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Purpose The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy. Methods The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan–Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables. Results Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7–30.8) vs. 43.2 (32.5–54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8–18.9) vs 17.6 (14.7–20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53–4.31), p Conclusion Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients.

Purpose:The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine–temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine–temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression.Experimental Design:We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1–3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically.Results:We identified 23 patients with 32 FET-PET scans. Within 5–25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, P = 0.029). The integration of relative changes of TBRmean further improved the accuracy (91%; P < 0.001). Moreover, the combination of static and dynamic parameters increased the specificity to 100% (P = 0.005).Conclusions:The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine–temozolomide chemoradiation.

Supplemental Figure 1 shows increase of time-to-peak supporting the diagnosis of pseudoprogression

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range

Postoperative intensive care unit (ICU) monitoring is an established option to ensure patient safety after resection of newly diagnosed glioblastoma. In contrast, secondary unplanned ICU readmission following complicating events during the initial postoperative course might be associated with severe morbidity and impair initially intended surgical benefit. In the present study, we assessed the prognostic impact of secondary ICU readmission and aimed to identify preoperatively ascertainable risk factors for the development of such adverse events in patients treated surgically for newly diagnosed glioblastoma. Between 2013 and 2018, 240 patients were surgically treated for newly diagnosed glioblastoma at the authors’ neuro-oncological center. Secondary ICU readmission was defined as any unplanned admission to the ICU during initial hospital stay. A multivariable logistic regression analysis was performed to identify preoperatively measurable risk factors for unplanned ICU readmission. Nineteen of 240 glioblastoma patients (8%) were readmitted to the ICU. Median overall survival of patients with unplanned ICU readmission was 9 months compared to 17 months for patients without secondary ICU readmission (p=0.008). Multivariable analysis identified “preoperative administration of dexamethasone > 7 days” (p=0.002) as a significant and independent predictor of secondary unplanned ICU admission. Secondary ICU readmission following surgery for newly diagnosed glioblastoma is significantly associated with poor survival and thus may negate surgically achieved prerequisites for further treatment. This underlines the indispensability of precise patient selection as well as the importance of further scientific debate on these highly relevant aspects for patient safety.

Object The conception of individual patient-adjusted treatment strategies is constantly emerging in the field of neuro-oncology. Systemic laboratory markers may allow insights into individual needs and estimated treatment benefit at an earliest possible stage. Therefore, the present study was aimed at analyzing the prognostic significance of preoperative routine laboratory values in patients with newly-diagnosed glioblastoma. Methods Between 2014 and 2019, 257 patients were surgically treated for newly-diagnosed glioblastoma at the Neuro-Oncology Center of the University Hospital Bonn. Preoperative routine laboratory values including red blood cell distribution width (RDW) and platelet count were reviewed. RDW to platelet count ratio (RPR) was calculated and correlated to overall survival (OS) rates. Results Median preoperative RPR was 0.053 (IQR 0.044–0.062). The receiver operating characteristic (ROC) curve indicated an optimal cut-off value for RPR to be 0.05 (AUC 0.62; p = 0.002, 95% CI 0.544–0.685). 101 patients (39%) presented with a preoperative RPR Conclusions The present study suggests the RPR to constitute a novel prognostic inflammatory marker for glioblastoma patients in the course of preoperative routine laboratory examinations and might contribute to a personalized medicine approach.

Purpose: The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine–temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine–temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression. Experimental Design: We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1–3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically. Results: We identified 23 patients with 32 FET-PET scans. Within 5–25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, Conclusions: The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine–temozolomide chemoradiation.

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.

The CeTeG/NOA-09 trial showed a survival benefit for combined CCNU/TMZ therapy in MGMT-promoter-methylated glioblastoma patients (quantitative methylation-specific PCR [qMSP] ratio > 2). Here, we report on the prognostic value of the MGMT promoter methylation ratio determined by qMSP and evaluate the concordance of MGMT methylation results obtained by qMSP, pyrosequencing (PSQ) or DNA methylation arrays (MGMT-STP27). A potential association of qMSP ratio with survival was analyzed in the CeTeG/NOA-09 trial population (n = 129; log-rank tests, Cox regression analyses). The concordance of MGMT methylation assays (qMSP, PSQ and MGMT-STP27) was evaluated in 76 screened patients. Patients with tumors of qMSP ratio > 4 showed superior survival compared to those with ratios 2-4 (P = .0251, log-rank test). In multivariate analysis, the qMSP ratio was not prognostic across the study cohort (hazard ratio [HR] = 0.88; 95% CI: 0.72-1.08). With different cutoffs for qMSP ratio (4, 9, 12 or 25), the CCNU/TMZ benefit tended to be larger in subgroups with lower ratios (eg, for cutoff 9: HR 0.32 for lower subgroup, 0.73 for higher subgroup). The concordance rates with qMSP were 94.4% (PSQ) and 90.2% (MGMT-STP27). Discordant results were restricted to tumors with qMSP ratios ≤4 and PSQ mean methylation rate ≤25%. Despite a shorter survival in MGMT-promoter-methylated patients with lower methylation according to qMSP, these patients had a benefit from combined CCNU/TMZ therapy, which even tended to be stronger than in patients with higher methylation rates. With acceptable concordance rates, decisions on CCNU/TMZ therapy may also be based on PSQ or MGMT-STP27.

