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Background The diffuse growth pattern of glioblastoma is one of the main challenges for improving patient survival. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy. Here, we performed clinical and biological validation of a novel, deep learning - based growth model, aiming to close the gap between the experimental state and clinical implementation. Methods 124 patients from The Cancer Genome Archive network and 397 patients from the UCSF Glioma MRI Dataset were assessed for correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration (Dw) as well as proliferation (r) parameters stemming from a Fisher-Kolmogorov growth model adjusted to the patients’ preoperative images using deep learning. Cox multivariable regression and Spearman correlation were performed to test for statistical significance. To further evaluate clinical potential, we performed the same growth modeling on preoperative MRI 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/r (p p

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

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.

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.

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.

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.

Both positron emission tomography (PET) and magnetic resonance imaging (MRI), including dynamic susceptibility contrast perfusion (DSC-PWI), are crucial for treatment monitoring of patients with high-grade gliomas. In clinical practice, they are usually conducted at separate time points. Whether this affects their diagnostic performance is presently unclear. To this end, we retrospectively reviewed 38 patients with pathologically confirmed glioblastoma (IDH wild-type) and suspected tumor recurrence after radiotherapy. Only patients who received both a PET–MRI (where DSC perfusion was acquired simultaneously with a FET-PET) and a separate MRI exam (including DSC perfusion) were included. Tumors were automatically segmented into contrast-enhancing tumor (CET), necrosis, and edema. To compare the simultaneous as well as the sequential DSC perfusion to the FET-PET, we calculated Dice overlap, global mutual information as well as voxel-wise Spearman correlation of hotspot areas. For the joint assessment of PET and MRI, we computed logistic regression models for the differentiation between true progression (PD) and treatment-related changes (TRC) using simultaneously or sequentially acquired images as input data. We observed no significant differences between Dice overlap (p = 0.17; paired t-test), mutual information (p = 0.18; paired t-test) and Spearman correlation (p = 0.90; paired t-test) when comparing simultaneous PET–MRI and sequential PET/MRI acquisition. This also held true for the subgroup of patients with >14 days between exams. Importantly, for the diagnostic performance, ROC analysis showed similar AUCs for differentiation of PD and TRC (AUC simultaneous PET: 0.77; AUC sequential PET: 0.78; p = 0.83, DeLong’s test). We found no relevant differences between simultaneous and sequential acquisition of FET-PET and DSC perfusion, also regarding their diagnostic performance. Given the increasing attention to multi-parametric assessment of glioma treatment response, our results reassuringly suggest that sequential acquisition is clinically and scientifically acceptable.

INTRODUCTION The CeTeG/NOA-09 trial demonstrated superior median overall survival (mOS, 48.1 months) in MGMT-methylated glioblastoma treated with lomustine/temozolomide compared to temozolomide. We retrospectively analyzed an off-study cohort of patients treated with lomustine/temozolomide to gather real-world data on this new regimen. METHODS Adult patients from 20 centers in Germany, Austria and Switzerland were included. Inclusion criteria were MGMT-methylated IDHwt glioblastoma newly diagnosed prior to end of 2020, and lomustine/temozolomide treatment as part of first-line therapy. RESULTS 321 patients with a median age of 57 years (range, 21-78) and a median follow-up of 19.9 months were included. In the whole cohort, mOS was 41.0 months (95%CI, 33.0 – not reached). In patients starting lomustine/temozolomide immediately upon initiation of radiotherapy strictly following the CeTeG protocol (88%), mOS was 52.8 months (35.8 – not reached) as compared to 24.6 months (17.6 – not reached) in patients starting lomustine/temozolomide after completion of radiotherapy/concomitant temozolomide (12%, logrank test: p = 0.06). Patients with a KPS < 80 had a shorter mOS of 19.7 months (95%CI, 16.6 – not reached) compared to 41.0 months (33.0 – not reached, p = 0.009) in KPS 80-100. Gross total resection (GTR, 53.9%) was associated with longer mOS (52.8 months, 95%CI 24.1 – not reached) compared to partial resection/biopsy (30.5 months, 95%CI 36.8 – not reached, p=0.004). Multivariable Cox regression analysis confirmed GTR (HR 0.66, p = 0.033) and younger age ( ≤ 50 years: HR 0.42, p = 0.001), but not KPS (80-100 vs. lower: HR 0.66, p = 0.12) as independent prognostic factors. DISCUSSION In this real-world multicenter cohort, survival was similar to the promising results of CeTeG/NOA-09. Further analyses should investigate a potentially reduced benefit from lomustine/temozolomide in patients with low KPS/no GTR and a possible detrimental effect from deferred lomustine/temozolomide initiation. The median follow-up is admittedly short, updated data will be presented.

