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Abstract Achieving non-invasive spatiotemporal control over cellular functions, tissue organization, and behavior is a desirable aim for advanced therapies. Magnetic fields, due to their negligible interaction with biological matter, are promising for in vitro and in vivo applications, even in deep tissues. Particularly, the remote manipulation of paramagnetic (including superparamagnetic and ferromagnetic, all with a positive magnetic susceptibility) entities through magnetic instruments has emerged as a promising approach across various biological contexts. However, variations in the properties and descriptions of these instruments have led to a lack of reproducibility and comparability among studies. This article addresses the need for standardizing the characterization of magnetic instruments, with a specific focus on their ability to control the movement of paramagnetic objects within organisms. While it is well known that the force exerted on magnetic particles depends on the spatial variation (gradient) of the magnetic field, the magnitude of the field is often overlooked in the literature. Therefore, we comprehensively analyze and discuss both actors and propose a novel descriptor, termed ‘effective gradient’, which combines both dependencies. To illustrate the importance of both factors, we characterize different magnet systems and relate them to experiments involving superparamagnetic nanoparticles. This standardization effort aims to enhance the reproducibility and comparability of studies utilizing magnetic instruments for biological applications.

There is increasing evidence that many intrinsically disordered regions (IDRs) in proteins play key functional roles through interactions with other proteins or nucleic acids. These interactions often exhibit a context-dependent structural behavior. We hypothesize that low complexity regions (LCRs), often found within IDRs, could have a role in inducing local structure in IDRs. To test this, we predicted IDRs in the human proteome and analyzed their structures or those of homologous sequences in the Protein Data Bank (PDB). We then identified two types of simple LCRs within IDRs: regions with only one (polyX or homorepeats) or with only two types of amino acids (polyXY). We were able to assign structural information from the PDB more often to these LCRs than to the surrounding IDRs (polyX 61.8% > polyXY 50.5% > IDRs 39.7%). The most frequently observed polyX and polyXY within IDRs contained E (Glu) or G (Gly). Structural analyses of these sequences and of homologs indicate that polyEK regions induce helical conformations, while the other most frequent LCRs induce coil structures. Our work proposes bioinformatics methods to help in the study of the structural behavior of IDRs and provides a solid basis suggesting a structuring role of LCRs within them.

Nanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions with the biological environment, which improves their biocompatibility. The molecular determinants of this reduction are not very well understood yet, and their knowledge may help improving nanoparticle design. Here we address, using molecular dynamics simulations, the interactions of human serum albumin, the most abundant serum protein, with two promising hydrophilic polymers used for the coating of therapeutic nanoparticles, poly(ethylene-glycol) and poly-sarcosine. By simulating the protein immersed in a polymer-water mixture, we show that the two polymers have a very similar affinity for the protein surface, both in terms of the amount of polymer adsorbed and also in terms of the type of amino acids mainly involved in the interactions. We further analyze the kinetics of adsorption and how it affects the polymer conformations. Minor differences between the polymers are observed in the thickness of the adsorption layer, that are related to the different degree of flexibility of the two molecules. In comparison poly-alanine, an isomer of poly-sarcosine known to self-aggregate and induce protein aggregation, shows a significantly larger affinity for the protein surface than PEG and PSar, which we show to be related not to a different patterns of interactions with the protein surface, but to the different way the polymer interacts with water. Keywords: PEG, Poly-peptoid, Poly-sarcosine, MD simulation, Nanoparticle protein corona

Fibrinogen is a serum multi-chain protein which, when activated, aggregates to form fibrin, one of the main components of a blood clot. Fibrinolysis controls blood clot dissolution through the action of the enzyme plasmin, which cleaves fibrin at specific locations. Although the main biochemical factors involved in fibrin formation and lysis have been identified, a clear mechanistic picture of how these processes take place is not available yet. This picture would be instrumental, for example, for the design of improved thrombolytic or anti-haemorrhagic strategies, as well as, materials with improved biocompatibility. Here, we present extensive molecular dynamics simulations of fibrinogen which reveal large bending motions centered at a hinge point in the coiled-coil regions of the molecule. This feature, likely conserved across vertebrates according to our analysis, suggests an explanation for the mechanism of exposure to lysis of the plasmin cleavage sites on fibrinogen coiled-coil region. It also explains the conformational variability of fibrinogen observed during its adsorption on inorganic surfaces and it is supposed to play a major role in the determination of the hydrodynamic properties of fibrinogen. In addition the simulations suggest how the dynamics of the D region of fibrinogen may contribute to the allosteric regulation of the blood coagulation cascade through a dynamic coupling between the a- and b-holes, important for fibrin polymerization, and the integrin binding site P1.

