Publications by authors named "Wolfgang Wick"

456 Publications

Radioresistance and transcriptional reprograming of invasive glioblastoma cells.

Int J Radiat Oncol Biol Phys 2021 Sep 14. Epub 2021 Sep 14.

Division of Molecular & Translational Radiation Oncology, Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg University Hospital (UKHD), Heidelberg, Germany; Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD), Faculty of Medicine (MFHD) of the Heidelberg University, and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany; CCU Translational Radiation Oncology, CCU Radiation Oncology, CCU Neurooncology, National Center for Tumor Diseases (NCT) German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD), Heidelberg, Germany; Departments of Neurology, Neurosurgery and Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany. Electronic address:

Purpose: Infiltrative growth pattern is a hallmark of glioblastoma (GBM). Radiotherapy aims to eradicate microscopic residual GBM cells post-surgical removal of the visible tumor bulk. However, in field recurrences remain the major pattern of therapy failure. We hypothesized that the radiosensitivity of peripheral invasive tumor cells (peri) may differ from predominantly investigated tumor bulk.

Material And Methods: Invasive GBM populations were generated via debulking of the visible tumor core and serial orthotopic transplantation of peri cells and sustained pro-invasive phenotype of peri cell was confirmed in-vitro by scratch assay and time lapse imaging. In parallel, invasive GBM cells were selected by transwell assay and from peri cells of patient derived 3D spheroid cultures. Transcriptome analysis deciphered a GBM invasion associated gene signature and functional involvement of key pathways was validated by pharmacological inhibition.

Results: Compared to the bulk cells, invasive GBM populations acquired a radioresistant phenotype characterized by increased cell survival, reduced cell apoptosis and enhanced DNA double strand break (DSB) repair proficiency. Transcriptome analysis revealed a reprograming of invasive cells towards augmented activation of EGFR and NF-κB related pathways while metabolic processes were downregulated. An invasive GBM score (iGS) derived from this transcriptional fingerprint correlated well with patient outcome. Inhibition of EGFR and NF-κB signaling re-sensitized invasive cells to irradiation. Invasive cells were eradicated with similar efficacy by particle therapy with carbon ions.

Conclusions: Our data indicate that invasive tumor cells constitute a phenotypically distinct and highly radioresistant GBM subpopulation with prognostic impact that may be vulnerable to targeted therapy and carbon-ions.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.017DOI Listing
September 2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Acta Neuropathol 2021 Aug 5. Epub 2021 Aug 5.

Institute of Neuropathology, University of Giessen, Giessen, Germany.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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http://dx.doi.org/10.1007/s00401-021-02356-6DOI Listing
August 2021

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Erasmus Medical Center Cancer Institute, Department of Neuro-Oncology, 3015 GD Rotterdam, The Netherlands.

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
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http://dx.doi.org/10.3390/cancers13143451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303185PMC
July 2021

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.

Neuro Oncol 2021 Jul 7. Epub 2021 Jul 7.

Brain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Glioblastoma is the most common primary malignancy of the central nervous system with dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, has failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials.

Methods: We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples.

Results: Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype.

Conclusion: This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.
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http://dx.doi.org/10.1093/neuonc/noab158DOI Listing
July 2021

Preventive effect of sensorimotor exercise and resistance training on chemotherapy-induced peripheral neuropathy: a randomised-controlled trial.

Br J Cancer 2021 Jul 5. Epub 2021 Jul 5.

Working Group Exercise Oncology, Division of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Heidelberg, Germany.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, unpleasant and usually long-lasting side effect of neurotoxic chemotherapeutic agents. This study aimed to investigate the preventive potential of sensorimotor- (SMT) and resistance training (RT) on CIPN.

