Richard Drexler

All Publications

• Mean global DNA methylation serves as independent prognostic marker in IDH wild type glioblastoma. Neuro-oncology Eckhardt, A., Drexler, R., Schoof, M., Struve, N., Capper, D., Jelgersma, C., Onken, J., Harter, P. N., Weber, K. J., Divé, I., Rothkamm, K., Hoffer, K., Klumpp, L., Ganser, K., Petersen, C., Ricklefs, F., Kriegs, M., Schüller, U. 2023

  Abstract

  The IDH wild type glioblastoma (GBM) patients have a devastating prognosis. Here, we analyzed the potential prognostic value of global DNA methylation of the tumors.DNA methylation of 492 primary samples and 31 relapsed samples, each treated with combination therapy, and of 148 primary samples treated with radiation alone were compared with patient survival. We determined the mean methylation values and estimated the immune cell infiltration from the methylation data. Moreover, the mean global DNA methylation of 23 GBM cell lines was profiled and correlated to their cellular radiosensitivity as measured by colony formation assay.High mean DNA methylation levels correlated with improved survival, which was independent from known risk factors (MGMT promoter methylation, age, extent of resection; p=0.009) and methylation subgroups. Notably, this correlation was also independent of immune cell infiltration since higher number of immune cells indeed was associated with significantly better OS but lower mean methylation. Radiosensitive GBM cell lines had a significantly higher mean methylation than resistant lines (p=0.007), and improved OS of patients treated with radiotherapy alone was also associated with higher DNA methylation (p=0.002). Furthermore, specimens of relapsed GBM revealed a significantly lower mean DNA methylation compared to the matching primary tumor samples (p=0.041).Our results indicate that mean global DNA methylation is independently associated with outcome in glioblastoma. The data also suggest that a higher DNA methylation is associated with better radiotherapy response and less aggressive phenotype, both of which presumably contribute to the observed correlation with OS.

  View details for DOI 10.1093/neuonc/noad197

  View details for PubMedID 37818983

• Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and EGFR amplification in IDH-wildtype glioblastoma. Neuro-oncology practice Drexler, R., Sauvigny, T., Schüller, U., Eckhardt, A., Maire, C. L., Khatri, R., Hausmann, F., Hänzelmann, S., Huber, T. B., Bonn, S., Bode, H., Lamszus, K., Westphal, M., Dührsen, L., Ricklefs, F. L. 2023; 10 (5): 462-471

  Abstract

  5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of IDH-wildtype glioblastoma patients. A small subset of IDH-wildtype glioblastoma shows no 5-ALA fluorescence. An explanation for these cases is missing. In this study, we used DNA methylation profiling to further characterize non-fluorescent glioblastomas.Patients with newly diagnosed and recurrent IDH-wildtype glioblastoma that underwent surgery were analyzed. The intensity of intraoperative 5-ALA fluorescence was categorized as non-visible or visible. DNA was extracted from tumors and genome-wide DNA methylation patterns were analyzed using Illumina EPIC (850k) arrays. Furthermore, 5-ALA intensity was measured by flow cytometry on human gliomasphere lines (BT112 and BT145).Of 74 included patients, 12 (16.2%) patients had a non-fluorescent glioblastoma, which were compared to 62 glioblastomas with 5-ALA fluorescence. Clinical characteristics were equally distributed between both groups. We did not find significant differences between DNA methylation subclasses and 5-ALA fluorescence (P = .24). The distribution of cells of the tumor microenvironment was not significantly different between the non-fluorescent and fluorescent tumors. Copy number variations in EGFR and simultaneous EGFRvIII expression were strongly associated with 5-ALA fluorescence since all non-fluorescent glioblastomas were EGFR-amplified (P < .01). This finding was also demonstrated in recurrent tumors. Similarly, EGFR-amplified glioblastoma cell lines showed no 5-ALA fluorescence after 24 h of incubation.Our study demonstrates an association between non-fluorescent IDH-wildtype glioblastomas and EGFR gene amplification which should be taken into consideration for recurrent surgery and future studies investigating EGFR-amplified gliomas.

  View details for DOI 10.1093/nop/npad025

  View details for PubMedID 37720395

  View details for PubMedCentralID PMC10502788

• Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis. World neurosurgery Findlay, M. C., Drexler, R., Azab, M., Karbe, A., Rotermund, R., Ricklefs, F. L., Flitsch, J., Smith, T. R., Kilgallon, J. L., Honegger, J., Nasi-Kordhishti, I., Gardner, P. A., Gersey, Z. C., Abdallah, H. M., Jane, J. A., Marino, A. C., Knappe, U. J., Uksul, N., Rzaev, J. A., Bervitskiy, A. V., Schroeder, H. W., Eördögh, M., Losa, M., Mortini, P., Gerlach, R., Antunes, A. C., Couldwell, W. T., Budohoski, K. P., Rennert, R. C., Karsy, M. 2023

  Abstract

  Crooke cell adenomas (CCA) are a rare, aggressive subset of adrenocorticotrophin secreting pituitary corticotroph adenomas (sCTA) found in 5-10% of patients with Cushing's disease. Multiple studies support worse outcomes in CCA but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers.Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included.2826 patients from 12 international centers were compared (n=20 CCA and n=480 sCTA). No difference in baseline demographics, tumor characteristics or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection (GTR) was higher in CCA patients (100% vs. 83%, p=0.05). Among patients that had GTR according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, p<0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, p<0.01). This was present despite CCA having better local control rates (100% vs. 96%, p<0.01) and fewer patients with remnant on MRI (0% vs. 7.2%, p<0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients.This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced post-surgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches.

  View details for DOI 10.1016/j.wneu.2023.09.076

  View details for PubMedID 37757948

• Global Outcomes for Microsurgical Clipping of Unruptured Intracranial Aneurysms: A Benchmark Analysis of 2245 Cases. Neurosurgery Drexler, R., Sauvigny, T., Pantel, T. F., Ricklefs, F. L., Catapano, J. S., Wanebo, J. E., Lawton, M. T., Sanchin, A., Hecht, N., Vajkoczy, P., Raygor, K., Tonetti, D., Abla, A., El Naamani, K., Tjoumakaris, S. I., Jabbour, P., Jankowitz, B. T., Salem, M. M., Burkhardt, J. K., Wagner, A., Wostrack, M., Gempt, J., Meyer, B., Gaub, M., Mascitelli, J. R., Dodier, P., Bavinzski, G., Roessler, K., Stroh, N., Gmeiner, M., Gruber, A., Figueiredo, E. G., da Silva Coelho, A. C., Bervitskiy, A. V., Anisimov, E. D., Rzaev, J. A., Krenzlin, H., Keric, N., Ringel, F., Park, D., Kim, M. C., Marcati, E., Cenzato, M., Westphal, M., Dührsen, L. 2023

  Abstract

  Benchmarks represent the best possible outcome and help to improve outcomes for surgical procedures. However, global thresholds mirroring an optimal and reachable outcome for microsurgical clipping of unruptured intracranial aneurysms (UIA) are not available. This study aimed to define standardized outcome benchmarks in patients who underwent clipping of UIA.A total of 2245 microsurgically treated UIA from 15 centers were analyzed. Patients were categorized into low- ("benchmark") and high-risk ("nonbenchmark") patients based on known factors affecting outcome. The benchmark was defined as the 75th percentile of all centers' median scores for a given outcome. Benchmark outcomes included intraoperative (eg, duration of surgery, blood transfusion), postoperative (eg, reoperation, neurological status), and aneurysm-related factors (eg, aneurysm occlusion). Benchmark cutoffs for aneurysms of the anterior communicating/anterior cerebral artery, middle cerebral artery, and posterior communicating artery were determined separately.Of the 2245 cases, 852 (37.9%) patients formed the benchmark cohort. Most operations were performed for middle cerebral artery aneurysms (53.6%), followed by anterior communicating and anterior cerebral artery aneurysms (25.2%). Based on the results of the benchmark cohort, the following benchmark cutoffs were established: favorable neurological outcome (modified Rankin scale ≤2) ≥95.9%, postoperative complication rate ≤20.7%, length of postoperative stay ≤7.7 days, asymptomatic stroke ≤3.6%, surgical site infection ≤2.7%, cerebral vasospasm ≤2.5%, new motor deficit ≤5.9%, aneurysm closure rate ≥97.1%, and at 1-year follow-up: aneurysm closure rate ≥98.0%. At 24 months, benchmark patients had a better score on the modified Rankin scale than nonbenchmark patients.This study presents internationally applicable benchmarks for clinically relevant outcomes after microsurgical clipping of UIA. These benchmark cutoffs can serve as reference values for other centers, patient registries, and for comparing the benefit of other interventions or novel surgical techniques.

  View details for DOI 10.1227/neu.0000000000002689

  View details for PubMedID 37732745

• In Reply: A Multicenter, Propensity Score-Matched Assessment of Endoscopic Versus Microscopic Approaches in the Management of Pituitary Adenomas. Neurosurgery Findlay, M. C., Drexler, R., Karsy, M. 2023

  View details for DOI 10.1227/neu.0000000000002657

  View details for PubMedID 37668399

• Defining Benchmark Outcomes for Transsphenoidal Surgery of Pituitary Adenomas: A Multicenter Analysis. European journal of endocrinology Drexler, R., Rotermund, R., Smith, T. R., Kilgallon, J. L., Honegger, J., Nasi-Kordhishti, I., Gardner, P. A., Gersey, Z. C., Abdallah, H. M., Jane, J. A., Marino, A. C., Knappe, U. J., Uksul, N., Rzaev, J. A., Galushko, E. V., Gormolysova, E. V., Bervitskiy, A. V., Schroeder, H. W., Eördögh, M., Losa, M., Mortini, P., Gerlach, R., Azab, M., Budohoski, K. P., Rennert, R. C., Karsy, M., Couldwell, W. T., Antunes, A. C., Westphal, M., Ricklefs, F. L., Flitsch, J. 2023