2050 Background: Pre-clinical studies consistently demonstrate that inhibition of the CXCL12/CXCR4/CXCR7 axis abrogates recruitment of pro-vasculogenic bone marrow-derived cells after radiotherapy (RT) of glioblastoma (GBM) and promotes T cell exclusion from the tumor microenvironment (TME). The German multicenter phase 1/2 trial GLORIA (NCT04121455) assesses safety of RT plus escalating dose levels (DL) of the CXCL12-neutralizing RNA-Spiegelmer Olaptesed pegol (OLA; NOX-A12) in patients with chemotherapy-resistant GBM. Methods: Until now, GLORIA enrolled 10 patients newly diagnosed with incompletely resected (n = 8) or biopsied (n = 2) GBM with ECOG≤2, age ≥18 and without MGMT promoter hypermethylation. All patients receive standard RT (60 Gy in 30 fractions or 40.05 Gy in 15 fractions) and continuous (24/7) i.v. infusions of either 200 mg (DL1; n = 3), 400 mg (DL2; n = 3) or 600 mg (DL3; n = 4) per week of OLA for 26 weeks. The primary endpoint (EP) is safety as per incidence of treatment-related adverse events (AE). Secondary EPs include radiographic response as per mRANO criteria, dynamic susceptibility contrast perfusion (DSC) and the fraction of highly-perfused tumor (FTBhigh) as well as the apparent diffusion coefficient (ADC). Target lesions (TL) and non-target lesions (NTL, i.e. in-field satellite lesions) are analyzed separately. Tumor tissue is assessed by high-plex immunofluorescence imaging (co-detection by indexing; CODEX). Matched reference cohorts serve as controls for MRI (n = 14) and CODEX (n = 8) data. Results: Combination of RT and OLA was well-tolerated and safe. Of all G ≥ 2 AEs (n = 77), 3 (4%) were deemed to be solely OLA-related, including 1 grade 3 AE at DL3. There were no dose limiting toxicities and no treatment-related deaths. In total, eight of the nine patients (89%) with TLs at baseline showed a TL response during OLA therapy, with four (40%) reaching partial remission (PR) as per radiologic mRANO criteria (n = 2 at DL1 and n = 2 at DL3). All three patients treated at DL1 and all four of DL3 reached PR of one or more NTLs. In three cases (n = 2 at DL1; n = 1 at DL3), at least one NTL completely disappeared. Under OLA, radiographic responses of NTL were best at the highest DL (DL1 +49.5/DL2 +488.3/DL3 -59%), as was the increase in diffusion (mean ADC increase +46.4/+28.2/+56.7%) and the decrease in FTBhigh (mean -33.5/-32.8/-47.7%). Matched pre-/post-surgery CODEX of a confirmed pseudoprogression revealed intralesional clusters of proliferating cytotoxic T cells. Analysis of tissue from a non-responding patient showed T-cell encapsulation by M2-polarized macrophages in an immune-cell enriched TME. Additional follow-up is ongoing. Conclusions: Interim data from the ongoing GLORIA trial demonstrates safety of RT plus OLA and suggests promising clinical efficacy of a new class of drugs targeting CXCL12 in GBM. Clinical trial information: NCT04121455.

ObjectIntra-tumoral hemorrhage is considered an imaging characteristic of advanced cancer disease. However, data on the influence of intra-tumoral hemorrhage in patients with brain metastases (BM) remains scarce. We aimed at investigating patients with BM who underwent neurosurgical resection of the metastatic lesion for a potential impact of preoperative hemorrhagic transformation on overall survival (OS).MethodsBetween 2013 and 2018, 357 patients with BM were surgically treated at the authors’ neuro-oncological center. Preoperative magnetic resonance imaging (MRI) examinations were assessed for the occurrence of malignant hemorrhagic transformation.Results122 of 375 patients (34%) with BM revealed preoperative intra-tumoral hemorrhage. Patients with hemorrhagic transformed BM exhibited a median OS of 5 months compared to 12 months for patients without intra-tumoral hemorrhage. Multivariate analysis revealed preoperative hemorrhagic transformation as an independent and significant predictor for worsened OS.ConclusionsThe present study identifies preoperative intra-tumoral hemorrhage as an indicator variable for poor prognosis in patients with BM undergoing neurosurgical treatment.

Background: Brain metastases (BM) indicate advanced states of cancer disease and cranial surgery represents a common treatment modality. In the present study, we aimed to identify the risk factors for a reduced survival in patients receiving a surgical treatment of BM derived from non-small cell lung cancer (NSCLC). Methods: A total of 154 patients with NSCLC that had been surgically treated for BM at the authors’ institution between 2013 and 2018 were included for a further analysis. A multivariate analysis was performed to identify the predictors of a poor overall survival (OS). Results: The median overall survival (mOS) was 11 months (95% CI 8.2–13.8). An age &gt, 65 years, the infratentorial location of BM, elevated preoperative C-reactive protein levels, a perioperative red blood cell transfusion, postoperative prolonged mechanical ventilation (&gt, 48 h) and the occurrence of postoperative adverse events were identified as independent factors of a poor OS. Conclusions: The present study identified several predictors for a worsened OS in patients that underwent surgery for BM of NSCLC. These findings might guide a better risk/benefit assessment in the course of metastatic NSCLC therapy and might help to more sufficiently cope with the challenges of cancer therapy in these advanced stages of disease.