Summary Background There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. Methods In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18–70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m 2 per day concomitant to radiotherapy [59–60 Gy] followed by six courses of temozolomide 150–200 mg/m 2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m 2 on day 1) plus temozolomide (100–200 mg/m 2 per day on days 2–6 of the 6-week course) in addition to radiotherapy (59–60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. Findings Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7–47·1) with temozolomide to 48·1 months (32·6 months–not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35–1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35–1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. Interpretation Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. Funding German Federal Ministry of Education and Research.

Purpose: 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: 123 patients (58 females/65 males, mean age 67.4 ± 13.4 years) met the inclusion criteria. 75 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. The median OS was 123 ± 220 days (IR 52–395 days). Age (pConclusion: Patients with a preoperative KPSS of ≤ 60% benefit from low postoperative residual tumour volumes. Age and MGMT-methylation status were also significant prognostic parameters in this patient cohort.

Purpose To evaluate diagnostic accuracy of fully automated analysis of multimodal imaging data using [18F]-FET-PET and MRI (including amide proton transfer-weighted (APTw) imaging and dynamic-susceptibility-contrast (DSC) perfusion) in differentiation of tumor progression from treatment-related changes in patients with glioma. Material and methods At suspected tumor progression, MRI and [18F]-FET-PET data as part of a retrospective analysis of an observational cohort of 66 patients/74 scans (51 glioblastoma and 23 lower-grade-glioma, 8 patients included at two different time points) were automatically segmented into necrosis, FLAIR-hyperintense, and contrast-enhancing areas using an ensemble of deep learning algorithms. In parallel, previous MR exam was processed in a similar way to subtract preexisting tumor areas and focus on progressive tumor only. Within these progressive areas, intensity statistics were automatically extracted from [18F]-FET-PET, APTw, and DSC-derived cerebral-blood-volume (CBV) maps and used to train a Random Forest classifier with threefold cross-validation. To evaluate contribution of the imaging modalities to the classifier’s performance, impurity-based importance measures were collected. Classifier performance was compared with radiology reports and interdisciplinary tumor board assessments. Results In 57/74 cases (77%), tumor progression was confirmed histopathologically (39 cases) or via follow-up imaging (18 cases), while remaining 17 cases were diagnosed as treatment-related changes. The classification accuracy of the Random Forest classifier was 0.86, 95% CI 0.77–0.93 (sensitivity 0.91, 95% CI 0.81–0.97; specificity 0.71, 95% CI 0.44–0.9), significantly above the no-information rate of 0.77 (p = 0.03), and higher compared to an accuracy of 0.82 for MRI (95% CI 0.72–0.9), 0.81 for [18F]-FET-PET (95% CI 0.7–0.89), and 0.81 for expert consensus (95% CI 0.7–0.89), although these differences were not statistically significant (p > 0.1 for all comparisons, McNemar test). [18F]-FET-PET hot-spot volume was single-most important variable, with relevant contribution from all imaging modalities. Conclusion Automated, joint image analysis of [18F]-FET-PET and advanced MR imaging techniques APTw and DSC perfusion is a promising tool for objective response assessment in gliomas.