Methods: Patients (N = 170) were randomised to SMT, RT or usual care (UC). Both exercise groups trained 3×/week for a total of 105 min/week during neurotoxic chemotherapy (mean length: 20 weeks). Before and 3 weeks after neurotoxic chemotherapy, CIPN signs/symptoms were assessed via Total Neuropathy Score (TNSr; primary endpoint) and EORTC QLQ-CIPN15 questionnaire. In addition, balance (centre of pressure), muscle strength (isokinetic), quality of life (QoL, EORTC QLQ-C30) and relative chemotherapy dose intensity (RDI) were investigated. The follow-up period covered 6 months after the end of chemotherapy.

Results: Intention-to-treat analyses (N = 159) revealed no differences regarding CIPN signs/symptoms. Exploratory per-protocol analyses (minimum training attendance rate 67%; N = 89) indicated that subjectively perceived sensory symptoms in the feet increased less during chemotherapy in the adherent exercisers (pooled group: SMT+RT) than in the UC group (-8.3 points (-16.1 to -0.4); P = 0.039, ES = 1.27). Furthermore, adherent exercisers received a higher RDI (96.6 ± 4.8 vs. 92.2 ± 9.4; P = 0.045), showed a better course of muscular strength (+20.8 Nm (11.2-30.4); P < 0.001, ES = 0.57) and QoL (+12.9 points (3.9-21.8); P = 0.005, ES = 0.64). During follow-up, CIPN signs/symptoms persisted in all groups.

Conclusions: This study demonstrates that SMT and/or RT alleviate subjectively perceived sensory CIPN symptoms in the feet and other clinically relevant cancer therapy-related outcomes, if an appropriate training stimulus is achieved.

Clinical Trial Registration: NCT02871284.
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http://dx.doi.org/10.1038/s41416-021-01471-1DOI Listing
July 2021

The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis.

Neuro Oncol 2021 Jul 3. Epub 2021 Jul 3.

Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Brain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions.

Methods: To investigate the temporo-spatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice.

Results: In vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation - permanent intravascular arrest, extravasation, and initial perivascular growth - are most vulnerable to dual PI3K/mTOR inhibition.

Conclusion: These findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.
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http://dx.doi.org/10.1093/neuonc/noab159DOI Listing
July 2021

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

J Immunother Cancer 2021 Jul;9(7)

Duke Cancer Institute, Duke University, Durham, North Carolina, USA

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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http://dx.doi.org/10.1136/jitc-2021-002459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256733PMC
July 2021

SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

Neuro Oncol 2021 Jun 26. Epub 2021 Jun 26.

Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA and Harvard Medical School, Boston, MA, USA.

Objective: To update the 2000 American Academy of Neurology (AAN) practice parameter on anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

Methods: Following the 2017 AAN methodologies, a systematic literature review utilizing PubMed, EMBASE, Cochrane, and Web of Science databases was performed. The studies were rated based on the AAN therapeutic or causation classification of evidence (Class I-IV).

Results: Thirty-seven articles were selected for final analysis. There were limited high level, Class I studies and mostly Class II and III studies. The AAN affirmed the value of these guidelines.

Recommendations: In patients with newly diagnosed brain tumors who have not had a seizure, clinicians should not prescribe anti-epileptic drugs (AEDs) to reduce the risk of seizures (Level A). In brain tumor patients undergoing surgery, there is insufficient evidence to recommend prescribing AEDs to reduce the risk of seizures in the peri- or postoperative period (Level C). There is insufficient evidence to support prescribing valproic acid or levetiracetam with the intent to prolong progression-free or overall survival (Level C). Physicians may consider use of levetiracetam over older AEDs to reduce side effects (Level C). There is insufficient evidence to support using tumor location, histology, grade, molecular/imaging features, when deciding whether or not to prescribe prophylactic AEDs (Level U).
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http://dx.doi.org/10.1093/neuonc/noab152DOI Listing
June 2021

Oncolytic virotherapy: Potentially a game-changing tumor treatment.

Cancer Cell 2021 Jun;39(6):753-755

Department of Neurology, University Clinic Heidelberg, Heidelberg, Germany; German Cancer Center (DKTK) Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

A two-center phase I trial published in the New England Journal of Medicine shows safety and feasibility of locally administered oncolytic herpes simplex virus-1 virus plus 5 Gy radiation for progressive pediatric high-grade gliomas. Patients seemed to have an unusually good clinical course and showed immune activation in post-treatment tissues.
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http://dx.doi.org/10.1016/j.ccell.2021.05.014DOI Listing
June 2021

Emergency intubation during thrombectomy for acute ischemic stroke in patients under primary procedural sedation.