Purpose Outcome prediction of large vessel occlusion of the anterior circulation in patients with wake-up stroke is important to identify patients that will benefit from thrombectomy. Currently, mismatch concepts that require MRI or CT-Perfusion (CTP) are recommended to identify these patients. We evaluated machine learning algorithms in their ability to discriminate between patients with favorable (defined as a modified Rankin Scale (mRS) score of 0–2) and unfavorable (mRS 3–6) outcome and between patients with poor (mRS5–6) and non-poor (mRS 0–4) outcome. Methods Data of 8395 patients that were treated between 2018 and 2020 from the nationwide registry of the German Society for Neuroradiology was retrospectively analyzed. Five models were trained with clinical variables and Alberta Stroke Program Early CT Score (ASPECTS). The model with the highest accuracy was validated with a test dataset with known stroke onset and with a test dataset that consisted only of wake-up strokes. Results 2419 patients showed poor and 3310 patients showed favorable outcome. The best performing Random Forest model achieved a sensitivity of 0.65, a specificity of 0.81 and an AUC of 0.79 on the test dataset of patients with wake-up stroke in the classification analysis between favorable and unfavorable outcome and a sensitivity of 0.42, a specificity of 0.83 and an AUC of 0.72 in the classification analysis between poor and non-poor outcome. Conclusion Machine learning algorithms have the potential to aid in the decision making for thrombectomy in patients with wake-up stroke especially in hospitals, where emergency CTP or MRI imaging is not available.

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.

BACKGROUND We recently reported favorable safety, promising clinical efficacy and immunohistochemical indicators of response after radiotherapy (RT) plus escalating doses of the CXCL12-neutralizing RNA-Spiegelmer olaptesed pegol (NOX-A12) for glioblastoma in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report outcomes after RT plus dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab). METHODS After establishing safety in the monotherapy arm, we enrolled six patients with incompletely resected GBM, ECOG ≤ 2, age ≥ 18 and without MGMT promoter hypermethylation into a pre-planned expansion arm. Patients received standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response, perfusion/diffusion imaging and neurologic performance. RESULTS Dual treatment was well-tolerated and safe. Of all G ≥ 2 AEs (n = 37), two G2 events (5.4%) were deemed related to NOX-A12. There were no dose-limiting toxicities and no treatment-related deaths. Longitudinal NANO assessment revealed stable neurologic functioning in all patients. Five out of six patients achieved partial responses (PRs) as per mRANO in week 9. All PRs remained durable at a median follow up of 5.6 months (range 3.6 to 9.3 months). No progression occurred. The mean best response was -65.9% (-13.3% to -99.9%) for target lesion sums and -92.1% (-76.2% to -100%) for non-target lesion (NTL) sums. In all three patients with NTL at least one lesion disappeared. The mean best change from baseline of the highly perfused-tumor fraction was -84.5% (-51.9% to -100%) and the mean best change of the apparent diffusion coefficient was 20.1% (-24.5% to 59.1%). CONCLUSION Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 and suggest improved efficacy of dual inhibition of post-radiogenic angio- and vasculogenesis by the addition of bevacizumab.

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: The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine–temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine–temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression. Experimental Design: We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1–3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically. Results: We identified 23 patients with 32 FET-PET scans. Within 5–25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, Conclusions: The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine–temozolomide chemoradiation.

INTRODUCTION Detection of tumor progression in glioblastoma patients remains a major challenge for clinicians due to equivocal MRI results. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of tumor patients. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as a marker for tumor progression in adjunction with MRI assessment. METHODS Glioblastoma patients from two independent cohorts, one from the multicenter Phase III CeTeG/NOA-09 trial (n=36) and the other from patients treated at the University of Bonn (n=31), were included in this study. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. RESULTS EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29 (p=0.08), CD44 (p< 0.0001), CD81 (p< 0.0001), CD146 (p< 0.0001), C1QA (p=0.003), and histone H3 (p< 0.0001) as compared to serum EVs from healthy volunteers. For both independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. Notably, six patients with worse survival compared to the median survival of the cohort did not fulfill RANO criteria at the time of suspected progression, yet showed an elevation of at least one out of these three markers. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. CONCLUSION Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, could improve detection of true tumor progression and thus be a useful tool for clinical decision making.

Surgical resection is highly effective in the treatment of tumor-related epilepsy (TRE) in patients with brain metastases (BM). Nevertheless, some patients suffer from postoperative persistent epilepsy which negatively impacts health-related quality of life. Therefore, early identification of patients with potentially unfavorable seizure outcome after BM resection is important. Patients with TRE that had undergone surgery for BM at the authors’ institution between 2013 and 2018 were analyzed with regard to preoperatively identifiable risk factors for unfavorable seizure outcome. Tumor tissue and tumor necrosis ratios were assessed volumetrically. According to the classification of the International League Against Epilepsy (ILAE), seizure outcome was categorized as favorable (ILAE 1) and unfavorable (ILAE 2–6) after 3 months in order to avoid potential interference with adjuvant cancer treatment. Among all 38 patients undergoing neurosurgical treatment for BM with concomitant TRE, 34 patients achieved a favorable seizure outcome (90%). Unfavorable seizure outcome was significantly associated with larger tumor volumes (p = 0.012), a midline shift > 7 mm (p = 0.025), and a necrosis/tumor volume ratio > 0.2 (p = 0.047). The present study identifies preoperatively collectable risk factors for unfavorable seizure outcome in patients with BM and TRE. This might enable to preselect for highly vulnerable patients with postoperative persistent epilepsy who might benefit from accompanying neuro-oncological expertise during further systemical treatment regimes.

