhemispherical approach. About 80% of the tumour mass was resected leaving behind a shell-shaped tumour remnant. In the second step, carried out after the patients' recovery from the first surgery and decline of oedema, the remaining part of the tumour was removed completely followed by duro- and cranioplasty.

Results: Ten patients recovered quickly from first surgery and the second operation was performed after a mean of 12.4 days. In eight patients, the second operation was carried out later between day 25 and 68 due to surgery-related complications, development of a trigeminal zoster, or to a persisting frontal brain oedema. Mean follow-up was 49.3 months and all but one patient had a good outcome regardless of surgery-related complications.

Conclusions: Our results suggest that a two-step staged resection of giant OGMs minimizes the increase of postoperative brain oedema as far as possible and translates into lower morbidity and mortality.
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http://dx.doi.org/10.1007/s00701-021-04910-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599346PMC
December 2021

Clinical Outcome and Risk Factors of Red Blood Cell Transfusion in Patients Undergoing Elective Primary Meningioma Resection.

Cancers (Basel) 2021 Jul 18;13(14). Epub 2021 Jul 18.

Department of Neurosurgery, University Hospital, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany.

Transfusion of red blood cells (RBC) in patients undergoing major elective cranial surgery is associated with increased morbidity, mortality and prolonged hospital length of stay (LOS). This retrospective single center study aims to identify the clinical outcome of RBC transfusions on skull base and non-skull base meningioma patients including the identification of risk factors for RBC transfusion. Between October 2009 and October 2016, 423 patients underwent primary meningioma resection. Of these, 68 (16.1%) received RBC transfusion and 355 (83.9%) did not receive RBC units. Preoperative anaemia rate was significantly higher in transfused patients (17.7%) compared to patients without RBC transfusion (6.2%; = 0.0015). In transfused patients, postoperative complications as well as hospital LOS was significantly higher ( < 0.0001) compared to non-transfused patients. After multivariate analyses, risk factors for RBC transfusion were preoperative American Society of Anaesthesiologists (ASA) physical status score ( = 0.0247), tumor size ( = 0.0006), surgical time ( = 0.0018) and intraoperative blood loss ( < 0.0001). Kaplan-Meier curves revealed significant influence on overall survival by preoperative anaemia, RBC transfusion, smoking, cardiovascular disease, preoperative KPS ≤ 60% and age (elderly ≥ 75 years). We concluded that blood loss due to large tumors or localization near large vessels are the main triggers for RBC transfusion in meningioma patients paired with a potential preselection that masks the effect of preoperative anaemia in multivariate analysis. Further studies evaluating the impact of preoperative anaemia management for reduction of RBC transfusion are needed to improve the clinical outcome of meningioma patients.
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http://dx.doi.org/10.3390/cancers13143601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307823PMC
July 2021

Correlation of Bone Density Values of Quantitative Computed Tomography and Hounsfield Units Measured in Native Computed Tomography in 902 Vertebral Bodies.

World Neurosurg 2021 07 29;151:e599-e606. Epub 2021 Apr 29.

Department of Neurosurgery, Jena University Hospital - Friedrich Schiller University, Jena, Germany. Electronic address:

Objective: Due to the increasing age of patients, the evaluation of bone density is crucial, especially in preparation for spinal surgery. The aim of this study was to determine bone density using a computed tomography (CT) and to correlate Hounsfield units (HU) with bone density values of a quantitative computed tomography (QCT).

Methods: The study is a monocentric, retrospective data analysis. We examined 902 vertebral bodies from a total of 369 patients who received a CT of the thoracolumbar spine in the period from 2015 to 2019 and compared the HU with values of a QCT. A general equation for calculation the QCT values was established.

Results: We found a significant correlation between the Hounsfield units and the corresponding QCT-values (r = 0.944, P < 0.001). We also demonstrated that the calculated QCT values are independent of patient sex (P < 0.942). Furthermore, we could not demonstrate differences in the correlation of the 3 measured levels (axial, sagittal, and coronary) to the QCT values. The QCT-values can be calculated on the basis of a native CT of the lumbar spine using the equation: QCT = 17.8 + 0.7 × HU.

Conclusions: The equation allows calculating bone density values without the need for an additional QCT and without further radiation exposure or costs. With this measuring method it is possible to obtain additional information from a computed tomography.
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http://dx.doi.org/10.1016/j.wneu.2021.04.093DOI Listing
July 2021

Meningioma Surgery in Patients ≥70 Years of Age: Clinical Outcome and Validation of the SKALE Score.