Purpose: Seizures related to tumor growth are common in glioma patients, especially in low-grade glioma patients this is often the first tumor manifestation. We hypothesize that there are associations between preoperative seizures and morphologic features (e.g., tumor size, location) and histogram features in patients with glioblastoma (GB). Methods: Retrospectively, 160 consecutive patients with initial diagnosis and surgery of GB (WHO IV) and preoperative MRI were analyzed. Preoperative MRI sequences were co-registered (T2-FLAIR, T1-contrast, DTI) and tumors were segmented by a neuroradiologist using the software ITK-snap blinded to the clinical data. Tumor volume (FLAIR, T1-contrast) and histogram analyses of ADC- and FA-maps were recorded in the contrast enhancing tumor part (CET) and the non-enhancing peritumoral edema (FLAIR). Location was determined after co-registration of the data with an atlas. Permutation-based multiple-testing adjusted t statistics were calculated to compare imaging variables between patients with and without seizures. Results: Patients with seizures showed significantly smaller tumors (CET, adj. p = 0.029) than patients without preoperative seizures. Less seizures were observed in patients with tumor location in the right cingulate gyrus (adj. p = 0.048) and in the right caudate nucleus (adj. p = 0.009). Significant differences of histogram analyses of FA in the contrast enhancing tumor part were observed between patients with and without seizures considering also tumor location and size. Conclusion: Preoperative seizures in GB patients are associated with lower preoperative tumor volume. The different histogram analyses suggest that there might be microstructural differences in the contrast enhancing tumor part of patients with seizures measured by fractional anisotropy. Higher variance of GB presenting without seizures might indicate a more aggressive growth of these tumors.

We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test. At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42). The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

Tumor heterogeneity is considered to be a hallmark of glioblastoma (GBM). Only more recently, it has become apparent that GBM is not only heterogeneous between patients (intertumoral heterogeneity) but more importantly, also within individual patients (intratumoral heterogeneity). In this study, we focused on assessing intratumoral heterogeneity. For this purpose, the heterogeneity of 38 treatment-na&iuml, ve GBM was characterized by immunohistochemistry. Perceptible areas were rated for ALDH1A3, EGFR, GFAP, Iba1, Olig2, p53, and Mib1. By clustering methods, two distinct groups similar to subtypes described in literature were detected. The classical subtype featured a strong EGFR and Olig2 positivity, whereas the mesenchymal subtype displayed a strong ALDH1A3 expression and a high fraction of Iba1-positive microglia. 18 tumors exhibited both subtypes and were classified as &ldquo, subtype-heterogeneous&rdquo, whereas the areas of the other tumors were all assigned to the same cluster and named &ldquo, subtype-dominant&rdquo, Results of epigenomic analyses corroborated these findings. Strikingly, the subtype-heterogeneous tumors showed a clearly shorter overall survival compared to subtype-dominant tumors. Furthermore, 21 corresponding pairs of primary and recurrent GBM were compared, showing a dominance of the mesenchymal subtype in the recurrent tumors. Our study confirms the prognostic impact of intratumoral heterogeneity in GBM, and more importantly, makes this hallmark assessable by routine diagnostics.

The treatment of malignant gliomas has undergone a significant intensification during the past decade, and the interdisciplinary treatment team has learned that all treatment opportunities, including surgery and radiotherapy (RT), also have a central role in recurrent gliomas. Throughout the decades, re-irradiation (re-RT) has achieved a prominent place in the treatment of recurrent gliomas. A solid body of evidence supports the safety and efficacy of re-RT, especially when modern techniques are used, and justifies the early use of this regimen, especially in the case when macroscopic disease is present. Additionally, a second adjuvant re-RT to the resection cavity is currently being investigated by several investigators and seems to offer promising results. Although advanced RT technologies, such as stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT) have become available in many centers, re-RT should continue to be kept in experienced hands so that they can select the optimal regimen, the ideal treatment volume, and the appropriate techniques from their tool-boxes. Concomitant or adjuvant use of systemic treatment options should also strongly be taken into consideration, especially because temozolomide (TMZ), cyclohexyl-nitroso-urea (CCNU), and bevacizumab have shown a good safety profile; they should be considered, if available. Nonetheless, the selection of patients for re-RT remains crucial. Single factors, such as patient age or the progression-free interval (PFI), fall too short. Therefore, powerful prognostic scores have been generated and validated, and these scores should be used for patient selection and counseling.

AimsO(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is a high predictive factor for therapy results of temozolomide in patients with glioma. The objective of this work was to analyse the impact of MGMT promoter methylation in patients with primary diagnosed glioblastoma (GBM) relating to survival using a quantitative method (methylation quantification of endonuclease-resistant DNA, MethyQESD) by verifying a cut-off point for MGMT methylation provided by the literature (Methods67 patients aged 70 years or younger, operated between January 2013 and December 2015, with newly diagnosed IDH wild-type GBM and clinical follow-up were retrospectively investigated in this study. A known MGMT promoter methylation status was the inclusion criteria.ResultsMedian overall survival (OS) was 16.9 months. Patients who had a methylated MGMT promoter region of ≥10% had an improved OS compared with patients with a methylated promoter region of ConclusionThe results confirm that the quantitative level of MGMT promoter methylation is a positive prognostic factor in newly diagnosed patients with GBM. The cut-off provided by the literature (

The treatment of gliomas became more sophisticated during the last decades. As by now, adjuvant treatment after maximum safe resection is considered an important and effective treatment strategy in most gliomas, yet the decision is based on several factors. This review summarizes the available evidence for the current adjuvant treatment algorithms with a focus on the impact on the survival of glioma patients. The review is based on the current guidelines, but it also includes new insights which have not yet been included into the official guidelines.

High-precision radiotherapy has been established as a valid and effective treatment option in patients with pituitary adenomas. We report on outcome after fractionated stereotactic radiotherapy (FSRT) in correlation with patient-reported outcomes (PROs). We analyzed 69 patients treated between 2000 and 2019. FSRT was delivered with a median total dose of 54 Gy (single fraction: 1.8 Gy). PRO questionnaires were sent to 28 patients. Median overall survival was 17.2 years, mean local control was 15.6 years (median not reached). Median follow-up was 5.8 years. Twenty (71%) patients participated in the PRO assessment. Physicians reported symptoms grade &ge, 3 in 6 cases (9%). Of all, 35 (51%) patients suffered from hypopituitarism at baseline, and during follow-up, new or progressive hypopituitarism was observed in 11 cases (16%). Patients reported 10 cases of severe side effects. Most of these symptoms were already graded as CTCAE (Common Terminology Criteria for Adverse Events) grade 2 by a physician in a previous follow-up exam. PROs are an essential measure and only correlate to a certain extent with the physician-reported outcomes. For high-precision radiotherapy of pituitary adenomas, they confirm excellent overall outcomes and low toxicity. In the future, the integration of PROs paired with high-end treatment will further improve outcomes.

The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase promoter non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). To identify subpopulations with a particularly favorable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers before treatment onset. MRIs at baseline (before treatment onset) were analyzed for T1-hyperintense and diffusion-restricted lesions; as well as the presence of both hyperintense and diffusion-restricted (double positive) lesions. The MRI findings were correlated with overall and progression-free survival. MRI scans were evaluable in 71% of the GLARIUS modified intention-to-treat population (n = 121 of 170; 88 patients in the BEV/IRI arm, and 33 patients in the TMZ control arm). Diffusion-restricted and T1 hyperintense lesions were present in 60% and 65% of patients in BEV/IRI arm, while 57% and 63% were found in the TMZ arm, respectively. Double positive lesions were found in 37% of BEV/IRI patients and in 39% of TMZ patients. Neither the presence of T1-hyperintense, diffusion-restricted lesions, nor double positive lesions were associated with improved survival. Baseline T1-hyperintense and diffusion-restricted lesions are not suitable to predict progression-free or overall survival of patients treated with bevacizumab/irinotecan or temozolomide.

