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INTRODUCTION In the randomized CeTeG/NOA-09 trial, combined CCNU/TMZ was superior to TMZ therapy regarding overall survival (OS) in newly diagnosed patients with MGMT-methylated glioblastoma. Using modified RANO criteria, however, progression-free survival (PFS) and pseudoprogression rates were similar in both arms. Exploring the hypothesis of undetected pseudoprogressions being accountable for this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at RANO-defined progression. METHODS 86 CeTeG/NOA-09 patients with progression (modified RANO criteria) and MRI evaluable for standardized T1 and FLAIR volumetry at baseline and progression were included. Patients were further subdivided to short PPS (< 24 months) or long PPS (> 24 months) and a PPS/PFS ratio was calculated. RESULTS In the CCNU/TMZ arm, long PPS patients (n=10) tended to a shorter PFS (median 7.3 months) than short PPS patients in the same arm (n=33, 14 months, p=0.089, logrank test) and long PPS patients in the TMZ arm (n=9, 12.7 months, p=0.21). The mean PPS/PFS ratio in the long PPS group was markedly higher in the CCNU/TMZ arm (5.8) compared to the TMZ arm (3.3, p=0.043, Mann-Whitney test). Patients with long PPS of the CCNU/TMZ arm showed a nonsignificant tendency to a stronger volumetric increase in T1 enhancement (mean delta 6184,86 vs. 697.5 mm³) and FLAIR–T1-enhancement (mean delta 42671 vs 16860 mm³) at progression as compared to long PPS patients of the TMZ arm. CONCLUSION Combining a substantially increased PPS/PFS ratio (long OS despite particularly short PFS according to RANO) with indications for increased contrast enhancement and FLAIR volume at progression, the patients with long PPS in the CCNU/TMZ arm appear to differ from those in the TMZ arm. These observations support the hypothesis that this group (~25% of CCNU/TMZ-treated patients) contained patients with pseudoprogression undetected by modified RANO criteria.

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.

Background Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587). Methods Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days 1-5 of every 28-day cycle × 6)] or PBO + RT + TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients. Results As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO + RT + TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO + RT + TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively. Conclusions NIVO added to RT + TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed.

Superficial siderosis is a consequence of repetitive bleeding into the subarachnoid space, leading to toxic iron and hemosiderin deposits on the surface of the brain and spine. The clinical and radiological phenotypes of superficial siderosis are known to manifest over long time intervals. In contrast, this study defines the “acute superficial siderosis syndrome” and illustrates typical imaging and histopathological findings of this entity. We describe the case of a 61-year-old male patient who was diagnosed with a melanoma metastasis in the right frontal cortex in February 2019. Within a few weeks he developed a progressive syndrome characterized by cerebellar ataxia, gait disturbance, signs of myelopathy, and radiculopathy. MRI revealed ongoing hemorrhage from the metastasis into the lateral ventricle and the subarachnoid space. A semiquantitative assessment of three subsequent MRI within an 8-week period documented the rapid development of superficial siderosis along the surface of the cerebellum, the brain stem, and the lower parts of the supratentorial regions on T2*-weighted sequences. The diagnosis of a superficial siderosis was histopathologically confirmed by identifying iron and hemosiderin deposits on the cortex along with astrogliosis. The recognition of this “acute superficial siderosis syndrome” triggered surgical removal of the hemorrhagic metastasis. Based on a single case presentation, we define the “acute superficial siderosis syndrome” as a clinical entity and describe the radiological and histopathological characteristics of this entity. Early recognition of this syndrome may allow timely elimination of the bleeding source, in order to prevent further clinical deterioration.

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.

Outside of clinical trials, the occurrence of objective responses (OR) to chemotherapy in patients with recurrent gliomas is poorly characterized. Further, the predictive value of OR for PFS and OS is unclear. We screened the German Glioma Network Database for patients who had received chemotherapy only for recurrent glioma. As PFS was not available for a large number of patients we used the composite endpoint time-to-treatment-failure (progressive disease, start of a new therapy or death). We included 485 patients who received 646 chemotherapy regimens for treatment of recurrent glioma. Of these, only 32 chemotherapies in 32 patients resulted in an OR (30 PR, 2 CR) after central review according to RANO criteria. OR rates were 2.8%, 11.0% and 10.6% for glioblastoma, anaplastic glioma WHO grade III and diffuse glioma WHO grade II, respectively. Temozolomide (n=232) resulted in ORs in 7.8% of the patients, while nitrosourea (n=212) and imatinib (n=27) resulted in ORs in 6.1% and 3.7%, respectively. Overall, responders showed a significantly improved OS compared to non-responders (median OS 33.3 versus 15 months, p=0.054). Yet, a Cox regression analysis adjusted for diagnosis and age did not reveal a significant association of objective responses with overall survival (relative risk 0.8, p=0.391). In addition, we generated a 1:3 cohort (n=96) of non-responders matched for diagnosis. There was no relevant difference in OS comparing responders to the matched cohort (median OS 33.3 versus 25.6 months, p=0.929). When comparing non-responders with longer time-to-treatment-failure (>14 weeks, assumed stable disease as best response) with responders (n=32) the difference in outcome was lost (median OS 24.3 versus 33.3 months, p=0.86). In this prospective trial ORs to chemotherapy in the recurrent setting were rare. Notably, when comparing responders with a matched cohort or patients with assumed stable disease as best response, ORs were not associated with improved survival.

