Resolving spatial response heterogeneity in glioblastoma.

PURPOSE: Spatial intratumoral heterogeneity poses a significant challenge for accurate response assessment in glioblastoma. Multimodal imaging coupled with advanced image analysis has the potential to unravel this response heterogeneity. METHODS: Based on automated tumor segmentation and longitudinal registration with follow-up imaging, we categorized contrast-enhancing voxels of 61 patients with suspected recurrence of glioblastoma into either true tumor progression (TP) or pseudoprogression (PsP). To allow the unbiased analysis of semantically related image regions, adjacent voxels with similar values of cerebral blood volume (CBV), FET-PET, and contrast-enhanced T1w were automatically grouped into supervoxels. We then extracted first-order statistics as well as texture features from each supervoxel. With these features, a Random Forest classifier was trained and validated employing a 10-fold cross-validation scheme. For model evaluation, the area under the receiver operating curve, as well as classification performance metrics were calculated. RESULTS: Our image analysis pipeline enabled reliable spatial assessment of tumor response. The predictive model reached an accuracy of 80.0% and a macro-weighted AUC of 0.875, which takes class imbalance into account, in the hold-out samples from cross-validation on supervoxel level. Analysis of feature importances confirmed the significant role of FET-PET-derived features. Accordingly, TP- and PsP-labeled supervoxels differed significantly in their 10th and 90th percentile, as well as the median of tumor-to-background normalized FET-PET. However, CBV- and T1c-related features also relevantly contributed to the model's performance. CONCLUSION: Disentangling the intratumoral heterogeneity in glioblastoma holds immense promise for advancing precise local response evaluation and thereby also informing more personalized and localized treatment strategies in the future.

Quantitative Assessment of Tumor Contact with Neurogenic Zones and Its Effects on Survival: Insights beyond Traditional Predictors.

So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult neurogenesis primarily occurs in two brain regions: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether the proximity of GBM to these neurogenic niches affects patient outcome remains uncertain. Previous studies often rely on subjective assessments, limiting the reliability of those results. In this study, we assessed the impact of GBM's relationship with the cortex, SVZ and SGZ on clinical variables using fully automated segmentation methods. In 177 glioblastoma patients, we calculated optimal cutpoints of minimal distances to the SVZ and SGZ to distinguish poor from favorable survival. The impact of tumor contact with neurogenic zones on clinical parameters, such as overall survival, multifocality, MGMT promotor methylation, Ki-67 and KPS score was also examined by multivariable regression analysis, chi-square test and Mann-Whitney-U. The analysis confirmed shorter survival in tumors contacting the SVZ with an optimal cutpoint of 14 mm distance to the SVZ, separating poor from more favorable survival. In contrast, tumor contact with the SGZ did not negatively affect survival. We did not find significant correlations with multifocality or MGMT promotor methylation in tumors contacting the SVZ, as previous studies discussed. These findings suggest that the spatial relationship between GBM and neurogenic niches needs to be assessed differently. Objective measurements disprove prior assumptions, warranting further research on this topic.

Comparative study of virus and lymphocyte distribution with clinical data suggests early high dose immunosuppression as potential key factor for the therapy of patients with BoDV-1 infection.

ABSTRACTBorna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies.ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1act: general activation of microglial cells; Iba1nod: formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; patearly: patients treated with early high dose steroid shot; patlate: patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum.

Adjuvant re-irradiation vs. no early re-irradiation of resected recurrent glioblastoma: pooled comparative cohort analysis from two tertiary centers.

BACKGROUND: The optimal management strategy for recurrent glioblastoma (rGBM) remains uncertain, and the impact of re-irradiation (Re-RT) on overall survival (OS) is still a matter of debate. This study included patients who achieved gross total resection (GTR) after a second surgery after recurrence, following the GlioCave criteria. METHODS: Inclusion criteria include being 18 years or older, having histologically confirmed locally recurrent IDHwt or IDH unknown GBM, achieving MRI-proven GTR after the second surgery, having a Karnofsky performance status of at least 60% after the second surgery, having a minimum interval of 6 months between the first radiotherapy and the second surgery, and a maximum of 8 weeks from second surgery to the start of Re-RT. RESULTS: A total of 44 patients have met the inclusion criteria. The median OS after the second surgery was 14 months. All patients underwent standard treatment after initial diagnosis, including maximum safe resection, adjuvant radiochemotherapy and adjuvant chemotherapy. Re-RT did not significantly impact OS. However, MGMT promoter methylation status and a longer interval (> 12 months) between treatments were associated with better OS. Multivariate analysis revealed the MGMT status as the only significant predictor of OS. CONCLUSION: Factors such as MGMT promoter methylation status and treatment interval play crucial roles in determining patient outcomes after second surgery. Personalized treatment strategies should consider these factors to optimize the management of rGBM. Prospective research is needed to define the value of re-RT after second surgery and to inform decision making in this situation.