The aim of this study is to investigate the association between postoperative tumor volume and overall survival (OS) of O6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma patients. One hundred-twenty-six patients with MGMT-unmethylated glioblastoma who were treated either with surgical resection or needle biopsy between 2006 and 2015 were included in this retrospective cohort. Pre- and postcontrast T1 weighted images were evaluated in order to determine pre- and postoperative contrast-enhancing tumor volumes (CE-TV). Cox regression models adjusted for other significant prognostic factors were used to investigate the association between postoperative tumor volume and survival. Complete resection of CE-TV was significantly associated with longer OS in the univariate analysis (HR 0.61; 95% CI 0.40–0.94; p = 0.02). However, this fact could not be confirmed after adjusting the model for other relevant prognostic factors (HR 1.01; 95% CI 0.65–1.55; p = 0.962). Postoperative CE-TV was significantly associated with survival in both univariate (HR: 1.04; 95% CI 1.025–1.055; p

Due to a metadata tagging error the names of Stephanie E. Combs and Jan S. Kirschke were indexed incorrectly. Stephanie E. is the author's given name, and Jan S. is the author's given name.

Though cognitive function is proven to be an independent predictor of survival in patients with intrinsic brain tumors, cognitive functions are still rarely considered. Aim of this study was to assess neurocognitive function and to identify risk factors for neurocognitive deficits. 103 patients with primary neuroepithelial tumors who received tumor resections or biopsies were included in this prospective study. The following data was acquired: mini-mental state examination, preoperative tumor volume, WHO grade, tumor entity and location, and the Karnofsky performance status scale. Furthermore, patients participated in extensive neuropsychological testing of attentional, memory and executive functions. General factors like age, clinical status, WHO grade, tumor volume and tumor location correlated with patients' neurocognitive functions. Affection of the parietal lobe resulted in significant impairment of attention and memory functions. Frontal lobe involvement significantly affected patients' abilities in planning complex actions and novel problem solving. Patients with temporal lesions were more likely to have impaired memory and executive functions. Comparing results among neuroepithelial tumor patients enables the identification of risk factors for cognitive impairment. General parameters such as age, KPS score, tumor size, and WHO grade are apart from the respective tumor location of high importance for neurocognitive function.

Recent studies suggested that postoperative hypoxia might trigger invasive tumor growth, resulting in diffuse/multifocal recurrence patterns. Aim of this study was to analyze distinct recurrence patterns and their association to postoperative infarct volume and outcome. 526 consecutive glioblastoma patients were analyzed, of which 129 met our inclusion criteria: initial tumor diagnosis, surgery, postoperative diffusion-weighted imaging and tumor recurrence during follow-up. Distinct patterns of contrast-enhancement at initial diagnosis and at first tumor recurrence (multifocal growth/progression, contact to dura/ventricle, ependymal spread, local/distant recurrence) were recorded by two blinded neuroradiologists. The association of radiological patterns to survival and postoperative infarct volume was analyzed by uni-/multivariate survival analyses and binary logistic regression analysis. With increasing postoperative infarct volume, patients were significantly more likely to develop multifocal recurrence, recurrence with contact to ventricle and contact to dura. Patients with multifocal recurrence (Hazard Ratio (HR) 1.99, P = 0.010) had significantly shorter OS, patients with recurrent tumor with contact to ventricle (HR 1.85, P = 0.036), ependymal spread (HR 2.97, P = 0.004) and distant recurrence (HR 1.75, P = 0.019) significantly shorter post-progression survival in multivariate analyses including well-established prognostic factors like age, Karnofsky Performance Score (KPS), therapy, extent of resection and patterns of primary tumors. Postoperative infarct volume might initiate hypoxia-mediated aggressive tumor growth resulting in multifocal and diffuse recurrence patterns and impaired survival.

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.

Incomplete resection of glioblastoma is discussed controversially in the era of combined radiochemotherapy. The aim of this study was to analyze the benefit of subtotal tumor resection for glioblastoma patients as this was recently questioned in the era of radiochemotherapy. Overall, 209 patients undergoing surgery for newly diagnosed WHO grade IV gliomas were retrospectively analyzed, and pre- and postoperative tumor volumes were manually segmented (cm3). Survival analyses were performed, including prognostic factors such as age, Karnofsky performance score (KPS), O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status, and adjuvant treatment regimen. Pre- and postoperative tumor volume is significantly associated with pre- and postoperative KPS, as well as age (p