Neurol Res Pract 2021 May 17;3(1):27. Epub 2021 May 17.

Department of Neurology, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg, Germany.

Background: Emergency intubation is an inherent risk of procedural sedation regimens for endovascular treatment (EVT) of acute ischemic stroke. We aimed to characterize the subgroup of patients, who had to be emergently intubated, to identify predictors of the need for intubation and assess their outcomes.

Methods: This is a retrospective analysis of the single-center study KEEP SIMPLEST, which evaluated a new in-house SOP for EVT under primary procedural sedation. We used descriptive statistics and regression models to examine predictors and functional outcome of emergently intubated patients.

Results: Twenty of 160 (12.5%) patients were emergently intubated. National Institutes of Health Stroke Scale (NIHSS) on admission, premorbid modified Rankin scale (mRS), Alberta Stroke Program Early CT Score, age and side of occlusion were not associated with need for emergency intubation. Emergency intubation was associated with a lower rate of successful reperfusion (OR, 0.174; 95%-CI, 0.045 to 0.663; p = 0.01). Emergently intubated patients had higher in-house mortality (30% vs 6.4%; p = 0.001) and a lower rate of mRS 0-2 at 3 months was observed in those patients (10.5% vs 37%, p = 0.024).

Conclusions: Emergency intubation during a primary procedural sedation regimen for EVT was associated with lower rate of successful reperfusion. Less favorable outcome was observed in the subgroup of emergently intubated patients. More research is required to find practical predictors of intubation need and to determine, whether emergency intubation is safe under strict primary procedural sedation regimens for EVT.
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http://dx.doi.org/10.1186/s42466-021-00125-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130257PMC
May 2021

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

Lancet Oncol 2021 06 14;22(6):813-823. Epub 2021 May 14.

Radiotherapy Department, Gustave Roussy University Hospital, Villejuif, Cedex, France.

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.

Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.

Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.

Interpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.

Funding: Merck Sharpe & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00090-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191233PMC
June 2021

Radiomic Analysis to Predict Outcome in Recurrent Glioblastoma Based on Multi-Center MR Imaging From the Prospective DIRECTOR Trial.

Front Oncol 2021 14;11:636672. Epub 2021 Apr 14.

Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.

Background: Based on promising results from radiomic approaches to predict ( status) and clinical outcome in patients with newly diagnosed glioblastoma, the current study aimed to evaluate radiomics in recurrent glioblastoma patients.

Methods: Pre-treatment MR-imaging data of 69 patients enrolled into the DIRECTOR trial in recurrent glioblastoma served as a training cohort, and 49 independent patients formed an external validation cohort. Contrast-enhancing tumor and peritumoral volumes were segmented on MR images. 180 radiomic features were extracted after application of two MR intensity normalization techniques: fixed number of bins and linear rescaling. Radiomic feature selection was performed principal component analysis, and multivariable models were trained to predict status, progression-free survival from first salvage therapy, referred to herein as PFS, and overall survival (OS). The prognostic power of models was quantified with concordance index (CI) for survival data and area under receiver operating characteristic curve (AUC) for the status.

Results: We established and validated a radiomic model to predict status using linear intensity interpolation and considering features extracted from gadolinium-enhanced T1-weighted MRI (training AUC = 0.670, validation AUC = 0.673). Additionally, models predicting PFS and OS were found for the training cohort but were not confirmed in our validation cohort.

Conclusions: A radiomic model for prediction of promoter methylation status from tumor texture features in patients with recurrent glioblastoma was successfully established, providing a non-invasive approach to anticipate patient's response to chemotherapy if biopsy cannot be performed. The radiomic approach to predict PFS and OS failed.
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http://dx.doi.org/10.3389/fonc.2021.636672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079773PMC
April 2021

Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.