Toward image-based personalization of glioblastoma therapy: A clinical and biological validation study of a novel, deep learning-driven tumor growth model.

Background: The diffuse growth pattern of glioblastoma is one of the main challenges for accurate treatment. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy. Here, we performed clinical and biological validation of a novel growth model, aiming to close the gap between the experimental state and clinical implementation. Methods: One hundred and twenty-four patients from The Cancer Genome Archive (TCGA) and 397 patients from the UCSF Glioma Dataset were assessed for significant correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration (Dw) as well as proliferation (ρ) parameters stemming from a Fisher-Kolmogorov growth model. To further evaluate clinical potential, we performed the same growth modeling on preoperative magnetic resonance imaging data from 30 patients of our institution and compared model-derived tumor volume and recurrence coverage with standard radiotherapy plans. Results: The parameter ratio Dw/ρ (P < .05 in TCGA) as well as the simulated tumor volume (P < .05 in TCGA/UCSF) were significantly inversely correlated with overall survival. Interestingly, we found a significant correlation between 11 proliferation pathways and the estimated proliferation parameter. Depending on the cutoff value for tumor cell density, we observed a significant improvement in recurrence coverage without significantly increased radiation volume utilizing model-derived target volumes instead of standard radiation plans. Conclusions: Identifying a significant correlation between computed growth parameters and clinical and biological data, we highlight the potential of tumor growth modeling for individualized therapy of glioblastoma. This might improve the accuracy of radiation planning in the near future.

Amino acid PET vs. RANO MRI for prediction of overall survival in patients with recurrent high grade glioma under bevacizumab therapy.

PURPOSE: To summarize evidence on the comparative value of amino acid (AA) PET and conventional MRI for prediction of overall survival (OS) in patients with recurrent high grade glioma (rHGG) under bevacizumab therapy. METHODS: Medical databases were screened for studies with individual data on OS, follow-up MRI, and PET findings in the same patient. MRI images were assessed according to the RANO criteria. A receiver operating characteristic curve analysis was used to predict OS at 9 months. RESULTS: Five studies with a total of 72 patients were included. Median OS was significantly lower in the PET-positive than in the PET-negative group. PET findings predicted OS with a pooled sensitivity and specificity of 76% and 71%, respectively. Corresponding values for MRI were 32% and 82%. Area under the curve and sensitivity were significantly higher for PET than for MRI. CONCLUSION: For monitoring of patients with rHGG under bevacizumab therapy, AA-PET should be preferred over RANO MRI.

The role of molecular tumor boards in neuro-oncology: a nationwide survey.

BACKGROUND: In neuro-oncology, the inclusion of tumor patients in the molecular tumor board has only become increasingly widespread in recent years, but so far there are no standards for indication, procedure, evaluation, therapy recommendations and therapy implementation of neuro-oncological patients. The present work examines the current handling of neuro-oncological patients included in molecular tumor boards in Germany. METHODS: We created an online based survey with questions covering the handling of neuro-oncologic patient inclusion, annotation of genetic analyses, management of target therapies and the general role of molecular tumor boards in neuro-oncology in Germany. We contacted all members of the Neuro-Oncology working group (NOA) of the German Cancer Society (DKG) by e-mail. RESULTS: 38 responses were collected. The majority of those who responded were specialists in neurosurgery or neurology with more than 10 years of professional experience working at a university hospital. Molecular tumor boards (MTB) regularly take place once a week and all treatment disciplines of neuro-oncology patients take part. The inclusions to the MTB are according to distinct tumors and predominantly in case of tumor recurrence. An independently MTB member mostly create the recommendations, which are regularly implemented in the tumor treatment. Recommendations are given for alteration classes 4 and 5. Problems exist mostly within the cost takeover of experimental therapies. The experimental therapies are mostly given in the department of medical oncology. CONCLUSIONS: Molecular tumor boards for neuro-oncological patients, by now, are not standardized in Germany. Similarities exists for patient inclusion and interpretation of molecular alterations; the time point of inclusion and implementation during the patient treatment differ between the various hospitals. Further studies for standardization and harmonisation are needed. In summary, most of the interviewees envision great opportunities and possibilities for molecular-based neuro-oncological therapy in the future.