BACKGROUND Generally, re-irradiation (Re-RT) is offered to patients with glioma recurrences with macroscopic lesions. Results are discussed controversially, and some centers postulate limited benefit of Re-RT. Re-RT is generally offered to tumors up to 4 cm in diameter. Re-resection is also discussed controversially; however, recent studies have shown significant benefit. OBJECTIVE To combine proactive re-resection and early Re-RT in patients with recurrent glioma. METHODS We included 108 patients treated between 2002 and 2016 for recurrent glioma. All patients underwent surgical resection for recurrence; Re-RT was applied with a median dose of 37.5 Gy (range 25 Gy-57Gy/equivalent dose in 2Gy fractions [EQD2]) with high-precision techniques. All patients were followed prospectively in an interdisciplinary follow-up program. RESULTS Median follow-up after Re-RT was 7 mo. Median survival after surgery and Re-RT was 12 mo (range 1-102 mo). Complete resection had a significant impact on the outcome (P = .03). The strongest predictors of outcome were MGMT-promotor methylation and Karnofsky Performance Score and time interval between primary and second RT. CONCLUSION Proactive resection of tumor recurrences combined with early Re-RT conveys into promising outcome in recurrent glioma. Complete resection and early Re-RT lead to improved survival. Thus, moving Re-RT to an earlier timepoint during the treatment of recurrent glioma, eg after complete macroscopic removal of the tumor, may be crucial for treatment optimization. Using advanced RT techniques, side effects are low. Currently, this concept is evaluated in the GLIOCAVE/NOA 17 trial.

Currently, patients with gross total resection (GTR) of recurrent glioblastoma (rGBM) undergo adjuvant chemotherapy or are followed up until progression. Re-irradiation, as one of the most effective treatments in macroscopic rGBM, is withheld in this situation, as uncertainties about the pattern of re-recurrence, the target volume, and also the efficacy of early re-irradiation after GTR exist. Imaging and clinical data from 26 consecutive patients with GTR of rGBM were analyzed. The spatial pattern of recurrences was analyzed according to the RANO-HGG criteria (“response assessment in neuro-oncology criteria for high-grade gliomas”). Progression-free (PFS) and overall survival (OS) were analyzed by the Kaplan–Meier method. Furthermore, a systematic review was performed in PubMed. All but 4 patients underwent adjuvant chemotherapy after GTR. Progression was diagnosed in 20 of 26 patients and 70% of recurrent tumors occurred adjacent to the resection cavity. The median extension beyond the edge of the resection cavity was 20 mm. Median PFS was 6 months; OS was 12.8 months. We propose a target volume containing the resection cavity and every contrast enhancing lesion as the gross tumor volume (GTV), a spherical margin of 5–10 mm to generate the clinical target volume (CTV), and a margin of 1–3 mm to generate the planning target volume (PTV). Re-irradiation of this volume is deemed to be safe and likely to prolong PFS. Re-irradiation is worth considering also after GTR, as the volumes that need to be treated are limited and re-irradiation has already proven to be a safe treatment option in general. The strategy of early re-irradiation is currently being tested within the GlioCave/NOA 17/Aro 2016/03 trial.

Background: Re-irradiation (Re-RT) is offered widely in clinical routine, and has been established as a key element in the treatment of recurrent gliomas. At our center, generally re-resection is performed widely by an experienced neurosurgical team. Thus, Re-RT mostly offered to patients with macroscopic residuals or irresectable lesions, is applied later compared to other centers. Therefore, we sought to validate the Combs Prognostic Score developed in 2012 using our independent patient cohort. Patients and methods: We included 199 patients treated from 2002 until April 2016 for recurrent glioma at the Department of Radiation Oncology at the Klinikum Rechts der Isar, Munich. Different concepts of Re-RT were applied. Results: Median follow-up after Re-RT was 2.5 months. Median overall survival (OS) after Re-RT was 7.9 months for WHO IV gliomas, 11.3 months for WHO III gliomas, and 13.6 months for low-grade gliomas (WHO I/II). Univariate analyses confirmed the prognostic factors primary histology (p = 0.001), age (p = 0.002), and time between primary radiotherapy and Re-RT (p&thinsp