  Abstract

  Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available. We aimed to establish standardized outcome benchmarks for transsphenoidal surgery of pituitary adenomas.A total of 2685 transsphenoidal tumor resections from 9 expert centers in 3 continents were analyzed. Patients were risk stratified and the median values of each center's outcomes were established. The benchmark was defined as the 75th percentile of all median values for a particular outcome. The postoperative benchmark outcomes included surgical factors, endocrinology-specific values, and neurology-specific values.Of 2685 patients, 1149 (42.8%) defined the low-risk benchmark cohort. Within these benchmark cases, 831 (72.3%) patients underwent microscopic (MTS) and 308 (26.8%) patients endoscopic endonasal resection (EES). Of all tumors, 799 (29.8%) cases invaded the cavernous sinus. The postoperative complication rate was 19.6% with a mortality between 0.0-0.8%. Benchmark cutoffs were ≤ 2.9% for reoperation rate, ≤ 1.9% for CSF leak requiring intervention, and ≤ 15.5% for transient diabetes insipidus. At 6 months, benchmark cutoffs were calculated as follows: readmission rate: ≤ 6.9%, new hypopituitarism ≤ 6.0%, and tumor remnant ≤ 19.2%.This analysis defines benchmark values for TS targeting morbidity and mortality and represent the best outcomes in the best patients in expert centers. These cutoffs can be used to assess different centers, patients' populations, and novel surgical techniques. It should be noted that the benchmark values may influence each other and must be evaluated in their own context.

  View details for DOI 10.1093/ejendo/lvad124

  View details for PubMedID 37668325

• Grade 3 meningioma survival and recurrence outcomes in an international multicenter cohort. Journal of neurosurgery Tosefsky, K., Rebchuk, A. D., Wang, J. Z., Ellenbogen, Y., Drexler, R., Ricklefs, F. L., Sauvigny, T., Schüller, U., Cutler, C. B., Lucke-Wold, B., Mehkri, Y., Lama, S., Sutherland, G. R., Karsy, M., Hoh, B. L., Westphal, M., Zadeh, G., Yip, S., Makarenko, S. 2023: 1-11

  Abstract

  Grade 3 meningioma represents a rare meningioma subtype, for which limited natural history data are available. The objective of this study was to identify demographics and pathologic characteristics, clinical and functional status outcomes, and prognostic factors in an international cohort of grade 3 meningioma patients.Clinical and histopathological data were collected for patients treated at 7 sites across North America and Europe between 1991 and 2022.A total of 103 patients (54% female, median age 65 [IQR 52, 72] years) were included. Sixty-seven (65%) patients had de novo grade 3 lesions, whereas 29 (28%) had malignant transformations of lower-grade meningiomas. All patients underwent initial resection of their tumor. Patients were followed for a median of 46 (IQR 24, 108) months, during which time there were 65 (73%) recurrences and 50 (49%) deaths. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 66% (95% CI 56%-77%) and 37% (95% CI 28%-48%), respectively. Age ≥ 65 years and male sex were independent predictors of worse OS and PFS in multivariate regression analysis, while postoperative radiotherapy was independently associated with improved OS. Karnofsky Performance Status (KPS) remained stable relative to baseline over 5 years postdiagnosis among participants who were alive at the end of the follow-up period.This large multicenter study provides insight into the longitudinal outcomes of grade 3 meningioma, with respect to recurrence, survival, and functional status. This study affirms the survival benefit conferred by radiotherapy in this population and suggests good functional status outcomes for patients surviving to 5 years postoperatively.

  View details for DOI 10.3171/2023.6.JNS23465

  View details for PubMedID 37877968

• Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability. bioRxiv : the preprint server for biology Drexler, R., Khatri, R., Sauvigny, T., Mohme, M., Maire, C. L., Ryba, A., Zghaibeh, Y., Dührsen, L., Salviano-Silva, A., Lamszus, K., Westphal, M., Gempt, J., Wefers, A. K., Neumann, J., Bode, H., Hausmann, F., Huber, T. B., Bonn, S., Jütten, K., Delev, D., Weber, K. J., Harter, P. N., Onken, J., Vajkoczy, P., Capper, D., Wiestler, B., Weller, M., Snijder, B., Buck, A., Weiss, T., Keough, M. B., Ni, L., Monje, M., Silverbush, D., Hovestadt, V., Suvà, M. L., Krishna, S., Hervey-Jumper, S. L., Schüller, U., Heiland, D. H., Hänzelmann, S., Ricklefs, F. L. 2023

  Abstract

  Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.

  View details for DOI 10.1101/2023.08.04.552017

  View details for PubMedID 37609137

  View details for PubMedCentralID PMC10441357

• Association of the classification of intraoperative adverse events (ClassIntra) with complications and neurological outcome after neurosurgical procedures: a prospective cohort study. Acta neurochirurgica Drexler, R., Ricklefs, F. L., Pantel, T., Göttsche, J., Nitzschke, R., Zöllner, C., Westphal, M., Dührsen, L. 2023