J Clin Med 2021 Apr 22;10(9). Epub 2021 Apr 22.

Department of Neurosurgery, University Hospital Frankfurt, Goethe University, 60528 Frankfurt, Germany.

Along with increasing average life expectancy, the number of elderly meningioma patients has grown proportionally. Our aim was to evaluate whether these specific patients benefit from surgery and to investigate a previously published score for decision-making in meningioma patients (SKALE). Of 421 patients who underwent primary intracranial meningioma resection between 2009 and 2015, 71 patients were ≥70 years of age. We compared clinical data including World Health Organization (WHO) grade, MIB-1 proliferation index, Karnofsky Performance Status Scale (KPS), progression free survival (PFS) and mortality rate between elderly and all other meningioma patients. Preoperative SKALE scores (Sex, KPS, ASA score, location and edema) were determined for elderly patients. SKALE ≥8 was set for dichotomization to determine any association with outcome parameters. In 71 elderly patients (male/female 37/34) all data were available. Postoperative KPS was significantly lower in elderly patients ( < 0.0001). Pulmonary complications including pneumonia (10% vs. 3.2%; = 0.0202) and pulmonary embolism (12.7% vs. 6%; = 0.0209) occurred more frequently in our elderly cohort. Analyses of the Kaplan Meier curves revealed differences in three-month (5.6% vs. 0.3%; = 0.0033), six-month (7% vs. 0.3%; = 0.0006) and one-year mortality (8.5% vs. 0.3%; < 0.0001) for elderly patients. Statistical analysis showed significant survival benefit in terms of one-year mortality for elderly patients with SKALE scores ≥8 (5.1 vs. 25%; = 0.0479). According to our data, elderly meningioma patients face higher postoperative morbidity and mortality than younger patients. However, resection is reasonable for selected patients, particularly when reaching a SKALE score ≥ 8.
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http://dx.doi.org/10.3390/jcm10091820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122404PMC
April 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

Association of Isocitrate Dehydrogenase (IDH) Status With Edema to Tumor Ratio and Its Correlation With Immune Infiltration in Glioblastoma.

Front Immunol 2021 25;12:627650. Epub 2021 Mar 25.

Department of Neurosurgery, Goethe University Hospital, Frankfurt, Germany.

Purpose: The extent of preoperative peritumoral edema in glioblastoma (GBM) has been negatively correlated with patient outcome. As several ongoing studies are investigating T-cell based immunotherapy in GBM, we conducted this study to assess whether peritumoral edema with potentially increased intracranial pressure, disrupted tissue homeostasis and reduced local blood flow has influence on immune infiltration and affects survival.

Methods: A volumetric analysis of preoperative imaging (gadolinium enhanced T1 weighted MRI sequences for tumor size and T2 weighted sequences for extent of edema (including the infiltrative zone, gliosis etc.) was conducted in 144 patients using the Brainlab® software. Immunohistochemical staining was analyzed for lymphocytic- (CD 3+) and myelocytic (CD15+) tumor infiltration. A retrospective analysis of patient-, surgical-, and molecular characteristics was performed using medical records.

Results: The edema to tumor ratio was neither associated with progression-free nor overall survival (p=0.90, p=0.74). However, GBM patients displaying IDH-1 wildtype had significantly higher edema to tumor ratio than patients displaying an IDH-1 mutation (p=0.01). Immunohistopathological analysis did not show significant differences in lymphocytic or myelocytic tumor infiltration (p=0.78, p=0.74) between these groups.

Conclusion: In our cohort, edema to tumor ratio had no significant correlation with immune infiltration and outcome. However, patients with an IDH-1wildtype GBM had a significantly higher edema to tumor ratio compared to their IDH-1 mutated peer group. Further studies are necessary to elucidate the underlying mechanisms.
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http://dx.doi.org/10.3389/fimmu.2021.627650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044904PMC
September 2021

Beware of Nihilism: Favorable Outcome despite Poor Admission Status in Posterior Circulation Aneurysms after Aneurysmal Subarachnoid Hemorrhage.

J Neurol Surg A Cent Eur Neurosurg 2021 Nov 22;82(6):512-517. Epub 2021 Feb 22.

Department of Neurosurgery, Goethe University Frankfurt, Frankfurt, Germany.