Biomarkers in Adult-Type Diffuse Gliomas: Elevated Levels of Circulating Vesicular Heat Shock Protein 70 Serve as a Biomarker in Grade 4 Glioblastoma and Increase NK Cell Frequencies in Grade 3 Glioma.

The presence of circulating Hsp70 levels and their influence on the immunophenotype of circulating lymphocyte subsets were examined as diagnostic/prognostic biomarkers for the overall survival (OS) in patients with IDH-mutant WHO grade 3 oligodendroglioma, astrocytoma, and IDH-wildtype grade 4 glioblastoma (GBM). Vesicular and free Hsp70 in the plasma/serum was measured using the Hsp70-exo and R&D Systems DuoSet® Hsp70 ELISAs. The immunophenotype and membrane Hsp70 status was determined by multiparameter flow cytometry on peripheral blood lymphocytes and single-cell suspensions of tumor specimens and cultured cells. Compared to healthy controls, circulating vesicular Hsp70 levels were significantly increased in patients with GBM, concomitant with a significant decrease in the proportion of CD3+/CD4+ helper T cells, whereas the frequency of NK cells was most prominently increased in patients with grade 3 gliomas. Elevated circulating Hsp70 levels and a higher prevalence of activated CD3-/CD56+/CD94+/CD69+ NK cells were associated with an improved OS in grade 3 gliomas, whereas high Hsp70 levels and low CD3+/CD4+ frequencies were associated with an adverse OS in GBM. It is assumed that a reduced membrane Hsp70 density on grade 4 versus grade 3 primary glioma cells and reduced CD3+/CD4+ T cell counts in GBM might drive an immunosuppressive tumor microenvironment.

Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma.

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.

Imaging the WHO 2021 Brain Tumor Classification: Fully Automated Analysis of Imaging Features of Newly Diagnosed Gliomas.

BACKGROUND: The fifth version of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) in 2021 brought substantial changes. Driven by the enhanced implementation of molecular characterization, some diagnoses were adapted while others were newly introduced. How these changes are reflected in imaging features remains scarcely investigated. MATERIALS AND METHODS: We retrospectively analyzed 226 treatment-naive primary brain tumor patients from our institution who received extensive molecular characterization by epigenome-wide methylation microarray and were diagnosed according to the 2021 WHO brain tumor classification. From multimodal preoperative 3T MRI scans, we extracted imaging metrics via a fully automated, AI-based image segmentation and processing pipeline. Subsequently, we examined differences in imaging features between the three main glioma entities (glioblastoma, astrocytoma, and oligodendroglioma) and particularly investigated new entities such as astrocytoma, WHO grade 4. RESULTS: Our results confirm prior studies that found significantly higher median CBV (p = 0.00003, ANOVA) and lower median ADC in contrast-enhancing areas of glioblastomas, compared to astrocytomas and oligodendrogliomas (p = 0.41333, ANOVA). Interestingly, molecularly defined glioblastoma, which usually does not contain contrast-enhancing areas, also shows significantly higher CBV values in the non-enhancing tumor than common glioblastoma and astrocytoma grade 4 (p = 0.01309, ANOVA). CONCLUSIONS: This work provides extensive insights into the imaging features of gliomas in light of the new 2021 WHO CNS tumor classification. Advanced imaging shows promise in visualizing tumor biology and improving the diagnosis of brain tumor patients.

Flipping the classroom in neurological bedside teaching: a prospective controlled study.