Neuro Oncol 2021 Sep;23(9):1547-1559

Pathology Department, Erasmus MC, Rotterdam, the Netherlands.

Background: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.

Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.

Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.

Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
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http://dx.doi.org/10.1093/neuonc/noab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408862PMC
September 2021

Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1.

Acta Neuropathol 2021 07 19;142(1):179-189. Epub 2021 Apr 19.

Division of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.

Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
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http://dx.doi.org/10.1007/s00401-021-02302-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217054PMC
July 2021

Prognostic Value of microRNA-221/2 and 17-92 Families in Primary Glioblastoma Patients Treated with Postoperative Radiotherapy.

Int J Mol Sci 2021 Mar 15;22(6). Epub 2021 Mar 15.

German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222; miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients ( = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials.
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http://dx.doi.org/10.3390/ijms22062960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998975PMC
March 2021

Primary CNS lymphoma after CLIPPERS: a case series.

J Neurol Neurosurg Psychiatry 2021 Mar 31. Epub 2021 Mar 31.

Department of Neurology, Heidelberg University Hospital, Heidelberg, Baden-Württemberg, Germany

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http://dx.doi.org/10.1136/jnnp-2020-325759DOI Listing
March 2021

A vaccine targeting mutant IDH1 in newly diagnosed glioma.

Nature 2021 Apr 24;592(7854):463-468. Epub 2021 Mar 24.

Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany.

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H) tumours in syngeneic MHC-humanized mice. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H) astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG and CXCL13 T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
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http://dx.doi.org/10.1038/s41586-021-03363-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046668PMC
April 2021

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

Acta Neuropathol 2021 06 19;141(6):945-957. Epub 2021 Mar 19.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1 mutations. Patients harbouring IDH1 mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1 have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1 mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
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http://dx.doi.org/10.1007/s00401-021-02291-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113211PMC
June 2021

Diagnostic biomarkers from proteomic characterization of cerebrospinal fluid in patients with brain malignancies.

J Neurochem 2021 Jul 9;158(2):522-538. Epub 2021 Apr 9.

Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.
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http://dx.doi.org/10.1111/jnc.15350DOI Listing
July 2021

Prophylactic anticoagulation in patients with glioblastoma or brain metastases and atrial fibrillation: an increased risk for intracranial hemorrhage?

J Neurooncol 2021 May 5;152(3):483-490. Epub 2021 Mar 5.

Department of Neurology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Purpose: Patients with glioblastoma (GBM) or brain metastases (MET) and atrial fibrillation (AF) might be at an increased risk of intracranial hemorrhage (ICH) due to anticoagulation (AC). Our aim was to assess this risk.

Methods: Our institution's database (from 2005 to 2017) was screened for patients with GBM or MET and AF with an indication for AC according to their CHADSVASc stroke risk score (≥ 2). Required follow-up was at least 3 months. AC was either performed with heparins, phenprocoumon or non-Vitamin K antagonist oral anticoagulants. Applying the propensity score approach, patient cohorts (matched according to primary tumor, age, sex) were generated (GBM [or MET] with AF ± AC, GBM [or MET] without AF/AC, no GBM [or MET] but AF on AC). ICH was defined as clinical deterioration caused by new blood on imaging. A log rank test was performed to compare the risk for ICH between the three groups.

Results: In total, 104 patients were identified of which 49 with GBM (37% on AC) and 37 with MET (46% on AC) were successfully matched. Median follow up was 8.6 and 7.2 months, respectively. ICH occurred in 10.2% of GBM + AF and 12.2% GBM-AF, whereas 8% of patients with AF on AC suffered ICH (p = 0.076). 13.5% of patients with MET + AF had ICHs, in the controls it was 16% for MET-AF and 8% for AF on AC (p = 0.11).

Conclusion: AC did not seem to influence the incidence of ICH in patients with glioblastoma or brain metastases within follow up of just under 9 months.
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http://dx.doi.org/10.1007/s11060-021-03716-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084835PMC
May 2021

Telomerase reverse transcriptase promoter mutation- and O-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Eur J Cancer 2021 Apr 22;147:84-94. Epub 2021 Feb 22.

Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany; German Cancer Consortium, Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Aim Of The Study: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.

Methods: MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).

Results: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.

Conclusions: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.
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http://dx.doi.org/10.1016/j.ejca.2021.01.014DOI Listing
April 2021

Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors.

Clin Cancer Res 2021 May 23;27(10):2723-2733. Epub 2021 Feb 23.

Pharmaceuticals Division, Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.

Patients And Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with m solid tumors.

Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG ( = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.

Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4256DOI Listing
May 2021

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma.

Nat Commun 2021 02 12;12(1):1014. Epub 2021 Feb 12.

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy-independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.
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http://dx.doi.org/10.1038/s41467-021-21117-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881116PMC
February 2021

Adult precision medicine: learning from the past to enhance the future.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa145. Epub 2020 Oct 24.

Department of Oncology, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.

Despite therapeutic advances for other malignancies, gliomas remain challenging solid tumors to treat. Complete surgical resection is nearly impossible due to gliomas' diffuse infiltrative nature, and treatment is hampered by restricted access to the tumors due to limited transport across the blood-brain barrier. Recent advances in genomic studies and next-generation sequencing techniques have led to a better understanding of gliomas and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in the management of gliomas, with encouraging results in preclinical studies and early clinical trials. However, molecular characterization of gliomas revealed significant heterogeneity, which poses a challenge for targeted therapeutic approaches. In this context, leading neuro-oncology researchers and clinicians, industry innovators, and patient advocates convened at the inaugural annual Remission Summit held in Orlando, FL in February 2019 to discuss the latest advances in immunotherapy and precision medicine approaches for the treatment of adult and pediatric brain tumors and outline the unanswered questions, challenges, and opportunities that lay ahead for advancing the duration and quality of life for patients with brain tumors. Here, we provide historical context for precision medicine in other cancers, present emerging approaches for gliomas, discuss their limitations, and outline the steps necessary for future success. We focus on the advances in small molecule targeted therapy, as the use of immunotherapy as an emerging precision medicine modality for glioma treatment has recently been reviewed by our colleagues.
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http://dx.doi.org/10.1093/noajnl/vdaa145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846182PMC
October 2020

Sarcoma classification by DNA methylation profiling.

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs.

Mol Cancer Res 2021 04 22;19(4):688-701. Epub 2020 Dec 22.

Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Specific biological properties of those circulating cancer cells that are the origin of brain metastases (BM) are not well understood. Here, single circulating breast cancer cells were fate-tracked during all steps of the brain metastatic cascade in mice after intracardial injection over weeks. A novel two-photon microscopy methodology was developed that allowed to determine the specific cellular and molecular features of breast cancer cells that homed in the brain, extravasated, and successfully established a brain macrometastasis. Those BM-initiating breast cancer cells (BMIC) were mainly originating from a slow-cycling subpopulation that included only 16% to 20% of all circulating cancer cells. BMICs showed enrichment of various markers of cellular stemness. As a proof of principle for the principal usefulness of this approach, expression profiling of BMICs versus non-BMICs was performed, which revealed upregulation of NDRG1 in the slow-cycling BMIC subpopulation in one BM model. Here, BM development was completely suppressed when NDRG1 expression was downregulated. In accordance, in primary human breast cancer, NDRG1 expression was heterogeneous, and high NDRG1 expression was associated with shorter metastasis-free survival. In conclusion, our data identify temporary slow-cycling breast cancer cells as the dominant source of brain and other metastases and demonstrates that this can lead to better understanding of BMIC-relevant pathways, including potential new approaches to prevent BM in patients. IMPLICATIONS: Cancer cells responsible for successful brain metastasis outgrowth are slow cycling and harbor stemness features. The molecular characteristics of these metastasis-initiating cells can be studied using intravital microscopy technology.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0863DOI Listing
April 2021

Calculating the net clinical benefit in neuro-oncology clinical trials using two methods: quality-adjusted survival effect sizes and joint modeling.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa147. Epub 2020 Oct 29.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Two methods combining survival and health-related quality of life (HRQoL) data in glioma trials to calculate the "net clinical benefit" were evaluated: Quality-adjusted effect sizes (QASES) and joint modeling (JM).

Methods: The net clinical benefit in two trials was calculated as proof of concept for other trials. With the QASES method, effect sizes for differences in progression-free survival (PFS) or overall survival (OS) and HRQoL between the experimental arm and standard treatment arm were calculated, while the relative emphasis placed on survival/HRQoL varied. JM allows simultaneous modeling of HRQoL and OS/PFS.

Results: In the EORTC 26951 trial, combined radiochemotherapy significantly prolonged OS (difference 11.7 months), but also resulted in more patients experiencing clinically relevant worsening (≥10 points) in appetite loss and nausea/vomiting shortly after treatment. Using QASES, the survival benefit of additional procarbazine, lomustine, and vincristine (PCV) decreased from 42.3 months to 29.5 and 28.2 months when accounting for appetite loss and nausea/vomiting, respectively. JM analyses resulted in a loss of the beneficial effect of additional PCV between 13% and 24% when adjusting for different HRQoL parameters. The EORTC 22033 trial showed no significant PFS difference between radiotherapy or temozolomide alone (46 vs 39 months), nor clinically relevant differences in HRQoL. JM analyses also showed no significant association between PFS and HRQoL scales/items, whereas QASES showed that temozolomide alone was more favorable when considering symptom burden (47-49 instead of 39 months).

Conclusions: Both methods resulted in different outcomes, but adjusting for the impact of treatment on HRQoL resulted in theoretically reduced survival benefits.
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http://dx.doi.org/10.1093/noajnl/vdaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772555PMC
October 2020

Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank.

Neuro Oncol 2021 03;23(3):356-375

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.
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http://dx.doi.org/10.1093/neuonc/noaa277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992879PMC
March 2021

Objective neurocognitive functioning and neurocognitive complaints in patients with high-grade glioma: Evidence of cognitive awareness from the European Organisation for Research and Treatment of Cancer brain tumour clinical trials.

Eur J Cancer 2021 02 22;144:162-168. Epub 2020 Dec 22.

Department of Neurology and Brain Tumor Center Amsterdam at Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.

Background: Neurocognitively impaired patients with brain tumour are presumed to have reduced cognitive awareness preventing them from adequately valuing and reporting their own functioning, for instance, when providing patient-reported outcomes (PROs) such as health-related quality of life instruments. In this cross-sectional study, we aimed at assessing the concordance of neurocognitive complaints (NCCs) and objective neurocognitive functioning (NCF) as a measure of cognitive awareness.

Methods: NCF was assessed using an internationally accepted clinical trial battery. NCC was assessed using the cognitive functioning questionnaire from the Medical Outcome Study (MOS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire cognitive functioning subscale. Patients were divided in cognitively impaired and unimpaired groups, based on their NCF performance. Pearson's correlation coefficients between NCF and NCCs were calculated. The same procedure was used to evaluate the correlation of NCF and QLQ-C30 CF subscale.

Results: Data from EORTC trials 26091 and 26101 were pooled into a data set of 546 patients. Twenty percent of patients could be characterised as unimpaired (109) and 80% as impaired (437). Impaired patients reported more cognitive complaints on the MOS scale than unimpaired patients. Correlations between NCF and NCCs were weak but significant for impaired patients and non-significant for unimpaired ones. Similar results were found for the correlation between NCF test performance and the QLQ-C30 CF subscale.

Conclusion: Correlations between NCF test scores and complaints were weak but suggesting that neurocognitive impairment in patients with HGG does not preclude cognitive awareness. However, considering the findings of this study, we would suggest not to use PROs as a surrogate of performance-based neurocognitive evaluation.
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http://dx.doi.org/10.1016/j.ejca.2020.10.040DOI Listing
February 2021
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