  Abstract

  To analyze the reliability of the classification of intraoperative adverse events (ClassIntra) to reflect intraoperative complications of neurosurgical procedures and the potential to predict the postoperative outcome including the neurological performance. The ClassIntra classification was recently introduced and found to be reliable for assessing intraoperative adverse events and predicting postoperative complications across different surgical disciplines. Nevertheless, its potential role for neurosurgical procedures remains elusive.This is a prospective, monocentric cohort study assessing the ClassIntra in 422 adult patients who underwent a neurosurgical procedure and were hospitalized between July 1, 2021, to December 31, 2021. The primary outcome was the occurrence of intraoperative complications graded according to ClassIntra and the association with postoperative outcome reflected by the Clavien-Dindo classification and comprehensive complication index (CCI). The ClassIntra is defined as intraoperative adverse events as any deviation from the ideal course on a grading scale from grade 0 (no deviation) to grade V (intraoperative death) and was set at sign-out in agreement between neurosurgeon and anesthesiologist. Secondary outcomes were the neurological outcome after surgery as defined by Glasgow Coma Scale (GCS), modified Rankin scale (mRS), Neurologic Assessment in Neuro-Oncology (NANO) scale, National Institute Health of Strokes Scale (NIHSS), and Karnofsky Performance Score (KPS), and need for unscheduled brain scan.Of 442 patients (mean [SD] age, 56.1 [16.2]; 235 [55.7%] women and 187 [44.3%] men) who underwent a neurosurgical procedure, 169 (40.0%) patients had an intraoperative adverse event (iAE) classified as ClassIntra I or higher. The NIHSS score at admission (OR, 1.29; 95% CI, 1.03-1.63, female gender (OR, 0.44; 95% CI, 0.23-0.84), extracranial procedures (OR, 0.17; 95% CI, 0.08-0.61), and emergency cases (OR, 2.84; 95% CI, 1.53-3.78) were independent risk factors for a more severe iAE. A ClassIntra ≥ II was associated with increased odds of postoperative complications classified as Clavien-Dindo (p < 0.01), neurological deterioration at discharge (p < 0.01), prolonged hospital (p < 0.01), and ICU stay (p < 0.01). For elective craniotomies, severity of ClassIntra was associated with the CCI (p < 0.01) and need for unscheduled CT or MRI scan (p < 0.01). The proportion of a ClassIntra ≥ II was significantly higher for emergent craniotomies (56.2%) and associated with in-hospital mortality, and an unfavorable neurological outcome (p < 0.01).Findings of this study suggest that the ClassIntra is sensitive for assessing intraoperative adverse events and sufficient to identify patients with a higher risk for developing postoperative complications after a neurosurgical procedure.

  View details for DOI 10.1007/s00701-023-05672-w

  View details for PubMedID 37407852

  View details for PubMedCentralID 1360123

• A Multicenter, Propensity Score-Matched Assessment of Endoscopic Versus Microscopic Approaches in the Management of Pituitary Adenomas. Neurosurgery Findlay, M. C., Drexler, R., Khan, M., Cole, K. L., Karbe, A., Rotermund, R., Ricklefs, F. L., Flitsch, J., Smith, T. R., Kilgallon, J. L., Honegger, J., Nasi-Kordhishti, I., Gardner, P. A., Gersey, Z. C., Abdallah, H. M., Jane, J. A., Marino, A. C., Knappe, U. J., Uksul, N., Rzaev, J. A., Galushko, E. V., Gormolysova, E. V., Bervitskiy, A. V., Schroeder, H. W., Eordogh, M., Losa, M., Mortini, P., Gerlach, R., Antunes, A. C., Couldwell, W. T., Budohoski, K. P., Rennert, R. C., Azab, M., Karsy, M. 2023

  Abstract

  BACKGROUND: There is considerable controversy as to which of the 2 operating modalities (microsurgical or endoscopic transnasal surgery) currently used to resect pituitary adenomas (PAs) is the safest and most effective intervention.OBJECTIVE: To compare rates of clinical outcomes of patients with PAs who underwent resection by either microsurgical or endoscopic transnasal surgery.METHODS: To independently assess the outcomes of each modality type, we sought to isolate endoscopic and microscopic PA surgeries with a 1:1 tight-caliper (0.01) propensity score-matched analysis using a multicenter, neurosurgery-specific database. Surgeries were performed between 2017 and 2020, with data collected retrospectively from 12 international institutions on 4 continents. Matching was based on age, previous neurological deficit, American Society of Anesthesiologists (ASA) score, tumor functionality, tumor size, and Knosp score. Univariate and multivariate analyses were performed.RESULTS: Among a pool of 2826 patients, propensity score matching resulted in 600 patients from 9 surgery centers being analyzed. Multivariate analysis showed that microscopic surgery had a 1.91 odds ratio (OR) (P = .03) of gross total resection (GTR) and shorter operative duration (P < .01). However, microscopic surgery also had a 7.82 OR (P < .01) for intensive care unit stay, 2.08 OR (P < .01) for intraoperative cerebrospinal fluid (CSF) leak, 2.47 OR (P = .02) for postoperative syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was an independent predictor for longer postoperative stay (beta = 2.01, P < .01). Overall, no differences in postoperative complications or 3- to 6-month outcomes were seen by surgical approach.CONCLUSION: Our international, multicenter matched analysis suggests microscopic approaches for pituitary tumor resection may offer better GTR rates, albeit with increased intensive care unit stay, CSF leak, SIADH, and hospital utilization. Better prospective studies can further validate these findings as matching patients for outcome analysis remains challenging. These results may provide insight into surgical benchmarks at different centers, offer room for further registry studies, and identify best practices.