BACKGROUND: Bedside teaching is essential to foster core clinical competences in medical education, especially in Neurology. However, bedside skills are declining and new concepts to enhance the effectiveness of bedside teaching are needed, also in view of limited in-person teaching possibilities in the ongoing pandemic situation. If theoretical knowledge is taught prior to in-person sessions this might allow to better focus on practical application aspects during bedside teaching. We thus aimed to answer the question to what extent such an approach can enhance the effectiveness of neurological bedside teaching. METHODS: In this prospective controlled study, neurological bedside courses following a traditional and a flipped classroom (FC) approach were compared with regards to their effects on theoretical knowledge and practical skills of medical students. Evaluations were obtained from 161 students and their lecturers participating in a neurological bedside teaching course at a German university hospital between October 2020 and July 2021. Students were randomly assigned to course dates. However, the 74 students assigned to course dates from May to July 2021 completed a mandatory online preparation course prior to the bedside teaching. These students served as the interventional group (IG) and the remaining 87 students formed the control group (CG). Ratings of knowledge and skills provided by the students and their lecturers on numerical rating scales served as primary outcome measures. Moreover, the time needed to recapitulate theoretical contents during the in-person teaching session was assessed as a secondary outcome measure. Group comparisons were performed using t-statistics. RESULTS: Theoretical knowledge upon entering the course was rated significantly higher in the IG by the students (p < 0.001) and lecturers (p = 0.003). Lecturers also rated the practical skills of students in the IG significantly higher (p < 0.001). Furthermore, significantly less time was needed to recapitulate theoretical contents during the in-person session in the IG (p = 0.03). CONCLUSIONS: Using a FC approach enhances the effectiveness of in-person neurological bedside teaching. Thus, these concepts are particularly valuable in the ongoing pandemic situation. Moreover, they might allow to reuse e-learning contents developed during the pandemic and to develop future bedside teaching concepts.

A rare case of H3K27-altered diffuse midline glioma with multiple osseous and spinal metastases at the time of diagnosis.

BACKGROUND: H3K27-altered diffuse midline gliomas are uncommon central nervous system tumors with extremely poor prognoses. CASE PRESENTATION: We report the case of a 24-year-old man patient with multiple, inter alia osseous metastases who presented with back pain, hemi-hypoesthesia, and hemi-hyperhidrosis. The patient underwent combined radio-chemotherapy and demonstrated temporary improvement before deteriorating. CONCLUSIONS: H3K27-altered diffuse midline glioma presents an infrequent but crucial differential diagnosis and should be considered in cases with rapid neurological deterioration and multiple intracranial and intramedullary tumor lesions in children and young adults. Combined radio-chemotherapy delayed the neurological deterioration, but unfortunately, progression occurred three months after the diagnosis.

Bilateral mydriasis as first manifestation of Hodgkin's lymphoma: a case report.

BACKGROUND: Bilateral mydriasis is usually associated with severe brain stem damage or drug-induced sympathomimetic stimulation. Herein we report it as a unique neurologic complication of Hodgkin's lymphoma. CASE PRESENTATION: A 23-year-old woman presented at our emergency department with dilated pupils unresponsive to light stimuli. MRI and CT scans showed bilaterally enlarged lymph nodes in the mediastinum and supraclavicular compressing the carotid artery on both sides. The histologic examination of lymph node biopsy specimens confirmed the diagnosis of Hodgkin's lymphoma. CONCLUSION: Pathologies around the carotid artery causing oculosympathetic spasm should be considered among the possible causes of a mydriasis, especially when other common causes like brain stem impairment are excluded.

New concepts in neurology education: successful implementation of flipped classroom lectures.

In order to inspire and attract young people to Neurology, we must offer high-quality and attractive teaching! To improve neurological education at our Medical School (Technical University of Munich), we converted the main lecture into an e-learning concept using a flipped classroom model. Students had to prepare with a video and a text as well as answering multiple choice questions before each lecture. As a further incentive, students with ≥ 80% right answers in multiple choice questions received a bonus for the final exam. During the lectures, predominantely patient cases were discussed to apply, improve and enhance the previously acquired knowledge. The realignment of the main lecture in Neurology into a flipped classroom model was very successful and was further optimized in the following semesters based on the evaluations obtained for the new concept. Moreover, this enabled us to quickly switch to remote teaching during the COVID-19 pandemic, while still offering lectures of high quality. In addition, this new teaching concept attracts students for Neurology. Furthermore, the exemplary conversion of the Neurology main lecture to a flipped classroom concept also serves as best practice and motivation to adapt other courses in our faculty and far beyond.