INTRODUCTION: Classification as well as treatment of patients with lower grade gliomas (°II+°III) have changed fundamentally during the last years. Molecular markers have augmented diagnostic workup and combined radiochemotherapy was established for most of the subgroups. However, molecular markers have not been part of the inclusion criteria of most of the relevant clinical trials. Larger analyses outside of clinical trials are rare. MATERIALS AND METHODS: We screened our clinical cancer database for patients with lower grade glioma newly diagnosed from 1995 to 2015. We identified 774 patients of whom 345 had to be excluded, resulting in an evaluable cohort of 423 patients. We evaluated general characteristics, morphological diagnosis, molecular markers, treatment, time-to-treatment-failure (TTF; initiation of a new treatment or death) and overall survival (OS). RESULTS: According to the 2007 WHO classification our cohort included 145 (34.3%) Astrocytoma WHO °II, 56 (13.3%) Oligoastrocytoma/Oligodendroglioma WHO °II, 129 (52.5%) Astrocytoma WHO °III and 93 (22.0%) Oligoastrocytoma/Oligodendroglioma WHO °III. In 235 patients we were able to molecularly classify the tumors based on the 2017 WHO classification using IDH status and 1p/19q or ATRX status. Patients with a molecularly defined Oligodendroglioma showed a median TTF of 5.2, 4.2 and 7.8 years for radiotherapy, chemotherapy and radiochemotherapy, respectively. Patients with a molecularly defined Astrocytoma showed a median TTF of 1.6, 2.9 and 6.7 years for radiotherapy, chemotherapy and radiochemotherapy, respectively. In IDH wildtype tumors TTF was below 12 months without relevant differences. Treatment with combined radiochemotherapy resulted in markedly improve TTF in molecular defined oligodendroglioma and astrocytoma compared with either radiotherapy or chemotherapy alone. Due to the short follow-up of 5.3 years (mean) median OS has not been reached for any of the IDH mutant subgroups. CONCLUSIONS: Combined treatment with radiotherapy and chemotherapy resulted in markedly improved TTF in patients with molecularly defined oligodendroglioma and astrocytoma.

Previous ex vivo spectroscopic data from tissue samples revealed differences in phospholipid metabolites between isocitrate dehydrogenase mutated (IDHmut) and IDH wildtype (IDHwt) gliomas. We investigated whether these changes can be found in vivo usingThe study included 33 prospectively enrolled, mostly untreated patients who met spectral quality criteria according to the World Health Organization (WHO II n = 7, WHO III n = 17, WHO IV n = 9; 25 patients IDHmut, 8 patients IDHwt). The MRSI protocol includedIn our patient cohort we did not find significant differences for the ratio of phosphocholine (PC) and phosphoethanolamine (PE), PC/PE, (p = 0.24) for IDHmut compared to IDHwt gliomas. Furthermore, we found no elevated ratios of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), GPC/GPE, (p = 0.68) or GPC/PE (p = 0.12) for IDHmut gliomas. Even the ratio (PC+GPC)/(PE+GPE) showed no significant differences with respect to mutation status (p = 0.16). Nonetheless, changes related to tumor grade regarding intracellular pH (pHUsing 3D-CSI data acquisition, in vivo

The model elimination theorem prover SETHEO (version V3.3) and its equational extension E-SETHEO are presented. SETHEO employs sophisticated mechanisms of subgoal selection, elaborate iterative deepening techniques, and local failure caching methods. Its equational counterpart E-SETHEO transforms formulae containing equality (using a variant of Brand’s modification method) and processes the output with the standard SETHEO system. This article gives an overview of the theoretical background, the system architecture, and the performance of both systems.

We consider the termination problem of combinations of term-rewriting systems and the λ-calculus employing standard methods of the theory of term rewriting systems in contrast to (extensions of) Tait-Girard's technique. In particular for some class of higher-order rule systems, we explicitly construct a well-founded ordering over λ-terms whose combination with the β-reduction is terminating. Then, by embedding the higher-order rewriting relation into this ordering, we can prove termination for combinations of such a class of higher-order term rewriting systems and the λ-calculus.