  View details for DOI 10.1227/neu.0000000000002497

  View details for PubMedID 37057921

• Targeted anticonvulsive treatment of IDH-wildtype glioblastoma based on DNA methylation subclasses. Neuro-oncology Drexler, R., Göttsche, J., Sauvigny, T., Schüller, U., Khatri, R., Hausmann, F., Hänzelmann, S., Huber, T. B., Bonn, S., Heiland, D. H., Delev, D., Venkataramani, V., Winkler, F., Weller, J., Zeyen, T., Herrlinger, U., Gempt, J., Ricklefs, F. L., Dührsen, L. 2023

  View details for DOI 10.1093/neuonc/noad014

  View details for PubMedID 36860191

• Impact of the SARS-CoV-2 pandemic on the survival of patients with high-grade glioma and best practice recommendations. Scientific reports Vogel, M. M., Wagner, A., Gempt, J., Krenzlin, H., Zeyen, T., Drexler, R., Voss, M., Nettekoven, C., Abboud, T., Mielke, D., Rohde, V., Timmer, M., Goldbrunner, R., Steinbach, J. P., Dührsen, L., Westphal, M., Herrlinger, U., Ringel, F., Meyer, B., Combs, S. E. 2023; 13 (1): 2766

  Abstract

  The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has changed the clinical day-to-day practice. The aim of this study was to evaluate the impact of the pandemic on patients with high-grade glioma (HGG) as well as to derive best practice recommendations. We compared a multi-institutional cohort with HGG (n = 251) from 03/2020 to 05/2020 (n = 119) to a historical cohort from 03/2019 to 05/2019 (n = 132). The endpoints were outcome (progression-free survival (PFS) and overall survival (OS)) as well as patterns of care and time intervals between treatment steps. The median OS for WHO grade 4 gliomas was 12 months in 2019 (95% Confidence Interval 9.7-14.3 months), and not reached in 2020 (p = .026). There were no other significant differences in the Kaplan-Meier estimates for OS and PFS between cohorts of 2019 and 2020, neither did stratification by WHO grade reveal any significant differences for OS, PFS or for patterns of care. The time interval between cranial magnetic resonance imaging (cMRI) and biopsy was significantly longer in 2020 cohort (11 versus 21 days, p = .031). Median follow-up was 10 months (range 0-30 months). Despite necessary disease containment policies, it is crucial to ensure that patients with HGG are treated in line with the recent guidelines and standard of care (SOC) algorithms. Therefore, we strongly suggest pursuing no changes to SOC treatment, a timely diagnosis and treatment with short time intervals between first symptoms, initial diagnosis, and treatment, as well as a guideline-based cMRI follow-up.

  View details for DOI 10.1038/s41598-023-29790-8

  View details for PubMedID 36797335

  View details for PubMedCentralID PMC9933015

• DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients. Neuro-oncology Drexler, R., Schüller, U., Eckhardt, A., Filipski, K., Hartung, T. I., Harter, P. N., Divé, I., Forster, M. T., Czabanka, M., Jelgersma, C., Onken, J., Vajkoczy, P., Capper, D., Siewert, C., Sauvigny, T., Lamszus, K., Westphal, M., Dührsen, L., Ricklefs, F. L. 2023; 25 (2): 315-325

  Abstract

  DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive.Multicentric cohort study including 430 patients with newly diagnosed glioblastoma subjected to global DNA methylation profiling. Outcome measures included overall survival (OS), progression-free survival (PFS), prognostic relevance of EOR and MGMT promoter methylation status as well as a surgical benefit for recurrent glioblastoma.345 patients (80.2%) fulfilled the inclusion criteria and 305 patients received combined adjuvant therapy. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (RTK I: Ref.; RTK II: HR 0.9 [95% CI, 0.64-1.28]; p = 0.56; MES: 0.69 [0.47-1.02]; p = 0.06). Patients with RTK I (GTR/near GTR: Ref.; PR: HR 2.87 [95% CI, 1.36-6.08]; p < 0.01) or RTK II (GTR/near GTR: Ref.; PR: HR 5.09 [95% CI, 2.80-9.26]; p < 0.01) tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients. The MES subclass showed no survival benefit for a maximized EOR (GTR/near GTR: Ref.; PR: HR 1.45 [95% CI, 0.68-3.09]; p = 0.33). Therapy response predictive value of MGMT promoter methylation was evident for RTK I (HR 0.37 [95% CI, 0.19-0.71]; p < 0.01) and RTK II (HR 0.56 [95% CI, 0.34-0.91]; p = 0.02) but not the MES subclass (HR 0.52 [95% CI, 0.27-1.02]; p = 0.06). For local recurrence (n = 112), re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in RTK I (p = 0.03) and RTK II (p < 0.01) tumors, but not in MES tumors (p = 0.33).We demonstrate a survival benefit from maximized EOR for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II but not the MES subclass. Hence, it needs to be debated whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.