The glioblastoma multiforme tumor site promotes the commitment of tumor-infiltrating lymphocytes to the TH17 lineage in humans.

Although glioblastoma multiforme (GBM) is not an invariably cold tumor, checkpoint inhibition has largely failed in GBM. In order to investigate T cell-intrinsic properties that contribute to the resistance of GBM to endogenous or therapeutically enhanced adaptive immune responses, we sorted CD4+ and CD8+ T cells from the peripheral blood, normal-appearing brain tissue, and tumor bed of nine treatment-naive patients with GBM. Bulk RNA sequencing of highly pure T cell populations from these different compartments was used to obtain deep transcriptomes of tumor-infiltrating T cells (TILs). While the transcriptome of CD8+ TILs suggested that they were partly locked in a dysfunctional state, CD4+ TILs showed a robust commitment to the type 17 T helper cell (TH17) lineage, which was corroborated by flow cytometry in four additional GBM cases. Therefore, our study illustrates that the brain tumor environment in GBM might instruct TH17 commitment of infiltrating T helper cells. Whether these properties of CD4+ TILs facilitate a tumor-promoting milieu and thus could be a target for adjuvant anti-TH17 cell interventions needs to be further investigated.

DEGRO practical guideline for central nervous system radiation necrosis part 2: treatment.

PURPOSE: The Working Group for Neurooncology of the German Society for Radiation Oncology (DEGRO; AG NRO) in cooperation with members of the Neurooncological Working Group of the German Cancer Society (DKG-NOA) aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). METHODS: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN, including bevacizumab, in clinical routine. CONCLUSION: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neurooncologist. If the diagnosis of blood-brain barrier disruptions (BBD) or RN is likely, treatment should be initiated depending on the symptoms, location, and dynamic of the lesion. Multiple treatment options are available (such as observation, surgery, steroids, and bevacizumab) and the optimal approach should be discussed in an interdisciplinary setting. In this practice guideline, we offer detailed treatment strategies for various scenarios.

DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis.

PURPOSE: The Working Group for Neuro-Oncology of the German Society for Radiation Oncology in cooperation with members of the Neuro-Oncology Working Group of the German Cancer Society aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). METHODS: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN including bevacizumab in clinical routine. CONCLUSION: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neuro-oncologist. A multistep approach as an opportunity to review as many characteristics as possible to improve diagnostic confidence is recommended. Additional information about radiotherapy (RT) techniques is crucial for the diagnosis of RN. Misdiagnosis of untreated and progressive RN can lead to severe neurological deficits. In this practice guideline, we propose a detailed nomenclature of treatment-related changes and a multistep approach for their diagnosis.

Residents as teachers in Neurology: a Germany-wide survey on the involvement of neurological residents in clinical teaching.

BACKGROUND: Residents play an important role in the clinical training of medical students, spending up to 25% of their daily work teaching. In the US medical curriculum didactic courses for residents already exist and their role as a teacher is firmly anchored. In Germany, there are no fixed regulations or residents-as-teachers-programs. The aim of this study was to evaluate the activities of neurological residents in clinical teaching. METHODS: We conducted a prospective cross-sectional online survey among neurological residents in Germany. The evaluation was carried out descriptively and by means of text analysis. RESULTS: 138 residents from 39 German neurological university hospitals answered the survey. Nearly half of them needed the teaching activity as part of their career planning. The residents are mostly involved in practical courses. More than 80% stated, that they enjoy teaching. 64% stated that there were no preparatory courses for teaching at their hospital/university. 78.4% of the respondents received no or merely insufficient feedback for their own teaching and 62.5% had only little or even no knowledge about the university curriculum. CONCLUSIONS: By teaching medical students, residents play an outstanding role in recruiting students for neurology and, simultaneously, teaching leads an improvement in the residents' own learning. To encourage young neurologists as teachers and-at the same time as learners-Clinic directors and universities should promote residents-as-teachers programs in neurology and reward the residents' teaching activities.