Background: Metastatic melanoma disease is accompanied by highly systemic inflammatory responses. The prognostic value of preoperative laboratory inflammation markers in brain metastatic melanoma patients has not been adequately investigated so far. Methods: Preoperative inflammatory blood parameters were correlated to overall survival (OS) rates in melanoma patients that underwent surgery for brain metastasis (BM) between 2013 and 2019 at the authors’ institution. Receiver operating characteristic (ROC) analyses were used for cutoff determination of routine laboratory parameters. Results: Median OS in the present cohort of 30 melanoma patients with surgically treated BM was 7 months (95% confidence interval (CI) 5.7–8.3). Initial elevated C-reactive protein (CRP) levels (&gt, 10 mg/L), neutrophil-to-lymphocyte ratio (NLR) ≥ 4, platelet-to-lymphocyte ratio (PLR) ≥ 145, and lymphocyte-to-monocyte ratio (LMR) &lt, 2 were associated with significantly reduced OS rates. Conclusions: The present study identifies several preoperative peripheral inflammatory markers as indicators for poor prognosis in melanoma patients with BM undergoing neurosurgical treatment. Elevated initial CRP values, higher NLR and PLR, and lower LMR were associated with reduced OS and, thus, might be incorporated into preoperative interdisciplinary treatment planning and counseling for affected patients.

The CeTeG/NOA-09 trial showed a survival benefit for combined CCNU/TMZ therapy in MGMT-promoter-methylated glioblastoma patients (quantitative methylation-specific PCR [qMSP] ratio > 2). Here, we report on the prognostic value of the MGMT promoter methylation ratio determined by qMSP and evaluate the concordance of MGMT methylation results obtained by qMSP, pyrosequencing (PSQ) or DNA methylation arrays (MGMT-STP27). A potential association of qMSP ratio with survival was analyzed in the CeTeG/NOA-09 trial population (n = 129; log-rank tests, Cox regression analyses). The concordance of MGMT methylation assays (qMSP, PSQ and MGMT-STP27) was evaluated in 76 screened patients. Patients with tumors of qMSP ratio > 4 showed superior survival compared to those with ratios 2-4 (P =.0251, log-rank test). In multivariate analysis, the qMSP ratio was not prognostic across the study cohort (hazard ratio [HR] = 0.88; 95% CI: 0.72-1.08). With different cutoffs for qMSP ratio (4, 9, 12 or 25), the CCNU/TMZ benefit tended to be larger in subgroups with lower ratios (eg, for cutoff 9: HR 0.32 for lower subgroup, 0.73 for higher subgroup). The concordance rates with qMSP were 94.4% (PSQ) and 90.2% (MGMT-STP27). Discordant results were restricted to tumors with qMSP ratios ≤4 and PSQ mean methylation rate ≤25%. Despite a shorter survival in MGMT-promoter-methylated patients with lower methylation according to qMSP, these patients had a benefit from combined CCNU/TMZ therapy, which even tended to be stronger than in patients with higher methylation rates. With acceptable concordance rates, decisions on CCNU/TMZ therapy may also be based on PSQ or MGMT-STP27.

BACKGROUND Preclinical studies showed that CXCL12-mediated influx of highly angiogenic monocytes/macrophages is a key driver of tumor re-vascularization and re-growth after radiotherapy (RT) of glioblastoma (GBM). We report findings from a phase I/II proof-of concept (PoC) study on CXCL12 inhibition during and after RT of GBM. METHODS Patients ≥18years with incompletely or unresected GBM without MGMT promoter hypermethylation and ECOG≤2 were eligible to participate. Patients received continuous (24/7) i.v. infusions of 200mg/week (n=3), 400mg/week (n=3) or 600mg/week (n=3) of the CXCL12 inhibitor olaptesed pegol (OLA) for 26 weeks during and after normo- or hypofractionated RT (60Gy/40.05Gy). The primary endpoint was safety as per the incidence of treatment-related adverse events. The study was accompanied by PoC-research including multiparametric MRI biomarkers (relative cerebral blood volume, rCBV; fractional tumor burden with high perfusion, FTBhigh; apparent diffusion coefficient, ADC) and of multiplexed immunofluorescence imaging (CODEX®) of reference and patient samples. Initial results of these analyses are reported for the first six patients enrolled. RESULTS Five of six (83%) patients assessed with advanced MRI showed response under OLA in rCBV/FTBhigh and ADC. Maximum reduction in perfusion (rCBV) from baseline was 55%, maximum reduction of FTBhigh was 55% and maximum increase in ADC was 77%. Furthermore, five of six (83%) patients analyzed showed reduction of enhancing tissue volumes in at least one scan under OLA therapy. In both one patient and two reference samples CXCL12 co-localized with endothelial cells of the microvascular proliferation zone. In a paired sample (before/during OLA) of one patient, endothelial cells stained positive for CXCL12 before but not during treatment and almost all GBM cells were negative in Ki67 staining in the sample obtained under OLA therapy. CONCLUSIONS Advanced MRI and multiplexed immunofluorescence suggest efficacy of combined radiotherapy and CXCL12 inhibition in unmethylated GBM. Funded by NOXXON Pharma AG; ClinicalTrials.gov number, NCT04121455.

The influence of perioperative red blood cell (RBC) transfusion on prognosis of glioblastoma patients continues to be inconclusive. The aim of the present study was to evaluate the association between perioperative blood transfusion (PBT) and overall survival (OS) in patients with newly diagnosed glioblastoma. Between 2013 and 2018, 240 patients with newly diagnosed glioblastoma underwent surgical resection of intracerebral mass lesion at the authors’ institution. PBT was defined as the transfusion of RBC within 5 days from the day of surgery. The impact of PBT on overall survival was assessed using Kaplan–Meier analysis and multivariate regression analysis. Seventeen out of 240 patients (7%) with newly diagnosed glioblastoma received PBT. The overall median number of blood units transfused was 2 (95% CI 1–6). Patients who received PBT achieved a poorer median OS compared to patients without PBT (7 versus 18 months; p 65 years” (p p = 0.001, OR 3.2, 95% CI 1.6–6.1), “unmethylated MGMT status” (p p = 0.01, OR 6.0, 95% CI 1.5–23.4) as significantly and independently associated with 1-year mortality. Perioperative RBC transfusion compromises survival in patients with glioblastoma indicating the need to minimize the use of transfusions at the time of surgery. Obeying evidence-based transfusion guidelines provides an opportunity to reduce transfusion rates in this population with a potentially positive effect on survival.

Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EV) from the serum of glioblastoma patients and also in total serum without prior EV separation, and evaluated their correlation with the survival of these patients. Our study included 55 patients in total, 26 (47.3%) of which were treated within the multicenter Phase III CeTeG/NOA-09 trial and 29 (52.7%) in the Division of Clinical Neurooncology of the University Hospital of Bonn, as well as 10 healthy volunteers (HV). Blood was drawn from patients during the adjuvant chemotherapeutic treatment. A panel of 15 microRNAs was studied by quantitative real-time PCR in EV that were separated by size-exclusion chromatography, followed by CDxx* immunoprecipitation (SEC+CDxx*), and compared with those from total serum of glioblastoma patients and HV. Comparing SEC+CDxx* to total serum, we found evidence for enrichment of miR-21-3p and miR-106a-5p and, conversely, lower levels of miR-15b-3p in SEC+CDxx* EV. miR-15b-3p and miR-21-3p were upregulated in serum of glioblastoma patients compared to healthy subjects. Significant correlation with survival of the patients was found for levels of miR-15b-3p in total serum and miR-15b-3p, miR-21-3p, miR-106a-5p and miR-328-3p in SEC+CDxx* EV. Combining miR-15b-3p in serum or miR-106a-5p in SEC+CDxx* EV with any one of the other three microRNAs in SEC+CDxx* EV allowed for a prognostic stratification of glioblastoma patients. We have thus identified four microRNAs whose levels, in combination, can predict the prognosis for these patients. *=Cluster of Differentiation xx (CDxx); Molecule cannot be specifically mentioned due to pending patent.

Surgical resection is a key treatment modality for brain metastasis (BM). However, peri- and postoperative adverse events (PAEs) might be associated with a detrimental impact on postoperative outcome. We retrospectively analyzed our institutional database with regard to patient safety indicators (PSIs), hospital-acquired conditions (HACs) and specific cranial surgery-related complications (CSCs) as high-quality metric profiles for PAEs in patients who had undergone surgery for BM in our department between 2013 and 2018. The comorbidity burden was assessed by means of the Charlson comorbidity index (CCI). A multivariate analysis was performed to identify independent predictors for the development of PAEs after surgical resection of BM. In total, 33 patients (8.5%) suffered from PAEs after surgery for BM. Of those, 17 PSI, 5 HAC and 11 CSC events were identified. Multiple brain metastases (p = 0.02) and a higher comorbidity burden (CCI &gt, 10, p = 0.003) were associated with PAEs. In-hospital mortality of patients suffering from a PAE was significantly higher than that of patients without a PAE (24% vs. 0.6%, p &lt, 0.0001). Awareness of risk factors for postoperative complications enables future prevention and optimal response, particularly in vulnerable oncological patients. The present study identified the presence of multiple brain metastases and increased comorbidity burden associated with PAEs in patients suffering from BM.

ObjectiveAlthough the treatment of glioblastoma patients is well established in neuro-oncological surgery, precious scarce data is available on patients with glioblastoma requiring postoperative prolonged mechanical ventilation (PMV). Therefore, the aim of the present study was to determine the influence of PMV on overall survival (OS) in patients with glioblastoma.MethodsPatients with newly diagnosed glioblastoma who had undergone surgical therapy and complete subsequent neuro-oncological treatment at the authors’ neuro-oncological center from January 2013 to December 2018 were selected and included in the further analysis. PMV was defined as mechanical ventilation for more than 24 h after surgery. Survival analyses were performed, including established prognostic factors such as age, Karnofsky performance score, MGMT-promoter methylation status and extent of resection.ResultsA total of 240 patients with newly diagnosed glioblastoma and subsequent surgical treatment were identified. 13 patients (5%) suffered from PMV during the treatment course of glioblastoma. All but one patient were successfully weaned from mechanical ventilation. Patients suffering from PMV achieved significantly less often favorable functional outcome after 3, 6, 9, and 12 months compared to patients without PMV. Multivariate analysis revealed PMV to constitute a significant prognostic factor for OS, independent of other prognostic factors (pConclusionsThe present study identifies PMV as significantly associated with impaired functional outcome and poor OS in patients suffering from newly diagnosed glioblastoma. These findings encourage further efforts to investigate/assess this prognostic factor in future studies.

Object Increasing age is a known negative prognostic factor for glioblastoma. However, a multifactorial approach is necessary to achieve optimal neuro-oncological treatment. It remains unclear to what extent frailty, comorbidity burden, and obesity might exert influence on survival in geriatric glioblastoma patients. We have therefore reviewed our institutional database to assess the prognostic value of these factors in elderly glioblastoma patients. Methods Between 2012 and 2018, patients aged ≥ 65 years with newly diagnosed glioblastoma were included in this retrospective analysis. Patients frailty was analyzed using the modified frailty index (mFI), while patients comorbidity burden was assessed according to the Charlson comorbidity index (CCI). Body mass index (BMI) was used as categorized variable. Results A total of 110 geriatric patients with newly diagnosed glioblastoma were identified. Geriatric patients categorized as least-frail achieved a median overall survival (mOS) of 17 months, whereas most frail patients achieved a mOS of 8 months (p = 0.003). Patients with a CCI > 2 had a lower mOS of 6 months compared to patients with a lower comorbidity burden (12 months; p = 0.03). Multivariate analysis identified “subtotal resection” (p = 0.02), “unmethylated MGMT promoter status” (p = 0.03), “BMI 2 0.31). Conclusions The present study concludes that both increased frailty and comorbidity burden are significantly associated with poor OS in geriatric patients with glioblastoma. Further, the present series suggests an obesity paradox in geriatric glioblastoma patients.