  View details for DOI 10.1093/neuonc/noac177

  View details for PubMedID 35868257

  View details for PubMedCentralID PMC9925709

• Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and EGFR amplification in IDH -wildtype glioblastoma Neuro-Oncology Practice Drexler, R., Sauvigny, T., Schüller, U., Eckhardt, A., Maire, C., Khatri, R., Hausmann, F., Hänzelmann, S., Huber, T., Bonn, S., Bode, H., Lamszus, K., Westphal, M., Dührsen, L., Ricklefs, F. L. 2023

  View details for DOI 10.1093/nop/npad025

• DNA methylation subclass receptor tyrosine kinase II (RTK II) is predictive for seizure development in glioblastoma patients. Neuro-oncology Ricklefs, F. L., Drexler, R., Wollmann, K., Eckhardt, A., Heiland, D. H., Sauvigny, T., Maire, C., Lamszus, K., Westphal, M., Schüller, U., Dührsen, L. 2022; 24 (11): 1886-1897

  Abstract

  Seizures can present at any time before or after the diagnosis of a glioma. Roughly, 25%-30% of glioblastoma (GBM) patients initially present with seizures, and an additional 30% develop seizures during the course of the disease. Early studies failed to show an effect of general administration of antiepileptic drugs for glioblastoma patients, since they were unable to stratify patients into high- or low-risk seizure groups.111 patients, who underwent surgery for a GBM, were included. Genome-wide DNA methylation profiling was performed, before methylation subclasses and copy number changes inferred from methylation data were correlated with clinical characteristics. Independently, global gene expression was analyzed in GBM methylation subclasses from TCGA datasets (n = 68).Receptor tyrosine Kinase (RTK) II GBM showed a significantly higher incidence of seizures than RTK I and mesenchymal (MES) GBM (P < .01). Accordingly, RNA expression datasets revealed an upregulation of genes involved in neurotransmitter synapses and vesicle transport in RTK II glioblastomas. In a multivariate analysis, temporal location (P = .02, OR 5.69) and RTK II (P = .03, OR 5.01) were most predictive for preoperative seizures. During postoperative follow-up, only RTK II remained significantly associated with the development of seizures (P < .01, OR 8.23). Consequently, the need for antiepileptic medication and its increase due to treatment failure was highly associated with the RTK II methylation subclass (P < .01).Our study shows a strong correlation of RTK II glioblastomas with preoperative and long-term seizures. These results underline the benefit of molecular glioblastoma profiling with important implications for postoperative seizure control.

  View details for DOI 10.1093/neuonc/noac108

  View details for PubMedID 35511473

  View details for PubMedCentralID PMC9629427

• The Comprehensive Complication Index (CCI) as a Measure of Postoperative Morbidity and Neurological Outcome after Elective Intracranial Surgery. Journal of neurological surgery. Part A, Central European neurosurgery Drexler, R., Ricklefs, F. L., Pantel, T. F., Göttsche, J., Westphal, M., Dührsen, L. 2022

  Abstract

  The Comprehensive Complication Index (CCI) is a numerical scale based on the Clavien-Dindo classification (CDC) and both are widely used to assess outcome. However, the CCI had not been described for neurosurgical procedures.We aimed to investigate the value of the CCI to predict outcome in patients who underwent elective intracranial surgery.Prospective cohort study including patients who underwent elective intracranial surgery. Complications were graded using CDC, and the CCI was calculated daily. Neurological outcome was assessed using mRS, NANO, NIHSS, and KPS.Of 294 patients who underwent an elective intracranial procedure, 211 (71.8%) patients underwent a craniotomy, while 28 (9.5%) patients had a burr hole procedure and 55 (18.7%) patients a transsphenoidal approach. A higher blood loss was the only significant predictor for a higher CCI (OR 1.09, 95% CI 1.00-1.12, P < 0.01). Patients with a higher CCI had a longer LOS (mean: 5.4 versus 10.9 days, P < 0.01) and ICU stay (mean: 0.8 versus 2.4 days, P < 0.01). Daily CCI revealed a risk for complications after craniotomies until postoperative day (POD) 7. In patients who underwent brain tumor surgery, the resection of meningiomas and metastasis showed a similar developmental course of CCI. A significantly higher CCI was observed in patients who had a neurological deterioration at discharge ( P < 0.01).CCI is a valid scale to measure outcome after intracranial procedures and correlates with neurological outcome. Risk for adverse events after craniotomy is at highest until postoperative day 7.

  View details for DOI 10.1055/a-1962-0636

  View details for PubMedID 36252766

• Single-Center Experience Using a 3D4K Digital Operating Scope System for Aneurysm Surgery. Operative neurosurgery (Hagerstown, Md.) Pantel, T., Drexler, R., Göttsche, J., Piffko, A., Westphal, M., Regelsberger, J., Dührsen, L. 2022; 22 (6): 433-439

  Abstract

  In recent years, 3D4K exoscope systems (EXs) have been introduced to microneurosurgery and reported to be an alternative to conventional operating microscopes (OMs). This study reviews our single-center experience using an 3D4K EX in intracranial aneurysm surgery.To investigate the applicability of a novel 3D4K EX for intracranial aneurysm surgery.A retrospective analysis of patients who underwent microsurgical repair of incidentally or ruptured cerebral aneurysms between August 2018 and August 2020 was performed. Patient and aneurysm characteristics and technical features, including 3-dimensional indocyanine green fluorescence, were evaluated. Data on surgery duration were statically assessed for a time trend and comparability with the OM cohort.Overall, we collected 185 aneurysm cases in which the exoscope was used in 44 cases. The mean duration of surgery using the EX was in similar range to those using the OM (165.5 ± 45.8 minutes vs 160.5 ± 39.2 minutes, P > .05). Routine postoperative computed tomography angiography showed comparable rates of complete aneurysm occlusion (95.5% vs 92.2%, P > .05) and postoperative complications (9.1% vs 9.7%, P > .05). There was no necessity to revert to the OM from the EX. Three-dimensional indocyanine green fluorescence was used in all procedures without any malfunction.The 3D4K EX for vascular microsurgical cases proved to be as useful as the OM. Because of the ease of use and comparable surgical results, the EX has the potential to become an accepted and additional visualization tool in vascular microsurgery next to the OM.

  View details for DOI 10.1227/ons.0000000000000150

  View details for PubMedID 35383707

• Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry. Frontiers in neurology Drexler, R., Ben-Haim, S., Bien, C. G., Borger, V., Cardinale, F., Carpentier, A., Cendes, F., Chandra, S., Clusmann, H., Colon, A., de Curtis, M., Delev, D., Didato, G., Dührsen, L., Farah, J. O., Guenot, M., Ghatan, S., Haegelen, C., Hamer, H., Hauptmann, J. S., Jeffree, R. L., Kalbhenn, T., Kegele, J., Krayenbühl, N., Lang, J., Mathon, B., Naros, G., Onken, J., Panov, F., Raftopoulos, C., Ricklefs, F. L., Rijkers, K., Rizzi, M., Rössler, K., Schijns, O., Schneider, U. C., Spyrantis, A., Strzelczyk, A., Stodieck, S., Tripathi, M., Vadera, S., Alonso-Vanegas, M. A., Vaz, J. G., Wellmer, J., Wehner, T., Westphal, M., Sauvigny, T. 2021; 12: 782666

  Abstract

  Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298).

  View details for DOI 10.3389/fneur.2021.782666

  View details for PubMedID 34966349

  View details for PubMedCentralID PMC8710656

• Impact of acute kidney injury after extended liver resections. HPB : the official journal of the International Hepato Pancreato Biliary Association Reese, T., Kröger, F., Makridis, G., Drexler, R., Jusufi, M., Schneider, M., Brüning, R., von Rittberg, Y., Wagner, K. C., Oldhafer, K. J. 2021; 23 (7): 1000-1007

  Abstract

  Complex liver resection is a risk factor for the development of AKI, which is associated with increased morbidity and mortality. Aim of this study was to assess risk factors for acute kidney injury (AKI) and its impact on outcome for patients undergoing complex liver surgery.AKI was defined according to the KDIGO criteria. Primary endpoint was the occurrence of AKI after liver resection. Secondary endpoints were complications and mortality.Overall, 146 patients undergoing extended liver resection were included in the study. The incidence of AKI was 21%. The incidence of chronic kidney disease (CKD) and hepatocellular carcinoma were significantly higher in patients with AKI. In the AKI group, the proportion of extended right hepatectomies was the highest (53%), followed by ALPPS (43%). Increased intraoperative blood loss, increased postoperative complications and perioperative mortality was associated with AKI. Besides age and CKD, ALPPS was an independent risk factor for postoperative AKI. A small future liver remnant seemed to increase the risk of AKI in patients undergoing ALPPS.Following extended liver resection, AKI is associated with an increased morbidity and mortality. ALPPS is a major independent risk factor for the development of AKI and a sufficient future liver remnant could avoid postoperative AKI.

  View details for DOI 10.1016/j.hpb.2020.10.015

  View details for PubMedID 33191106

• The clinical relevance of the Hippo pathway in pancreatic ductal adenocarcinoma. Journal of cancer research and clinical oncology Drexler, R., Küchler, M., Wagner, K. C., Reese, T., Feyerabend, B., Kleine, M., Oldhafer, K. J. 2021; 147 (2): 373-391

  Abstract

  The Hippo pathway has broadened in cancer research in the past decade and revealed itself to be an important driver for tumorigenesis and metastatic spread. In this study, we investigated the clinical relevance of the Hippo pathway with regard to metastatic invasion, patients' outcome and histopathological features.Protein expression of components of the Hippo pathway were analyzed by immunohistochemistry (IHC) using paraffin-embedded tissue from 103 patients who had been diagnosed with pancreatic ductal adenocarcinoma and had undergone surgery. Results were correlated with clinicopathological data, disease-free and overall survival.Immunohistochemistry studies in pancreatic tumour tissues revealed a significant upregulation of MST1, MST2, pLATS, pYAP and 14-3-3, representing the active Hippo pathway, in non-metastasized patients (p < 0.01). In turn, the pathway is more inactive in metastasized patients and relating liver metastases as LATS1, LATS2, YAP, transcriptional factors TEAD2 and TEAD3 were upregulated in these patients (p < 0.01). A higher pYAP expression was associated with a favorable OS and DFS.The Hippo pathway is inactive in metastasized patients releasing the pro-metastatic and proliferative potential of the pathway. Furthermore, our study underlines the prognostic relevance of the Hippo pathway as a shift in the balance towards the inactive pathway predicts an unfavorable OS and DFS.

  View details for DOI 10.1007/s00432-020-03427-z

  View details for PubMedID 33098447

  View details for PubMedCentralID PMC7817599

• Association of subcellular localization of TEAD transcription factors with outcome and progression in pancreatic ductal adenocarcinoma. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] Drexler, R., Fahy, R., Küchler, M., Wagner, K. C., Reese, T., Ehmke, M., Feyerabend, B., Kleine, M., Oldhafer, K. J. 2021; 21 (1): 170-179

  Abstract

  Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive.A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival.Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival.Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.