Objective:  As shown in a previous study, aneurysm location seems to influence prognosis in patients with subarachnoid hemorrhage (SAH). We compared patients with ruptured aneurysms of anterior and posterior circulation, undergoing coil embolization, concerning differences in outcome and prognostic factors.

Methods:  Patients with SAH were entered into a prospectively collected database. We retrospectively identified 307 patients with aneurysms of the anterior circulation (anterior cerebral artery, carotid bifurcation, and middle cerebral artery) and 244 patients with aneurysms of the posterior circulation (aneurysms of the basilar artery, posterior inferior cerebellar artery, posterior communicating artery and posterior cerebral artery). All patients underwent coil embolization. The outcome was assessed using the modified Rankin Scale (mRS; favorable [mRS 0-2] vs. unfavorable [mRS 3-6]) 6 months after SAH.

Results:  In interventionally treated aneurysms of the anterior and posterior circulation, statistically significant risk factors for poor outcome were worse admission status and severe cerebral vasospasm. If compared with patients with ruptured aneurysms of the anterior circulation, patients with aneurysms of the posterior circulation had a significantly poorer admission status, and suffered significantly more often from an early hydrocephalus. Nonetheless, there were no differences in outcome or mortality rate between the two patient groups.

Conclusion:  Patients with a ruptured aneurysm of the posterior circulation suffer more often from an early hydrocephalus and have a significantly worse admission status, possibly related to the untreated hydrocephalus. Nonetheless, the outcome and the mortality rate were comparable between ruptured anterior and posterior circulation aneurysms, treated by coil embolisation. Therefore, despite the poorer admission status of patients with ruptured posterior circulation aneurysms, treatment of these patients should be considered.
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http://dx.doi.org/10.1055/s-0040-1719142DOI Listing
November 2021

Activation of Platelets and Occurrence of Cerebral Vasospasm and Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage in a Prospective Pilot-Trial.

Clin Lab 2021 Feb;67(2)

Background: Aneurysmal subarachnoid hemorrhage (SAH) often leads to poor outcome. The aim of the study was to assess platelet function in patients after SAH.

Methods: In this prospective observational study in patients suffering from SAH, platelet count and aggregability were assessed by multiple electrode aggregometry (MEA) over 14 days.

Results: In 12 of 18 patients, cerebral vasospasms (CVS) were diagnosed; of those, five developed delayed cerebral ischemia (DCI). We observed a significant increase in the platelet count compared to baseline from day 8 onwards (p < 0.037) and, in patients with CVS and DCI, a significant difference in outcome classified by the mRS (p = 0.047). Repeated measures ANOVA determined no differences in platelet aggregability in patients with or without CVS/DCI.

Conclusions: Besides an increase in platelet count, we detected no increase in platelet aggregability. Nevertheless, patients after SAH may have increased platelet aggregability, which is not reflected by MEA.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200454DOI Listing
February 2021

Influence of VEGF-A, VEGFR-1-3, and neuropilin 1-2 on progression-free: and overall survival in WHO grade II and III meningioma patients.

J Mol Histol 2021 Apr 2;52(2):233-243. Epub 2021 Feb 2.

Department of Neurosurgery, University Hospital Frankfurt, Goethe University, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany.

Higher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.
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http://dx.doi.org/10.1007/s10735-020-09940-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012320PMC
April 2021

Neurotoxicity of subarachnoid Gd-based contrast agent accumulation: a potential complication of intraoperative MRI?

Neurosurg Focus 2021 01;50(1):E12

5Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.

Objective: Intraoperative MRI with Gd-based contrast agent (GBCA) improves the extent of resection of contrast-enhancing brain tumors. Signal changes of CSF due to perioperative GBCA leakage in the subarachnoid space have been reported. However, although GBCA potentially exhibits neurotoxic effects, so far no associated complications have been described. In this case series, the authors report a single-center cohort of patients with subarachnoid GBCA extravasation after intraoperative MRI and discuss potential neurotoxic complications and potential ways of avoiding them.

Methods: All patients with CSF signal increase on unenhanced T1-weighted and FLAIR images on postoperative MRI, who had previously undergone tumor resection with use of intraoperative MRI, were retrospectively included and compared with a control cohort. The control group was matched in age, tumor characteristics, and extent of resection; comparisons were made regarding postoperative seizures and ICU stay. A subgroup with initially diagnosed malignant glioma was additionally analyzed for potential delay of initiation of adjuvant treatment and overall survival.