Glioblastoma Relapses Show Increased Markers of Vulnerability to Ferroptosis.

Background: Despite the availability of various therapy options and being a widely focused research area, the prognosis of glioblastoma (GBM) still remains very poor due to therapy resistance, genetic heterogeneity and a diffuse infiltration pattern. The recently described non-apoptotic form of cell death ferroptosis may, however, offer novel opportunities for targeted therapies. Hence, the aim of this study was to investigate the potential role of ferroptosis in GBM, including the impact of treatment on the expression of the two ferroptosis-associated players glutathione-peroxidase 4 (GPX4) and acyl-CoA-synthetase long-chain family number 4 (ACSL4). Furthermore, the change in expression of the recently identified ferroptosis suppressor protein 1 (FSP1) and aldehyde dehydrogenase (ALDH) 1A3 was investigated. Methods: Immunohistochemistry was performed on sample pairs of primary and relapse GBM of 24 patients who had received standard adjuvant treatment with radiochemotherapy. To identify cell types generally prone to undergo ferroptosis, co-stainings of ferroptosis susceptibility genes in combination with cell-type specific markers including glial fibrillary acidic protein (GFAP) for tumor cells and astrocytes, as well as the ionized calcium-binding adapter molecule 1 (Iba1) for microglial cells were performed, supplemented by double stains combining GPX4 and ACSL4. Results: While the expression of GPX4 decreased significantly during tumor relapse, ACSL4 showed a significant increase. These results were confirmed by analyses of data sets of the Cancer Genome Atlas. These profound changes indicate an increased susceptibility of relapsed tumors towards oxidative stress and associated ferroptosis, a cell death modality characterized by unrestrained lipid peroxidation. Moreover, ALDH1A3 and FSP1 expression also increased in the relapses with significant results for ALDH1A3, whereas for FSP1, statistical significance was not reached. Results obtained from double staining imply that ferroptosis occurs more likely in GBM tumor cells than in microglial cells. Conclusion: Our study implies that ferroptosis takes place in GBM tumor cells. Moreover, we show that recurrent tumors have a higher vulnerability to ferroptosis. These results affirm that utilizing ferroptosis processes might be a possible novel therapy option, especially in the situation of recurrent GBM.

Effectiveness of non-bedside teaching during the COVID-19 pandemic: a quasi-experimental study.

BACKGROUND: The COVID-19 pandemic poses a huge challenge for clinical teaching due to contact restrictions and social distancing. Medical teachers have to balance potential risks and benefits of bedside teaching, especially in course formats intended to foster practical clinical skills. In this context, we aimed to address the question, whether presence-based teaching formats without patient involvement are suitable to teach practical skills. METHODS: In this quasi-experimental study, presence-based teaching formats with and without patient contact were retrospectively compared regarding their effects on medical students' theoretical knowledge and practical skills, i.e. the performance and clinical interpretation of the neurological exam. To this end, evaluations from 102 students and their lecturers participating in a neurological bedside teaching course at a German university hospital between October 2020 and April 2021 were obtained. Students were initially randomly assigned to course dates. However, 53 students assigned to courses in November and December 2020, were not able to go bedside due to contact restrictions. These students formed the interventional group and the remaining 49 students the control group. The primary outcome measures were students' overall grading of the course (school grades, 1-6) as well as ratings of knowledge and skills provided by the students themselves and their lecturers on a numerical rating scale (0-10). Comparison between groups was performed using frequentist and Bayesian t-statistics. RESULTS: The teaching format without patient contact received a significantly poorer overall grade by the students (p = 0.018). However, improvements in the students' self-ratings of knowledge and skills did not differ between the two formats (all p > 0.05, BF10max = 0.42). Moreover, especially practical skills were even rated significantly better in the group without patient contact by the lecturers (p < 0.001). CONCLUSIONS: Teaching formats without patient contact are less well-received by the students. However, they are able to teach practical skills regarding the performance and clinical interpretation of examination techniques. Still, the evaluations obtained might not adequately capture the importance of bedside teaching in preparing future physicians for their practice. Perspectively, hybrid teaching approaches including flipped-classroom concepts hold considerable potential to enhance effectiveness of bedside teaching in the present pandemic situation and in the future.