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.

BACKGROUND The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy. METHODS All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis of their tumor and methylation subgroup annotation (Heidelberg brain tumor methylation classifier v11b4; calibrated score > 0.5 required). Overall survival (OS) was compared between a pooled cohort of tumors of the RTK I/MES subgroups and RTK II tumors. RESULTS In the CCNU/TMZ arm of CeTeG/NOA-09, OS was prolonged in RTK I/MES (n = 16; median not reached, 4-year OS 69%) as compared to RTK II patients (n = 14; median 20.6 months, 4-year OS 23%; p = 0.004 logrank test). In the standard temozolomide arm of CeTeG/NOA-09, OS tended to be shorter in RTK I/MES (n = 7; median 23.7 months, 4-year OS 17%) as compared to RTK II patients (n = 17; median 35.2 months; 4-year OS 38%, p = 0.15). CONCLUSION The CCNU/TMZ-dependent survival prolongation in patients with RTK I/MES tumors as opposed to RTK II seen in CeTeG/NOA-09 suggests that methylation-based subgrouping could be predictive for CCNU/TMZ efficacy in newly diagnosed MGMT-methylated glioblastoma.

BACKGROUND The CeTeG/NOA-09 trial demonstrated a significant survival benefit of radiotherapy plus lomustine-temozolomide chemotherapy in glioblastoma patients with methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter compared to standard temozolomide chemoradiation (1). However, data on pseudoprogression following treatment according to the CeTeG/NOA-09 trial is lacking. Due to the limited specificity of conventional MRI we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of pseudoprogression from actual tumor progression. METHODS Twenty-one patients with newly diagnosed IDH-wildtype glioblastoma and methylated MGMT promoter with conventional MRI findings suspicious for tumor progression according to RANO criteria (2) after radiotherapy completion were investigated using FET PET. The maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) were calculated. Pseudoprogression was diagnosed neuropathologically or clinicoradiologically (i.e, if (i) a stable clinical course, (ii) stable or improved MRI findings, and (iii) no treatment change occurred within the next six months). Diagnostic performance of FET PET parameters was evaluated using receiver-operating-characteristic (ROC) analyses and Fisher’s exact test. Imaging results were also related to progression-free survival (PFS). RESULTS Pseudoprogression was identified in 9 of 21 patients (43%). In the majority of patients (n=8; 89%), pseudoprogression was diagnosed clinicoradiologically. The median time between radiotherapy completion and pseudoprogression was nine weeks (range, 5-25 weeks). ROC analysis yielded an optimal cutoff value of 1.95 for TBRmean to differentiate between pseudoprogression and tumor progression (sensitivity, 89%; specificity, 75%; accuracy, 81%; area under the curve, 0.72±0.13; P = 0.008). CONCLUSIONS In a considerable number of patients, pseudoprogression may occur following radiotherapy plus off-study lomustine-temozolomide chemotherapy according to the CeTeG/NOA-09 trial. FET PET appears of value for the differentiation of pseudoprogression from tumor progression in this group of patients. Literature: 1. Herrlinger et al., 2019 Lancet; 2. Wen et al., 2010 J Clin Oncol

Summary Background The CeTeG/NOA-09 trial showed significantly longer overall survival with combined lomustine–temozolomide therapy compared with standard temozolomide for patients with glioblastoma with methylated MGMT promoter. The trial also aimed to investigate the effect of lomustine–temozolomide therapy on health-related quality of life (HRQOL) and neurocognitive function, which we report here. Methods In this randomised, multicentre, open-label, phase 3 trial, newly diagnosed, chemoradiotherapy-naive patients with MGMT-methylated glioblastoma, aged 18–70 years, with a Karnofsky performance score of 70% or higher, were recruited and enrolled at 17 university hospitals in Germany. Patients received standard radiotherapy (60 Gy) and were randomly assigned (1:1, stratified by centre by allocating complete blocks of six to a centre, without masking) to either six 6-week courses of oral combined lomustine (100 mg/m2 on day 1) plus temozolomide (100–200 mg/m2 on days 2–6) or standard oral temozolomide (75 mg/m2 daily during radiotherapy plus six 4-week courses of temozolomide [150–200 mg/m2] on days 1–5, every 4 weeks). The primary endpoint was overall survival. HRQOL, assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20); and neurocognitive function, assessed using the Mini Mental State Examination (MMSE), plus a neurocognitive test battery (NOA-07), including Trail Making Test A and B (TMT-A and B), working memory tests, and tests for lexical (Controlled Oral Word Association [COWA]) and semantic verbal fluency, were secondary endpoints analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who received at least one dose of study chemotherapy). We used linear mixed-model analyses to investigate differences between treatment groups regarding HRQOL (clinically relevant ≥10 points) and MMSE scores (clinically relevant ≥3 points). The trial is registered with ClinicalTrials.gov , NCT01149109 . Findings Between June 17, 2011 and April 8, 2014, 141 patients were randomly assigned and 129 patients began treatment and were included in the mITT population (63 in the temozolomide and 66 in the lomustine–temozolomide group). Median follow-up for HRQOL (the item global health) was 19·4 months (IQR 7·8–38·6), for MMSE was 15·3 months (4·1–29·6), and for COWA was 11·0 months (0–27·5). We found no significant impairment regarding any item of HRQOL in the lomustine–temozolomide group (difference between the groups for global health 0·30 [95% CI −0·23 to 0·83]; p=0·26). Differences in MMSE were in favour of the temozolomide group (difference −0·11 [95% CI −0·19 to −0·03]; p=0·0058) but were not clinically relevant (1·76/30 points over 4 years). We found no significant difference between the groups in any subtest of the neurocognitive test battery (difference for COWA 0·04 [95% CI −0·01 to 0·09]; p=0·14). Interpretation The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine–temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine–temozolomide as a treatment option for these patients. Funding German Federal Ministry of Education and Research.