Results: Seven patients with postoperative GBCA accumulation in the subarachnoid space were identified; 5 presented with focal seizures and altered mental status postoperatively. Poor patient condition led to extended ICU stay and prolonged delay of the initiation of adjuvant treatment in patients with newly diagnosed malignant glioma. Overall survival was reduced compared to the matched control group.

Conclusions: The results suggest that there might be a risk of neurotoxic complications if GBCA that is intravenously applied during neurosurgery leaks into the subarachnoid space. Patients with highly vascularized tumors with intraoperative bleeding seem to be especially at risk for GBCA accumulation and neurotoxic complications. Therefore, awareness of the potential risk of complicating GBCA leakage is mandatory in the application of intraoperative GBCA.
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http://dx.doi.org/10.3171/2020.10.FOCUS20402DOI Listing
January 2021

Microsurgical Treatment and Follow-Up of KOOS Grade IV Vestibular Schwannoma: Therapeutic Concept and Future Perspective.

Front Oncol 2020 20;10:605137. Epub 2020 Nov 20.

Department of Neurosurgery, University Hospital, Goethe-University, Frankfurt am Main, Germany.

Purpose: Surgery of KOOS IV vestibular schwannoma remains challenging regarding the balance of extent of tumor resection (EoR) and functional outcome. Our aim was to evaluate the outcome of surgical resection and define a cut-off value for safe resection with low risk for tumor regrowth of KOOS IV vestibular schwannoma.

Methods: All patients presenting at the authors' institution between 2000 and 2019 with surgically treated KOOS IV vestibular schwannoma were included. Outcome measures included EoR, facial/hearing nerve function, surgical complications and progression of residual tumor during the median follow-up period of 28 months.

Results: In 58 patients, mean tumor volume was 17.1 ± 9.2 cm, and mean EoR of 81.6 ± 16.8% could be achieved. Fifty-one patients were available for the follow-up analysis. Growth of residual tumor was observed in 11 patients (21.6%) followed by adjuvant treatment with stereotactic radiosurgery or repeat surgery in 15 patients (29.4%). Overall serviceable hearing preservation was achieved in 38 patients (74.5%) and good facial outcome at discharge was observed in 66.7% of patients, significantly increasing to 82.4% at follow-up. Independent predictors for residual tumor growth was EoR ≤ 87% (OR11.1) with a higher EoR being associated with a very low number of residual tumor progression amounting to 7.1% at follow-up (p=0.008).

Conclusions: Subtotal tumor resection is a good therapeutic concept in patients with KOOS IV vestibular schwannoma resulting in a high rate of good hearing and facial nerve function and a very low rate of subsequent tumor progression. The goal of surgery should be to achieve more than 87% of tumor resection to keep residual tumor progression low.
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http://dx.doi.org/10.3389/fonc.2020.605137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714957PMC
November 2020

Direct oral anticoagulants for therapeutic anticoagulation in postoperative pulmonary embolism after meningioma resection.

J Clin Neurosci 2020 Nov 16;81:265-269. Epub 2020 Oct 16.

Department of Neurosurgery, University Medicine of Rostock, Rostock, Germany.

Background: Acute postoperative pulmonary embolism (PE) is a dreaded complication with severe mortality rates. Brain tumor patients are at the highest risk for postoperative PE. The juxtaposition of low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA) and direct oral anticoagulation (DOAC) in the treatment of postoperative PE in meningioma patients is largely unexplored.

Patients/methods: This is a single center observational analysis of meningioma patients who underwent neurosurgical resection with a thoracic CT scan confirmation of postoperative PE. The treatment modality, clinical course and outcome were investigated.

Results: Of 538 meningioma patients operated, 30 (6%) developed acute postoperative PE. After diagnosis, these patients received different long-term anticoagulation regimes. No significant difference in postoperative hemorrhage (p < 0.56), re-operation rate (p < 0.70) or Karnofsky performance scale (KPS) at 3 (p < 0.34) and 12 months (p = 1) were identified, when compared according to the different anticoagulation regimes.

Conclusion: DOACs were not associated with elevated risk for hemorrhage, recurrent thrombosis or poor outcome when compared with traditional anticoagulation regimes. Prospective randomized trials are necessary to verify the non-inferiority of DOACs for long-term anticoagulation in postoperative pulmonary embolism after meningioma resection.
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http://dx.doi.org/10.1016/j.jocn.2020.09.059DOI Listing
November 2020

Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma.