  View details for DOI 10.1016/j.pan.2020.12.003

  View details for PubMedID 33317954

• Establishing a student-run free clinic in a major city in Northern Europe: a 1-year experience from Hamburg, Germany. Journal of public health (Oxford, England) Drexler, R., Fröschle, F., Predel, C., Sturm, B., Ustorf, K., Lehner, L., Janzen, J., Valentin, L., Scheer, T., Lehnert, F., Tadzic, R., Oldhafer, K. J., Meyer, T. N. 2020; 42 (4): 793-798

  Abstract

  Student-Run Free Clinics (SRFCs) have been an integral part of US medical schools since the 1960s and provide health care to underserved populations. In 2018, we established an SRFC in Hamburg, Germany, a major city in Northern Europe. The aim of this study was to describe the central problems and to investigate the usefulness of an SRFC in a country with free access to medical care, such as Germany.All consecutive patients treated at the SRFC Hamburg between February 2018 and March 2019 that consented to this study were analyzed regarding clinical characteristics, diagnosis, readmission rate and country of origin.Between February 2018 and March 2019, 229 patients were treated at the SRFC in Hamburg. The patients came from 33 different countries with a majority (n = 206, 90%) from countries inside the European Union. The most common reasons for visiting the SRFC were infections (23.2%), acute or chronic wounds (13.5%) and fractures (6.3%).Our multicultural patients suffer mainly from infections and traumatological and dermatological diseases. We find similarities to published Canadian SRFC patient cohorts but differences in diseases and treatment modalities compared to US SRFCs. Importantly, we demonstrate the relevance and necessity of the SRFC in a major city in Northern Europe.

  View details for DOI 10.1093/pubmed/fdz165

  View details for PubMedID 31840742

  View details for PubMedCentralID PMC7685854

• Involvement of Medical Students During the Coronavirus Disease 2019 Pandemic: A Cross-Sectional Survey Study. Cureus Drexler, R., Hambrecht, J. M., Oldhafer, K. J. 2020; 12 (8): e10147

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic affects the education of medical students around the world and countries have had differing responses in dealing with this dynamic situation. The role of medical students in fighting this pandemic is controversial and it is yet to be elucidated how they can best be of service. The aim of this study is to evaluate the working fields of volunteering students and the impact of the pandemic on final year students from a student's perspective.An anonymous online survey was conducted amongst 219 medical students from Hamburg (Germany), using an institutional online data collection program.A total of 137 questionnaires (63.5%) were completed. Of these, 97 participants were students from academic year three to five (70.8%) and 40 students were in the final year of medical school (29.2%). Of the 97 students from academic year three to five, 68 students (70.1%) signed up for voluntary duties during the pandemic. Interestingly, only 25.0% of the students were called for voluntary work in hospitals or health authorities. Final year students had already been working in hospitals since before the outbreak, with 35.0% of them assisting doctors in the treatment of COVID-19 positive patients during their placements. Using a 5-Point Likert Scale, the students who volunteered self-assessed their work as more useful and received more gratitude than final year students (p<0.01).The majority of medical students are willing to make a significant contribution in the response to COVID-19 and do not wish to be overlooked. Furthermore, the current pandemic offers novel educational opportunities for medical students.

  View details for DOI 10.7759/cureus.10147

  View details for PubMedID 33014645

  View details for PubMedCentralID PMC7526758

• Significance of unphosphorylated and phosphorylated heat shock protein 27 as a prognostic biomarker in pancreatic ductal adenocarcinoma. Journal of cancer research and clinical oncology Drexler, R., Wagner, K. C., Küchler, M., Feyerabend, B., Kleine, M., Oldhafer, K. J. 2020; 146 (5): 1125-1137

  Abstract

  Few studies reported about the potential of unphosphorylated heat shock protein 27 (HSP27) and phosphorylated heat shock protein 27 (pHSP27) as a predictor for survival and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we analysed the expression patterns of pHSP27 and HSP27 in a patient population after surgery and correlated the immunohistochemical results with clinicopathological data and long-term outcome of the patients.HSP27 and pHSP27 (Ser-15, Ser-78 and Ser-82) protein expression were analysed by immunohistochemistry using the immunoreactive score (IRS) from paraffin-embedded tissue of 106 patients with PDAC who underwent surgery. Immunohistochemical results were correlated with clinicopathological data, disease-free (DFS) and overall survival (OS).HSP27 expression was significantly lower in patients with a shorter OS (p = 0.006) and DFS (p < 0.0001). A higher HSP27 expression was associated with a better response to gemcitabine in the resected, non-metastasised patients group (p = 0.001). Furthermore, HSP27 was downregulated in patients suffering from metastases at time of surgery (p < 0.001) and in undifferentiated tumours (p = 0.007). In contrast, pHSP27-Ser15, -Ser78 and -Ser82 were not associated with any survival data of the study population.HSP27 seems to be a strong indicator for the prediction of OS and DFS. Moreover, HSP27 could play a role in the formation and migration of liver metastases of PDAC.

  View details for DOI 10.1007/s00432-020-03175-0

  View details for PubMedID 32200459

  View details for PubMedCentralID PMC7142055