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 value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV. We retrospectively analyzed 174 patients with recurrent glioblastoma treated with BEV at two German brain tumor centers. We evaluated general patient characteristics, MGMT status, pretreatment, concomitant oncologic treatment and overall survival. Karnofsky performance score, number of prior chemotherapies, number of prior recurrences and combined treatment with irinotecan (IRI) were significantly associated with OS in univariate analysis. We did not find differences in OS related to sex, age, histology, MGMT status, prior surgical treatment or number of prior radiotherapies. Combined treatment with IRI and higher KPS both remained significantly associated with prolonged survival in multivariate analysis, but patients receiving IRI co-treatment had less advanced disease. Grouping into clinically relevant categories revealed an OS of 16.9 months from start of BEV in patients with first recurrence and KPS ≥ 80 % (n = 25). In contrast, in patients with second recurrence and KPS

Large demyelinating inflammatory central nervous system (CNS) lesions may present with contrast enhancement on magnetic resonance imaging and may mimic CNS tumors such as glioma. In ambiguous cases, new diagnostic tools that may be helpful for distinguishing between demyelinating inflammatory and neoplastic CNS lesions are required. The current study presents the case of a patient with a large contrast-enhanced frontal brain lesion, who was initially diagnosed with tumefactive multiple sclerosis. Following the progression of the brain lesion, an 18F-fluoroethyl-L-tyrosine positron emission tomography (18F-FET PET) was performed, revealing markedly elevated static 18F-FET uptake parameters along with time activity-curves consistent with glioma. Subsequently, a biopsy was undertaken, which confirmed the presence of anaplastic oligoastrocytoma. This case illustrates that 18F-FET PET may provide useful diagnostic information in cases where distinction between neoplastic and demyelinating inflammatory CNS lesions is challenging. However, further systematic and prospective analyses are warranted to explore the value of this method in this setting.

Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EVs) from the serum of glioblastoma patients and evaluated their correlation with the prognosis of these patients. The levels of 15 microRNAs in EVs that were separated by size-exclusion chromatography were studied by quantitative real-time PCR, followed by CD44 immunoprecipitation (SEC + CD44), and compared with those from the total serum of glioblastoma patients (n = 55) and healthy volunteers (n = 10). Compared to total serum, we found evidence for the enrichment of miR-21-3p and miR-106a-5p and, conversely, lower levels of miR-15b-3p, in SEC + CD44 EVs. miR-15b-3p and miR-21-3p were upregulated in glioblastoma patients compared to healthy subjects. A significant correlation with survival of the patients was found for levels of miR-15b-3p in total serum and miR-15b-3p, miR-21-3p, miR-106a-5p, and miR-328-3p in SEC + CD44 EVs. Combining miR-15b-3p in serum or miR-106a-5p in SEC + CD44 EVs with any one of the other three microRNAs in SEC + CD44 EVs allowed for a prognostic stratification of glioblastoma patients. We have thus identified four microRNAs in glioblastoma patients whose levels, in combination, can predict the prognosis for these patients.

The CeTeG/NOA-09 trial demonstrated a significant survival benefit of radiotherapy with CCNU/temozolomide (TMZ) combination therapy compared to standard TMZ therapy as first-line treatment of O6-methylguanine-DNA methyltransferase (MGMT)-promotor hypermethylated glioblastoma. Quality of life (QoL) assessment was a secondary objective to investigate if CCNU/TMZ combination chemotherapy has a detrimental effect on patient’s QoL. PATIENTS AND METHODS: Patients (n=141) received standard radiotherapy and were randomized (1:1) for CCNU/TMZ or standard TMZ. The modified intention-to-treat population consisting of 129 patients was analyzed. At least every three months, Karnofsky performance score (KPS) was determined and QoL was measured using the EORTC-QLQ C30 and BN20 questionnaires. A longitudinal mixed-model analysis was used to evaluate differences between treatment arms in the course of KPS and QoL over time. Time to first deterioration was analyzed using a Cox regression model. RESULTS: Over a period of four years, longitudinal mixed-model analysis detected no significant impairment of QoL or KPS in the CCNU/TMZ arm as compared to the TMZ arm. Time to deterioration was prolonged in one QoL domain, motor dysfunction, for patients in the experimental arm. CONCLUSION: Intensified alkylating chemotherapy with CCNU/TMZ for patients with MGMT promotor-methylated glioblastoma did not lead to a reduction of QoL or KPS compared to TMZ standard therapy.