Neuropathol Appl Neurobiol 2021 04 7;47(3):379-393. Epub 2020 Nov 7.

Neurological Institute (Edinger Institute), University Hospital, Goethe University Frankfurt am Main, Frankfurt, Germany.

Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas.

Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29).

Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy.

Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
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http://dx.doi.org/10.1111/nan.12669DOI Listing
April 2021

Benefits of glioma resection in the corpus callosum.

Sci Rep 2020 10 6;10(1):16630. Epub 2020 Oct 6.

Department of Neurosurgery, Goethe University Hospital, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany.

Due to anticipated postoperative neuropsychological sequelae, patients with gliomas infiltrating the corpus callosum rarely undergo tumor resection and mostly present in a poor neurological state. We aimed at investigating the benefit of glioma resection in the corpus callosum, hypothesizing neuropsychological deficits were mainly caused by tumor presence. Between 01/2017 and 1/2020, 21 patients who underwent glioma resection in the corpus callosum were prospectively enrolled into this study. Neuropsychological function was assessed preoperatively, before discharge and after 6 months. Gross total tumor resection was possible in 15 patients, and in 6 patients subtotal tumor resection with a tumor reduction of 97.7% could be achieved. During a median observation time of 12.6 months 9 patients died from glioblastoma after a median of 17 months. Preoperatively, all cognitive domains were affected in up to two thirds of patients, who presented a median KPS of 100% (range 60-100%). After surgery, the proportion of impaired patients increased in all neurocognitive domains. Most interestingly, after 6 months, significantly fewer patients showed impairments in attention, executive functioning, memory and depression, which are domains considered crucial for everyday functionality. Thus, the results of our study strongly support our hypothesis that in patients with gliomas infiltrating the corpus callosum the benefit of tumor resection might outweigh morbidity.
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http://dx.doi.org/10.1038/s41598-020-73928-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538917PMC
October 2020

The ability to return to work: a patient-centered outcome parameter following glioma surgery.

J Neurooncol 2020 Sep 22;149(3):403-411. Epub 2020 Sep 22.

Department of Neurosurgery, Goethe-University Hospital, Schleusenweg 2-16, 60528, Frankfurt, Germany.

Background: With refinements in diagnosis and therapy of gliomas, the importance of survival time as the sole outcome parameter has decreased, and patient-centered outcome parameters have gained interest. Pursuing a profession is an indispensable component of human happiness. The aim of this study was to analyze the professional outcomes besides their neuro-oncological and functional evaluation after surgery for gliomas in eloquent areas.

Methods: We assessed neuro-oncological and functional outcomes of patients with gliomas WHO grades II and III undergoing surgery between 2012 and 2018. All patients underwent routine follow-up and adjuvant treatment. Treatment and survival parameters were collected prospectively. Repercussions of the disease on the patients' professional status, socio-economic situation, and neurocognitive function were evaluated retrospectively with questionnaires.

Results: We analyzed data of 58 patients with gliomas (WHO II: 9; III: 49). Median patient age was 35.8 years (range 21-63 years). Awake surgery techniques were applied in 32 patients (55.2%). Gross total and subtotal tumor resections were achieved in 33 (56.9%) and 17 (29.3%) patients, respectively, whereas in 8 patients (13.8%) resection had to remain partial. Most patients (n = 46; 79.3%) received adjuvant treatment. Median follow up was 43.8 months (range 11-82 months). After treatment 41 patients (70.7%) were able to resume a working life. Median time until returning to work was 8.0 months (range 0.2-22.0 months). To be younger than 40 at the time of the surgery was associated with a higher probability to return to work (p < .001). Multivariable regression analysis showed that patient age < 40 years as well as occupational group and self-reported fatigue were factors independently associated with the ability to return to work.

Conclusion: The ability to resume professional activities following brain tumor surgery is an important patient-oriented outcome parameter. We found that the majority of patients with gliomas were able to return to work following surgical and adjuvant treatment. Preservation of neurological function is of utmost relevance for individual patients´ quality of life.
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http://dx.doi.org/10.1007/s11060-020-03609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609423PMC
September 2020

Reactive Thrombocytosis in Non-aneurysmal Subarachnoid Hemorrhage.