We develop a multiscale hybrid scheme for simulations of soft condensed matter systems, which allows one to treat the system at the particle level in selected regions of space, and at the continuum level elsewhere. It is derived systematically from an underlying particle-based model by field theoretic methods. Particles in different representation regions can switch representations on the fly, controlled by a spatially varying tuning function. As a test case, the hybrid scheme is applied to simulate colloid–polymer composites with high resolution regions close to the colloids. The hybrid simulations are significantly faster than reference simulations of a pure particle-based model, and the results are in good agreement.

We study the interactions between lipid bilayers and rigid transmembrane proteins by Monte Carlo simulations of generic coarse-grain models. Different popular protein models are considered and compared with each other, and key parameters such as the hydrophobicity and the hydrophobic mismatch are varied systematically. Furthermore, the properties of the membrane are manipulated by applying different tensions. The response of the membrane to the insertion of single proteins is found to be mostly generic and independent of the choice of the protein model. Likewise, the orientational distributions of single proteins depend mainly on the hydrophobic mismatch and the hydrophobicity of the proteins, and are otherwise similar for all protein models. Orientational distributions are generally found to be very broad, i.e. tilt angles fluctuate very much, in agreement with experimental findings. Weakly hydrophobic proteins respond to positive hydrophobic mismatch by tilting. Strongly hydrophobic (strongly bound) proteins distort the surrounding membrane and tend to remain upright. For proteins with intermediate hydrophobicity, the two mechanisms compete, and as a result, the tilt only sets in if the hydrophobic mismatch exceeds a threshold. Clusters of several strongly hydrophobic proteins with negative positive mismatch may nucleate raft-like structures in membranes. This effect is more pronounced for proteins with rough, structured surfaces.

Borna 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

Abstract 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.

Abstract 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

Abstract 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.

Abstract 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.

Abstract 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.

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.

Abstract 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

Abstract 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.

Abstract Backround Median overall survival (OS) after diagnosis of glioblastoma (GBM) remains 15 months amongst patients receiving aggressive surgical resection, chemotherapy and irradiation. Treatment of patients with a poor preoperative Karnofsky Performance Status Scale (KPSS) is still controversial. Therefore, we retrospectively assessed the outcome after surgical treatment in patients with a KPSS of ≤60%. Methods We retrospectively included patients with a de-novo glioblastoma WHO °IV and preoperative KPSS ≤60%, who underwent surgery at two neurosurgical centres between September 2006 and March 2016. We recorded pre- and postoperative tumour volume, pre- and postoperative KPSS, OS, age and MGMT promoter status. Results One hundred twenty-three patients (58 females/65 males, mean age 67.4 ± 13.4 years) met the inclusion criteria. Seventy-five of the 123 patients (61%) underwent surgical resection. 48/123 patients (39%) received a biopsy. The median preoperative and postoperative tumour volume of all patients was 33.0 ± 31.3 cm3 (IR 15.0–56.5cm3) and 3.1 ± 23.8 cm3 (IR 0.2–15.0 cm3), respectively. The median KPSS was 60% (range 20–60%) preoperatively and 50% (range 0–80%) postoperatively. Patients who received a biopsy showed a median OS for patients who received a biopsy only was 3.0 months (95% CI 2.0–4.0 months), compared to patients who had a resection and had a median OS of 8 months (95% CI 3.1–12.9 months). Age (p

BackgroundDespite 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.MethodsImmunohistochemistry 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.ResultsWhile 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.ConclusionOur 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.

Abstract Background Over the past years, several treatment regimens have been recommended for elderly patients with glioblastoma (GBM), ranging from ultrahypofractionated radiotherapy (RT) over monochemotherapy (ChT) to combined radiochemotherapy (RChT). The current guidelines recommend active treatment in elderly patients in cases with a KPS of at least 60%. We established a score for selecting patients with a very poor prognosis from patients with a better prognosis. Methods One hundred eighty one patients ≥65 years old, histologically diagnosed with GBM, were retrospectively evaluated. Clinical characteristics were analysed for their impact on the overall survival (OS). Factors which were significant in univariate analysis (log-rank test, p 6 months were summarized as Group A and B, respectively. Results Age, KPS, MGMT status, the extent of resection, aphasia after surgery and motor dysfunction after surgery were significantly associated with OS on univariate analysis (p

Abstract Background The treatment recommendations for Low-grade Gliomas (LGG) underwent profound changes due to results from RTOG 9802 published in April 2016. This work aims to investigate whether the results from the trial were already incorporated into the treatment recommendations at German oncology centers before an update of the official guidelines. Methods An online based questionnaire with questions covering all aspects of adjuvant treatments of LGGs was generated, including three cases with distinct clinical situations. We contacted all members of the neuro-oncologic working group (NOA) of the German Cancer Society (DKG) as well as all German-speaking members of the European Low-Grade Glioma Network via E-mail. Results We collected 38 responses. All responders were at least specialists; they predominantly worked at tertiary hospitals with a high volume of LGGs treated annually (75% with more than 10 cases per year). All responders stated to consent treatment recommendation for LGGs within interdisciplinary oncologic boards. The treatment recommendations for LGGs changed profoundly between 2015 and 12/2016. There is a trend towards PCV-based multimodal treatments, especially for oligodendroglial LGGs, as well as a trend away from watchful-waiting-policies for astrocytic LGGs. Conclusion Neurooncologists do adapt results from clinical trials quickly. None the less, there is still an immense heterogeneity within the treatment recommendations, predominantly for astrocytic LGGs. Well planned clinical trials and concise treatment recommendations are warranted; additionally, individual counseling of patients is essential.