BACKGROUND: The GLARIUS trial, which investigated the efficacy of bevacizumab (BEV)/irinotecan (IRI) compared with standard temozolomide in the first-line therapy of O(6)-methylguanine-DNA methyltransferase (MGMT)-nonmethylated glioblastoma, showed that progression-free survival was significantly prolonged by BEV/IRI, while overall survival was similar in both arms. The present report focuses on quality of life (QoL) and Karnofsky performance score (KPS) during the whole course of the disease. METHODS: Patients (n = 170) received standard radiotherapy and were randomized (2:1) for BEV/IRI or standard temozolomide. At least every 3 months KPS was determined and QoL was measured using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life and 20-item Brain Neoplasm questionnaires. A generalized estimating equation (GEE) model evaluated differences in the course of QoL and KPS over time. Also, the time to first deterioration and the time to postprogression deterioration were analyzed separately. RESULTS: In all dimensions of QoL and KPS, GEE analyses and time to first deterioration analyses did not detect significant differences between the treatment arms. At progression, 82% of patients receiving second-line therapy in the standard arm received BEV second-line therapy. For the dimensions of motor dysfunction and headaches, time to postprogression deterioration was prolonged in the standard arm receiving crossover second-line BEV in the vast majority of patients at the time of evaluation. CONCLUSIONS: GLARIUS did not find indications for a BEV-induced detrimental effect on QoL in first-line therapy of MGMT-nonmethylated GBM patients. Moreover, GLARIUS provided some indirect corroborative data supporting the notion that BEV may have beneficial effects upon QoL in relapsed GBM.

BACKGROUND The CeTeG/NOA-09 trial recently showed a survival benefit for combination chemotherapy with CCNU/TMZ in glioblastoma patients with a methylated MGMT promoter as determined by quantitative Methylation-Specific PCR (qMSP). Identifying patient subgroups with a pronounced benefit from this novel treatment is crucial. Here, we report on the prognostic and predictive value of MGMT promoter methylation ratio determined by qMSP and investigate the concordance of pyrosequencing (PSQ) and qMSP for patients in this trial. METHODS qMSP and PSQ were used for MGMT promoter methylation analysis. The mITT population of the CeTeG/NOA-09 trial was used for multivariate analysis including the parameters MGMT promoter methylation ratio, RPA class and study center. RESULTS Patients of the mITT population of the CeTeG/NOA-09 trial (n=129) with MGMT promoter methylation ratio greater than 4 (qMSP) showed a superior overall survival compared to patients with borderline methylation ratio of 2–4 (p=0.0251). In the latter patients, treatment with CCNU/TMZ did not show a survival benefit (p=0.924). Multivariate analysis with treatment arm, RPA class and study center as covariates did not confirm a prognostic or predictive value of MGMT promoter methylation ratio (qMSP) for patients of the mITT population (n=129, HR=0.88; 95% CI: 0.72 – 1.08) or patients with a ratio greater than 4 (n=117, HR =0.86; 95% CI: 0.69 – 1.07). In a subset of 49 trial patients, qMSP and PSQ showed not only a high qualitative (45/49; 91.8%), but also a high quantitative concordance rate (Spearman correlation, r=0.83, p< 0.0001). CONCLUSION Glioblastoma patients with borderline MGMT promoter methylation (qMSP ratio 2–4) do not seem to benefit from combination treatment with CCNU/TMZ. Thus, we propose a qMSP cut-off of 4 as a novel decision tool for clinicians. qMSP and PSQ show a high concordance rate indicating that a decision for combination therapy can also be based on PSQ results.

BACKGROUND: Pseudoprogression is characterized by increasing contrast-enhancement in the tumor area mimicking tumor progression, which, however, remains stable or subsides in control MRI 4-8 weeks later. Pseudoprogression is thought to be a sign of response to therapy rather than rapid tumor growth. It mainly occurs within three months after radiochemotherapy but it is increasingly observed that pseudoprogression may also develop substantially later and may be particularly difficult to distinguish from true tumor progression which is much more prevalent at this stage. As conventional MRI lacks specificity for pseudoprogression, there is still an unmet need for additional imaging modalities in this setting. PATIENTS AND METHODS: Twenty-two clinically stable patients diagnosed with high-grade glioma were examined by F-18-fluoroethyl-tyrosine PET (FET PET) at the time of either new contrast enhancement or ≥25% increase of an existing contrast-enhanced lesion on conventional MRI ≥12 weeks after last radiochemotherapy. For static analysis, maximum and mean tumor/brain ratios (TBRmax, TBRmean) of FET uptake were determined. In addition, dynamic FET PET parameters were analysed: time-to peak (TTP) and time-activity curve patterns. Diagnosis of late pseudoprogression or progression was established according to RANO criteria relying on follow-up MRI obtained at least 6-8 weeks from the index MRI and served as reference for PET data evaluation. RESULTS: Based upon follow-up MRI 11 patients were diagnosed with late pseudoprogression, in 72.7% (8 out of 11) of whom MGMT methylation was tested positive. Both TBRmax and TBRmean were significantly lower compared with progressive tumor (TBRmax, 2.12 ± 0.22 vs. 3.63 ± 0.18; TBRmean, 1.47 ± 0.17 vs. 2.19 ± 0.05; both p < 0.001). Receiver-operating-characteristic (ROC) analysis yielded an optimal cut-off of 3.05 for TBRmax (sensitivity, 100%; specificity, 91.7%; AUC, 0.96; 95% CI, 0.88 - 1.0; p < 0.001) and 1.95 for TBRmean (specificity, 91.7%; sensitivity, 77.8%; AUC, 0.94; 95% CI, 0.47 - 1.0; p = 0.001). ROC analysis of TTP revealed at an optimal cutoff of 19 min a sensitivity of 100% along with a specificity of 90% for predicting pseudoprogression (AUC, 0.92; 95% CI, 0.76 - 1.0; p = 0.01). However, there was no significant association between the type of curve pattern and the diagnosis of late pseudoprogression (χ2 (1) = 3.19, p = 0.117). CONCLUSION: F-18-FET PET may provide valuable information for the assessment of late pseudoprogression. Systematic prospective analyses are warranted.