J Neurol Surg A Cent Eur Neurosurg 2020 Sep 21;81(5):412-417. Epub 2020 May 21.

Department of Neurosurgery, Goethe University Hospital, Frankfurt, Germany.

Background:  The role of reactive thrombocytosis in non-aneurysmal subarachnoid hemorrhage (NA-SAH) is largely unexplored to date. Therefore, the impact of a quantitative thrombocyte dynamic in patients with NA-SAH and its clinical relevance were analyzed in the present study.

Methods:  In this retrospective analysis, 113 patients with nontraumatic and NA-SAH treated between 2003 and 2015 at our institution were included. World Federation of Neurosurgical Societies admission status, cerebral vasospasm, delayed infarction, hydrocephalus, need for ventriculoperitoneal (VP) shunt, and Fisher grade were analyzed for their association with reactive thrombocytosis.

Results:  Reactive thrombocytosis was not associated with hydrocephalus ( ≥ 0.05), need for VP shunt implantation ( ≥ 0.05), cerebral vasospasm ( ≥ 0.05), or delayed cerebral ischemia ( ≥ 0.05).

Conclusion:  Our study is the first to investigate the role of thrombocyte dynamics, reactive thrombocytosis, and the clinical course of NA-SAH patients. Our analysis showed no significant impact of thrombocyte count on NA-SAH sequelae.
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http://dx.doi.org/10.1055/s-0040-1709167DOI Listing
September 2020

Pulmonary embolism in neurocritical care-introduction of a novel grading system for risk stratification: the Frankfurt AMBOS score.

Neurosurg Rev 2021 Apr 12;44(2):1165-1171. Epub 2020 May 12.

Department of Neurosurgery, University Hospital, Goethe University, Frankfurt, Germany.

Pulmonary embolism (PE) due to deep vein thrombosis is a complication with severe morbidity and mortality rates. Neurocritical care patients constitute an inhomogeneous cohort with often strict contraindications to conventional embolism treatment. The aim of the present study is to identify risk factors for pulmonary embolism for intensified risk stratification in this demanding cohort. In this retrospective analysis, 387 neurocritical care patients received computed tomography for clinical suspicion of PE (304 neurosurgical and 83 neurological patients). Analysed parameters included age, gender, disease pattern, the presence of deep vein thrombosis, resuscitation, in-hospital mortality, present anticoagulation, coronary artery disease, diabetes mellitus, smoking status, hypertension and ABO blood type. Computed tomography confirmed 165 cases of pulmonary embolism among 387 patients with clinical suspicion of pulmonary embolism (42%). Younger age (p < 0.0001), female gender (p < 0.006), neurooncological disease (p < 0.002), non-O blood type (p < 0.002) and the absence of Marcumar therapy (p < 0.003) were identified as significant risk factors for pulmonary embolism. On the basis of the identified risk factors, the AMBOS score system is introduced. Neurocritical care patients with high AMBOS score are at elevated risk for PE and should therefore be put under intensified monitoring for cardiovascular events in neurocritical care units.
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http://dx.doi.org/10.1007/s10143-020-01310-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035103PMC
April 2021

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy.

Front Immunol 2019 14;10:2683. Epub 2019 Nov 14.

Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.

Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained . NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
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http://dx.doi.org/10.3389/fimmu.2019.02683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868035PMC
November 2020

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients.

J Clin Med 2019 Nov 21;8(12). Epub 2019 Nov 21.

Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main POSTCODE, Germany.

(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients' serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.
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http://dx.doi.org/10.3390/jcm8122031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947028PMC
November 2019

Does aneurysm side influence the infarction side and patients´ outcome after subarachnoid hemorrhage?

PLoS One 2019 7;14(11):e0224013. Epub 2019 Nov 7.

Department of Neurosurgery, Goethe-University Hospital, Frankfurt am Main, Germany.

Background: The prognostic factors and outcome of aneurysms appear to be dependent on its locations. Therefore, we compared left- and right- sided aneurysms in patients with aneurysmal subarachnoid hemorrhage (SAH) in terms of differences in outcome and prognostic factors.

Methods: Patients with SAH were entered into a prospectively collected database. A total of 509 patients with aneurysmal subarachnoid hemorrhage were retrospectively selected and stratified in two groups depending on side of ruptured aneurysm (right n = 284 vs. left n = 225). Midline aneurysms of the basilar and anterior communicating arteries were excluded from the analysis. Outcomes were assessed using the modified Rankin Scale (mRS; favorable (mRS 0-2) vs. unfavorable (mRS 3-6)) six months after SAH.

Results: We did not identify any differences in outcome depending on left- and right-sided ruptured aneurysms. In both groups, the significant negative predictive factors included clinical admission status (WFNS IV+V), Fisher 3- bleeding pattern in CT, the occurrence of delayed cerebral ischemia (DCI), early hydrocephalus and later shunt-dependence. The side of the ruptured aneurysm does not seem to influence patients´ outcome. Interestingly, the aneurysm side predicts the side of infarction, with a significant influence on patients´ outcome in case of left-sided infarctions. In addition, the in multivariate analysis side of aneurysm was an independent predictor for the side of cerebral infarctions.

Conclusion: The side of the ruptured aneurysms (right or left) did not influence patients' outcome. However, the aneurysm-side predicts the side of delayed infarctions and outcome appear to be worse in patients with left-sided infarctions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837438PMC
March 2020

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

Surgery for Diffuse WHO Grade II Gliomas: Volumetric Analysis of a Multicenter Retrospective Cohort From the German Study Group for Intraoperative Magnetic Resonance Imaging.

Neurosurgery 2020 01;86(1):E64-E74

Department of Neurosurgery, University of Ulm, Günzburg, Germany.

Background: In diffuse WHO grade II gliomas (LGG), the extent of resection (EOR) required to achieve significant survival benefits remains elusive.

Objective: To evaluate the association of residual volume (RV) and EOR with progression-free survival (PFS) or overall survival (OS) in LGG in a retrospective, multicenter series by the German study group of intraoperative MRI (GeSGIM).

Methods: Consecutive cases were retrospectively assessed from 5 centers. Tumors were volumetrically quantified before and after surgery, and clinical data were analyzed, including IDH mutations and neurologic deficits. Kaplan-Meier estimates, accelerated failure time models (AFT), and multivariate Cox regression models were calculated to identify determinants of survival.

Results: A total of 140 cases were analyzed. Gross total resection (GTR) was associated with significantly longer PFS compared to any incomplete resection (P = .009). A significant survival disadvantage was evident even for small (>0-5 ml) residuals and increased for moderate (>5-20 ml) and large remnants (>20 ml) P = .001). Accordingly, PFS increased continuously for 20% incremental steps of EOR (P < .001). AFT models supported the notion of a continuous association of RV and EOR with PFS. Multivariate Cox regression models confirmed RV (P = .01) and EOR (P = .005) as continuous prognosticators of PFS. Univariate analysis showed significant associations of RV and EOR with OS.

Conclusion: Our data support the hypothesis of a continuous relationship of RV and EOR with survival for LGG with superiority seen for GTR. Hence, GTR should be achieved whenever safely feasible, and resections should be maximized whenever tumor has to be left behind to spare function.
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http://dx.doi.org/10.1093/neuros/nyz397DOI Listing
January 2020

Multicentric Registry Study on Epidemiological and Biological Disease Profile as Well as Clinical Outcome in Patients with Low-Grade Gliomas: The LoG-Glio Project.

J Neurol Surg A Cent Eur Neurosurg 2020 Jan 24;81(1):48-57. Epub 2019 Sep 24.

Department of Neurosurgery, University of Ulm, Ludwig Heilmeyerstr, Günzburg, Germany.

Background:  World Health Organization (WHO) grade II low-grade gliomas (LGGs) in adults are rare, and patients' mean overall survival (OS) is relatively long. Epidemiological data on factors influencing tumor genesis and progression are scarce, and prospective data on surgical management are still lacking. Because of the molecular heterogeneity of LGG, a comprehensive molecular characterization is required for any clinical and epidemiological research. Further, a detailed radiologic assessment is needed as the only established objective criterion for progressive disease. Both radiologic and molecular assessments have to be standardized to produce comparable data. The aim of the registry is to improve the evidence for surgical management of LGG patients by establishing a multicenter registry with a strong surgical and clinical focus including mandatory biobanking.

Methods:  The LoG-Glio project is a prospective national observational multicenter registry that began on November 1, 2015. Inclusion criteria encompass all patients > 18 years of age with a radiologic suspicion of LGG. Patients with severe neurologic or psychiatric disorders that may interfere with their informed consent or if there is no possibility for further follow-up are excluded. Diagnosis of glioblastoma WHO grade IV isocitrate dehydrogenase (IDH) wild type leads to a secondary exclusion of patients. In addition to demographic data, results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, add-on for patients with brain tumors, and National Health Institute Stroke Scale before and after surgery and during regular follow-ups are collected. At each time point a detailed recording of surgical and adjuvant treatment is performed. Radiologic assessment involves three-dimensional (3D) acquisition of T1, fluid-attenuated inversion recovery, and T2 sequences. For the final evaluation, a central detailed neuropathologic and molecular assessment of tumor samples and a radiologic evaluation of imaging sets are part of the study protocol.

Results:  We report the first 100 consecutively registered patients for LoG-Glio. Three patients dropped out due to loss of follow-up. Of the remaining recruited patients, 8 were classified as wait and scan; 89 had surgery. Using the inclusion criteria described previously, 70 patients had an IDH-mutated glioma, 10 had miscellaneous rare LGGs, and 8 patients had an IDH wild-type WHO grade II or III glioma.

Conclusion:  The LoG-Glio registry has been successfully implemented. Applied selection criteria result in an appropriately balanced patient cohort. Short-term outcome data on epidemiology as well as the influence of current surgical techniques and adjuvant treatment on patient outcomes are expected. In the long run, the aim of the registry is to validate the new molecular-based WHO classification and the influence of the extent of resection on progression-free survival and OS. The registry provides an open platform for future research projects benefiting patients with LGG.

Trial Registration:  NCT02686229 Clinical trials.
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http://dx.doi.org/10.1055/s-0039-1693650DOI Listing
January 2020

To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment.

J Neurosurg 2019 Jul 19:1-8. Epub 2019 Jul 19.

2Department of Neurosurgery, University of Heidelberg.

Objective: The level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade glioma, LGG) is low. In so-called "high-risk" patients most centers currently apply an early aggressive adjuvant treatment after surgery. The aim of this assessment was to compare progression-free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery.

Methods: Based on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with a confirmed isocitrate dehydrogenase (IDH) mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma.

Results: One hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8-6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance.

Conclusions: In this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment.
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http://dx.doi.org/10.3171/2019.4.JNS183395DOI Listing
July 2019

Management of hydrocephalus after resection of posterior fossa lesions in pediatric and adult patients-predictors for development of hydrocephalus.

Neurosurg Rev 2020 Aug 9;43(4):1143-1150. Epub 2019 Jul 9.

Department of Neurosurgery, University Hospital, Goethe-University, Frankfurt am Main, Germany.

The surgical management of hydrocephalus in patients with posterior fossa lesions (PFL) is critical for optimal patient outcome(s). Accordingly, it is prudent to identify patients in need of aggressive surgical intervention (i.e., ventriculoperitoneal [VP] shunting). To analyze prevalence of, and risk factors associated with, the development of post-operative hydrocephalus in both pediatrics and adults. A retrospective institutional analysis and review of patient records in those who had undergone PFL surgery was performed. In so doing, the authors identified patients that went on to develop post-operative hydrocephalus. The study included pediatric and adult patients treated between 2009 and 2017. Fifteen of 40 pediatric (37.5%) and 18 of 262 adult (6.9%) patients developed hydrocephalus after PFL surgery. The most common tumor entity in pediatrics was medulloblastoma (34%), astrocytoma (24.4%), and pilocytic astrocytoma (22%), whereas in adults, metastasis (29.5%), meningioma (22%), and acoustic neuroma (17.8%) were most common. Young age ≤ 2 years, medulloblastoma (OR 13.9), and brain stem compression (OR 5.4) were confirmed as independent predictors for hydrocephalus in pediatrics and pilocytic astrocytoma (OR 15.4) and pre-operative hydrocephalus (OR 3.6) in adults, respectively. All patients received VP shunts for hydrocephalus management and the mean follow-up was 29.5 months in pediatrics vs 19.2 months in adults. Overall complication rates related to VP shunts were 33.3% in pediatrics and 16.7% in adults, respectively. Shunt dependency and associated complications in pediatrics were noted to be higher than in adults. Given the identification of predictors for hydrocephalus, it is authors' contention that certain patients with those predictors may ultimately benefit from an alternative treatment regimen (e.g., pre-operative interventions) prior to PFT surgery.
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http://dx.doi.org/10.1007/s10143-019-01139-8DOI Listing
August 2020
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