Abstract Background Glioblastoma relapses in the vast majority of cases within 1 year. Maximum safe resection of the recurrent glioblastoma can be offered in some cases. Re-irradiation has been established for the treatment of recurrent glioblastoma, too. In both cases, adjuvant treatment, mostly using temozolomide, can improve PFS and OS after these interventions. However, combining gross tumor resection and adjuvant re-radiotherapy to the resection cavity has not been tested so far. Methods/Design In the multicenter two-armed randomized Phase II GlioCave Study, fractionated stereotactic radiotherapy to the resection cavity, after gross tumor resection of recurrent glioblastoma, will be compared to observation. Depending on the size of the target volume, a total dose of 46 Gy in 2 Gy per fraction or a total dose if 36 Gy in 3 Gy per fraction will be applied. Progression free survival will be the primary endpoint of the study. Discussion Adjuvant treatment after gross tumor resection of recurrent glioblastoma is currently deemed to be limited to chemotherapy. However, re-irradiation has proven safety and tolerability in the treatment of macroscopic disease. Performing re-irradiation as an adjuvant measure after gross tumor resection has not been tested so far. The GlioCave Study will investigate the efficacy and the safety profile of this approach. Trial registration The trial was prospectively registered at clinicaltrials.gov ( NCT02715297 , registration date February 29th, 2016). The protocol presented hereby refers to the version 1.2 of the protocol (January 11th, 2017).

Abstract Background Glioblastoma is usually diagnosed around the age of 60–70 years. Patients older than 65 years are frequently described as “elderly”. Several trials with monotherapy have established treatment regimens that offer therapies with reduced side effects but reduced efficacy. We analysed the outcome of elderly glioblastoma patients treated at our facility. Methods We performed a retrospective analysis of 62 consecutive patients older than 65 years treated for a primary glioblastoma at our facility from 2009 to 2015. Results Median age was 69.6 years (range 65.1–85.6 years); median OS of the entire cohort was 10.9 months. ECOG, MGMT and extent of resection but not age and the time from surgery to radiotherapy were associated with longer survival. Patients treated with adjuvant chemotherapy had a significantly longer survival (20.5 vs. 7.8 months). Furthermore, salvage therapies were associated with significant improved survival when compared to Best Supportive Care (22.3 vs. 8.8 months). Conclusion Also elderly patients are likely to benefit from an aggressive treatment after primary diagnosis of glioblastoma.

For about 30 years, researchers developed prognostic scores and searched for prognostic factors to predict outcomes for cancer patients. The "Combs Prognostic Score" for re-irradiation in recurrent glioma was recently validated and results showed that the score is a significant (p < .001) and reliable predictor for patients undergoing re-irradiation (re-RT). We sought to enhance the score and generated a novel scoring approach, taking into account the information on resection of recurrent tumors, KPS, and tumor volume.The prognostic score was generated based on 209 patients treated between 2002 and 2016 for recurrent glioma at the department of radiation oncology at the Klinikum rechts der Isar, Munich. To further enhance the previously validated Combs Prognostic Score, which uses the prognostic factors primary histology, time between primary RT and re-RT, and age, we added KPS, tumor volume (PTV) and re-resection into the scoring scheme.The median follow-up time was 3.5 months. 67.5% were WHO IV gliomas with a median OS after re-RT of 7.9 months, 17.7% were WHO III gliomas with an OS of 11.3 months and 14.8% were WHO I/II gliomas with an OS of 14.7 months. Multivariate analyses confirmed the prognostic factors KPS (p < .001) and showed a tendency to significance for tumor volume (p = .067) and re-resection (p = .064). The new prognostic score demonstrated a high significance (p < .001).The "New Combs Prognostics Score" is a significant and useful tool to predict the overall effect of re-RT in patients with recurrence gliomas. This modified score offers an even better way to classify patients in clinical routine and prospective clinical trials investigating re-irradiation.

Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin β-receptor (LTβR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTβR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTβR signaling inside and outside of the implanted tissue. We show that LTβR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTβR expressing cells in the animal (regenerate weights of 115 ± 8 mg in LTβR deficient recipients and of 12 ± 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTβR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTβR dependent suppressive activity. Thus, LTβR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases.