Publications by authors named "Michael Weller"

729 Publications

Anatomical phenotyping and staging of brain tumours.

Brain 2021 Sep 23. Epub 2021 Sep 23.

Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.

Unlike other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumor progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumor entities, to assess the association of anatomical tumor features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. Tumor probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumor prevalence to the relative volume of the respective structure. We analyzed the spatiotemporal tumor dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumor features at diagnosis. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary central nervous system lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumors mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behavior within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumors, a gradual deviation from this neuroepithelial spatiotemporal behavior was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumors through topographic probability and growth pattern assessment. The association of anatomical tumor features with survival defined critical steps in the anatomical sequence of neuroepithelial tumor progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.
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http://dx.doi.org/10.1093/brain/awab352DOI Listing
September 2021

Radiotherapy for glioblastoma patients with poor performance status.

J Cancer Res Clin Oncol 2021 Aug 26. Epub 2021 Aug 26.

Department of Radiation Oncology and Competence Center for Palliative Care, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.

Purpose: There is limited information on treatment recommendations for glioblastoma patients with poor performance status. Here, we aim to evaluate the association of radiotherapy on survival in glioblastoma patients presenting with poor postoperative performance status in first-line setting.

Methods: We retrospectively analyzed data of 93 glioblastoma patients presenting with poor postoperative performance status (ECOG 2-4) at the University Hospital Zurich, Switzerland, in the years 2005-2019. A total of 43 patients received radiotherapy with or without systemic therapy in the first-line setting, whereas 50 patients received no additive local or systemic treatment after initial biopsy or resection. Overall survival was calculated from primary diagnosis and from the end of radiotherapy. In addition, factors influencing survival were analyzed.

Results: Median overall survival from primary diagnosis was 6.2 months in the radiotherapy group (95% CI 6.2-14.8 weeks, range 2-149 weeks) and 2.3 months in the group without additive treatment (95% CI 1.3-7.4 weeks, range 0-28 weeks) (p < 0.001). This survival benefit was confirmed by landmark analyses. Factors associated with overall survival were extent of resection and administration of radiotherapy with or without systemic treatment. Median survival from end of radiotherapy was 3 months (95% CI 4.3-21.7 weeks, range 0-72 weeks), with 25.6% (n = 11) early termination of treatment and 83.7% (n = 36) requiring radiotherapy as in-patients. Performance status improved in 27.9% (n = 12) of patients after radiotherapy.

Conclusion: In this retrospective single-institution analysis, radiotherapy improved overall survival in patients with poor performance status, especially in patients who were amendable to neurosurgical resection.
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http://dx.doi.org/10.1007/s00432-021-03770-9DOI Listing
August 2021

The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy.

Eur J Cancer 2021 Oct 20;156:93-108. Epub 2021 Aug 20.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Recent therapeutic advances involving the use of systemic targeted treatments and immunotherapeutic agents in patients with advanced cancers have translated into improved survival rates. Despite the emergence of such promising pharmacological therapies and extended survival, the frequency of metastases in the central nervous system has steadily increased. Effective medical and surgical therapies are available for many patients with brain metastases and need to be incorporated into multi-disciplinary care protocols. The role of neurosurgeons is evolving within these multi-disciplinary care teams. Surgical resection of brain metastases can provide immediate relief from neurological symptoms due to large lesions and provides the histopathological diagnosis in cases of no known primary malignancy. In situations where immunotherapy is part of the oncological treatment plan, surgery may be proposed for expeditious relief of edema to remove the need for steroids. In patients with multiple brain metastases and mixed response to therapeutics or radiosurgery, tumour resampling allows tissue analysis for druggable targets or to distinguish radiation effects from progression. Ventriculo-peritoneal shunting may improve quality of life in patients with hydrocephalus associated with leptomeningeal tumour dissemination and may allow for time to administer more therapy thus prolonging overall survival. Addressing the limited efficacy of many oncological drugs for brain metastases due to insufficient blood-brain barrier penetrance, clinical trial protocols in which surgical specimens are analysed after pre-surgical administration of therapeutics offer pharmacodynamic insights. Comprehensive neurosurgical assessment remains an integral element of multi-disciplinary oncological care of patients with brain metastases and is integral to tumour biology research and therapeutic advancement.
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http://dx.doi.org/10.1016/j.ejca.2021.07.032DOI Listing
October 2021

Oligomerization and Nitration of the Grass Pollen Allergen Phl p 5 by Ozone, Nitrogen Dioxide, and Peroxynitrite: Reaction Products, Kinetics, and Health Effects.

Int J Mol Sci 2021 Jul 16;22(14). Epub 2021 Jul 16.

Multiphase Chemistry Department, Max Planck Institute for Chemistry, 55128 Mainz, Germany.

The allergenic and inflammatory potential of proteins can be enhanced by chemical modification upon exposure to atmospheric or physiological oxidants. The molecular mechanisms and kinetics of such modifications, however, have not yet been fully resolved. We investigated the oligomerization and nitration of the grass pollen allergen Phl p 5 by ozone (O), nitrogen dioxide (NO), and peroxynitrite (ONOO). Within several hours of exposure to atmospherically relevant concentration levels of O and NO, up to 50% of Phl p 5 were converted into protein oligomers, likely by formation of dityrosine cross-links. Assuming that tyrosine residues are the preferential site of nitration, up to 10% of the 12 tyrosine residues per protein monomer were nitrated. For the reaction with peroxynitrite, the largest oligomer mass fractions (up to 50%) were found for equimolar concentrations of peroxynitrite over tyrosine residues. With excess peroxynitrite, the nitration degrees increased up to 40% whereas the oligomer mass fractions decreased to 20%. Our results suggest that protein oligomerization and nitration are competing processes, which is consistent with a two-step mechanism involving a reactive oxygen intermediate (ROI), as observed for other proteins. The modified proteins can promote pro-inflammatory cellular signaling that may contribute to chronic inflammation and allergies in response to air pollution.
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http://dx.doi.org/10.3390/ijms22147616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303544PMC
July 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

Chemotherapy for adult patients with spinal cord gliomas.

Neurooncol Pract 2021 Aug 8;8(4):475-484. Epub 2021 Mar 8.

Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.

Background: The incidence of spinal cord gliomas, particularly in adults is low, and the role of chemotherapy has remained unclear.

Methods: We performed a multicenter, retrospective study of 21 patients diagnosed with spinal cord glioma who received chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by magnetic resonance imaging. Data on radiotherapy were taken into consideration.

Results: Thirteen patients were diagnosed with astrocytic gliomas World Health Organization (WHO) grades 1-4, the remaining eight patients with ependymomas WHO grades 1 or 3. Most patients had more than one neurosurgical intervention. Median age at time of first chemotherapy was 33 years (range 21-67 years). Seven patients had chemotherapy combined with radiotherapy as first-line treatment. Two patients had chemoradiotherapy at recurrence, without prior tumor-specific treatment beyond surgery. One patient received chemotherapy alone as first-line treatment and 2 patients had chemotherapy alone at recurrence, without prior treatment. Nine patients had received radiation therapy at an earlier time and chemotherapy was given at time of further recurrences. Best responses in astrocytomas were as follows: chemotherapy alone-2 stable disease (SD) and 3 progressive disease (PD); chemoradiotherapy-1 complete response, 3 SD, and 4 PD. Best responses in ependymomas were as follows: chemotherapy alone-1 partial response, 5 SD, and 1 PD; chemoradiotherapy-1 SD.

Conclusions: Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal cord glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.
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http://dx.doi.org/10.1093/nop/npab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278344PMC
August 2021

Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative.

Neurooncol Pract 2021 Aug 13;8(4):417-425. Epub 2021 Feb 13.

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

Background: The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.

Methods: A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.

Results: A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).

Conclusion: Many different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
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http://dx.doi.org/10.1093/nop/npab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278354PMC
August 2021

Economic Impact of Poststroke Delirium and Associated Risk Factors: Findings From a Prospective Cohort Study.

Stroke 2021 Jul 8:STROKEAHA120033005. Epub 2021 Jul 8.

University of Zurich, University Hospital Zurich, Switzerland (S.B.).

Background And Purpose: Delirium is a common severe complication of stroke. We aimed to determine the cost-of-illness and risk factors of poststroke delirium (PSD).

Methods: This prospective single-center study included n=567 patients with acute stroke from a hospital-wide delirium cohort study and the Swiss Stroke Registry in 2014. Delirium was determined by Delirium Observation Screening Scale or Intensive Care Delirium Screening Checklist 3 times daily during the first 3 days of admission. Costs reflected the case-mix index and diagnosis-related groups from 2014 and were divided into nursing, physician, and total costs. Factors associated with PSD were assessed with multiple regression analysis. Partial correlations and quantile regression were performed to assess costs and other factors associated with PSD.

Results: The incidence of PSD was 39.0% (221/567). Patients with delirium were older than non-PSD (median 76 versus 70 years; <0.001), 52% male (115/221) versus 62% non-PSD (214/346) and hospitalized longer (mean 11.5 versus 9.3 days; <0.001). Dementia was the most relevant predisposing factor for PSD (odds ratio, 16.02 [2.83-90.69], =0.002). Moderate to severe stroke (National Institutes of Health Stroke Scale score 16-20) was the most relevant precipitating factor (odds ratio, 36.10 [8.15-159.79], <0.001). PSD was a strong predictor for 3-month mortality (odds ratio, 15.11 [3.33-68.53], <0.001). Nursing and total costs were nearly twice as high in PSD (<0.001). There was a positive correlation between total costs and admission National Institutes of Health Stroke Scale (correlation coefficient, 0.491; <0.001) and length of stay (correlation coefficient, 0.787; <0.001) in all patients. Quantile regression revealed rising nursing and total costs associated with PSD, higher National Institutes of Health Stroke Scale, and longer hospital stay (all <0.05).

Conclusions: PSD was associated with greater stroke severity, prolonged hospitalization, and increased nursing and total costs. In patients with severe stroke, dementia, or seizures, PSD is anticipated, and additional costs are associated with hospitalization.
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http://dx.doi.org/10.1161/STROKEAHA.120.033005DOI Listing
July 2021

Patients with Primary Central Nervous System Lymphoma Not Eligible for Clinical Trials: Prognostic Factors, Treatment and Outcome.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23-25, D-44892 Bochum, Germany.

Patients with primary central nervous system lymphoma (PCNSL) not fulfilling inclusion criteria for clinical trials represent an underreported population. Thirty-four consecutive PCNSL patients seen at our center between 2005 and 2019 with exclusion criteria for therapeutic trials were analyzed (non-study patients) and compared with patients from the G-PCNSL-SG-1 (German PCNSL Study Group 1) study (study patients), the largest prospective multicenter trial on PCNSL, comprising 551 patients. Median follow up was 68 months (range 1-141) in non-study patients and 51 months (1-105) in study patients. Twenty-seven/34 (79.4%) non-study patients received high dose methotrexate (HDMTX), while seven/34 (20.6%) with a glomerular filtration rate (GFR) < 50 mL/min did not. Median overall survival (OS) was six months (95% confidence interval [CI] 0-21 months) in those 34 non-study patients. The 27 non-study patients treated with HDMTX were compared with 526/551 G-PCNSL-SG-1 study patients who had received HDMTX as well. Median OS was 20 months (95% CI 0-45)/21 months (95% CI 18-25) in 27 non-study/526 study patients ( = 0.766). Favorable prognostic factors in non-study patients were young age, application of HDMTX and early response on magnet resonance imaging (MRI). If HDMTX-based chemotherapy can be applied, long-term disease control is possible even in patients not qualifying for clinical trials. Initial response on early MRI might be useful for decision on treatment continuation.
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http://dx.doi.org/10.3390/cancers13122934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230869PMC
June 2021

Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma.

Cancers (Basel) 2021 Jun 20;13(12). Epub 2021 Jun 20.

Department of Neurology and Brain Tumor Center, University Hospital Zurich, 8091 Zurich, Switzerland.

This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far, limited therapeutic options. Small molecule targeted tyrosine kinase inhibitors, immunomodulatory agents, and immune checkpoint inhibitors will be discussed. The mechanisms of action, results of completed clinical studies, ongoing clinical trials, and future perspectives are summarized. Among the most promising clinical developments in the field of CNS lymphomas is ibrutinib, an inhibitor of Bruton's tyrosine kinase, which relays activation of nuclear factor kappa B upon integration of constitutive B cell receptor and Toll-like receptor signals. Down-stream of nuclear factor kappa B, the thalidomide analogs lenalidomide and pomalidomide exert immunomodulatory functions and are currently explored against CNS lymphomas. Finally, immune checkpoint inhibitors, such as drugs targeting the PD-1 pathway, may become novel therapeutic options to unleash anti-tumor immunity in patients with primary CNS lymphoma.
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http://dx.doi.org/10.3390/cancers13123073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234854PMC
June 2021

EANO guideline on the diagnosis and management of meningiomas.

Neuro Oncol 2021 Jun 28. Epub 2021 Jun 28.

Department of Neurology, University Hospital and University of Zurich, Clinical Neuroscience Center, Zurich, Switzerland.

Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if size or the vicinity of critical structures allow that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.
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http://dx.doi.org/10.1093/neuonc/noab150DOI Listing
June 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

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.

ACS Cent Sci 2021 May 14;7(5):868-881. Epub 2021 Apr 14.

Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.

The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL . Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.
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http://dx.doi.org/10.1021/acscentsci.1c00070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161495PMC
May 2021

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab058. Epub 2021 Apr 9.

Austin Brain Tumor Center, Austin, Texas, USA.

Background: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 antibody blocking PD-L1.

Methods: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety.

Results: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with -mutant GBM ( = 6) and 13.8% (3.9-31.7%) for patients with -wild-type GBM ( = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [ = 6]).

Conclusions: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.
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http://dx.doi.org/10.1093/noajnl/vdab058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156979PMC
April 2021

Hypermetabolism and impaired cerebrovascular reactivity beyond the standard MRI-identified tumor border indicate diffuse glioma extended tissue infiltration.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab048. Epub 2021 Mar 30.

Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Diffuse gliomas exhibit diffuse infiltrative growth, often beyond the magnetic resonance imaging (MRI)-detectable tumor lesion. Within this lesion, hypermetabolism and impaired cerebrovascular reactivity (CVR) are found, but its exact distribution pattern into the peritumoral environment is unknown. Our aim was to better characterize the extent of diffuse glioma tissue infiltration, beyond the visible lesion (ie, beyond the T1-contrast-enhancing lesion and/or T2/FLAIR-defined tumor border), with metabolic positron emission tomography (PET), and functional MRI CVR (blood oxygenation-level-dependent CVR [BOLD-CVR]) mapping.

Methods: From a prospective glioma database, 18 subjects (19 datasets) with diffuse glioma ( = 2 with anaplastic astrocytoma, = 10 with anaplastic oligodendroglioma, and = 7 with glioblastoma) underwent a BOLD-CVR and metabolic PET study between February 2016 and September 2019, 7 of them at primary diagnosis and 12 at tumor recurrence. In addition, 19 matched healthy controls underwent an identical BOLD-CVR study. The tumor lesion was defined using high-resolution anatomical MRI. Volumes of interest starting from the tumor lesion outward up to 30 mm were created for a detailed peritumoral PET and BOLD-CVR tissue analysis. Student's test was used for statistical analysis.

Results: Patients with diffuse glioma exhibit impaired BOLD-CVR 12 mm beyond the tumor lesion ( = .02) with normalization of BOLD-CVR values after 24 mm. Metabolic PET shows a difference between the affected and contralateral hemisphere of 6 mm ( = .05) with PET values normalization after 12 mm.

Conclusion: We demonstrate hypermetabolism and impaired CVR beyond the standard MRI-defined tumor border, suggesting active tumor infiltration in the peritumoral environment.
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http://dx.doi.org/10.1093/noajnl/vdab048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156976PMC
March 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

Fitness-to-drive for glioblastoma patients: Guidance from the Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM).

Swiss Med Wkly 2021 05 16;151:w20501. Epub 2021 May 16.

Department of Neurology and Brain Tumour Centre, University Hospital and University of Zurich, Switzerland.

Objective: The management of brain tumour patients who would like to resume driving is complex, and needs multidisciplinary input and a consensus among treating physicians. The Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM) aim to provide guidance on how to assess “fitness-to-drive” of glioblastoma patients and to harmonise the relevant procedures in Switzerland.

Methods: At several meetings, Swiss neuro-oncologists discussed common practices on how to advise patients with a stable, i.e., non-progressive, glioblastoma, who wish to resume driving after the initial standard tumour treatment. All participants of the SwissNOS meetings were invited twice to return a questionnaire (modified Delphi process) on specific tools/procedures they commonly use to assess “fitness-to-drive” of their patients. Answers were analysed to formulate a tentative consensus for a structured and reasonable approach.

Results: Consensus on minimum requirements for a “fitness-to-drive” programme for glioblastoma patients could be reached among Swiss neuro-oncologists. The recommendations were based on existing guidelines and expert opinions regarding patients with seizures, visual disturbances, cognitive impairment or focal deficits for safe driving. At this point in time, the Swiss neuro-oncologists agreed on the following requirements for glioblastoma patients after the initial standard therapy and without a seizure for at least 12 months: (1) stable cranial magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria, to be repeated every 3 months; (2) thorough medical history, including current or new medication, a comprehensive neurological examination at baseline (T0) and every 3 months thereafter, optionally an electrocencephalogram (EEG) at baseline; (3) ophthalmological examination including visual acuity and intact visual fields; and (4) optional neuropsychological assessment with a focus on safe driving. Test results have to be compatible with safe driving at any time-point. Patients should be informed about test results and optionally sign a document.

Conclusions: We propose regular thorough clinical neurological examination and brain MRI, optional EEG, neuropsychological and visual assessments to confirm “fitness-to-drive” for glioblastoma patients after initial tumour-directed therapy. The proposed “fitness-to-drive” assessments for glioblastoma patients serves as the basis for a prospective Swiss Pilot Project GLIODRIVE (BASEC ProjectID 2020-00365) to test feasibility, adherence and safety in a structured manner for patients who wish to resume driving. Research will focus on confirming the usefulness of the proposed tools in predicting “fitness-to-drive” and match results with events obtained from the road traffic registry (Strassenverkehrsamt).
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http://dx.doi.org/10.4414/smw.2021.20501DOI Listing
May 2021

Survival of brain tumour patients with epilepsy.

Brain 2021 May 11. Epub 2021 May 11.

Department of Neurology, Clinical Neuroscience Center and Brain Tumor Center, University and University Hospital Zurich, 8091 Zurich, Switzerland.

Pro-tumorigenic electrochemical synapses between neurons and brain tumor cells in pre-clinical studies suggest unfavorable effects of epilepsy on patient survival. We investigated associations of epilepsy and survival in three cohorts of brain tumor patients (meningioma, glioblastoma, brain metastases). Cohorts were segregated into three groups for comparative analyses: (i) no epilepsy, (ii) epilepsy without status epilepticus and (iii) status epilepticus. Status epilepticus was considered a surrogate of extensive neuronal hyperexcitability. Main outcome was progression-free survival (meningioma) and overall survival (glioblastoma and brain metastases), adjusted for established prognostic factors and onset of epilepsy by time-dependent multivariate Cox modeling. The primary analysis population comprised 1792 patients (742 meningioma, 249 glioblastoma, 801 brain metastases). Epilepsy was associated with favorable prognostic factors. On multivariate analyses, status epilepticus was however associated with inferior overall survival of patients with glioblastoma (status epilepticus vs no epilepsy multivariate HR 3.72, CI 1.78-7.76, P<0.001) and brain metastases (status epilepticus vs no epilepsy HR 2.30, CI 1.10-4.79, P=0.026). Among brain metastases patients, but not among patients with meningioma or glioblastoma, epilepsy was similarly associated with inferior overall survival (epilepsy vs no epilepsy HR 2.16, CI 1.60-2.93, P<0.001). We conclude that epilepsy may convey inferior survival of patients with malignant brain tumors.
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http://dx.doi.org/10.1093/brain/awab188DOI Listing
May 2021

Cancer is associated with inferior outcome in patients with ischemic stroke.

J Neurol 2021 May 4. Epub 2021 May 4.

Department of Neurology, University Hospital and University of Zurich, CH-8091, Zurich, Switzerland.

Background: Whether patients with stroke and cancer exhibit specific characteristics has remained controversial.

Methods: Medical records of patients with ischemic stroke in 2014 or 2015 registered in the Swiss Stroke Registry of Zurich were retrospectively analyzed and integrated with regional cancer registry data. Associations of clinical and outcome parameters with cancer diagnosed up to 5 years prior to stroke were tested.

Results: Of 753 patients with ischemic stroke, 59 patients with cancer were identified. History of venous thromboembolism (p < 0.001) was associated with cancer while age and cardiovascular risk factors were not. Higher levels of D-dimers (p = 0.001), erythrocyte sedimentation rate (p = 0.003), C-reactive protein (CRP) (p < 0.001), and lower levels of hemoglobin (p = 0.003) were associated with cancer. For platelets, pathologically low (p = 0.034) or high levels (p < 0.001) were linked to cancer. Modified Rankin scale (mRS) scores ≥ 4 on admission and at follow-up were more frequent in cancer patients (p = 0.038 and p = 0.001). Poor post-stroke survival was associated with cancer (HR 2.2, p < 0.001). Multivariable analysis identified venous thromboembolism (OR 5.1), pathologic platelet count (OR = 2.9), low hemoglobin (OR 2.5) and elevated CRP (OR 1.8) as independently associated with cancer. In multivariable Cox regression, risk for death was associated with cancer (HR 1.7), low hemoglobin (HR 2.6), mRS on admission ≥ 4 (HR 1.9), pathologic platelet count (HR 1.6), female sex (HR 1.7), and elevated CRP (HR 1.4).

Conclusions: Considering cancer as a cofactor for post-stroke outcome may impact clinical decision making.
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http://dx.doi.org/10.1007/s00415-021-10528-3DOI Listing
May 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

PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression.

J Neurooncol 2021 Jun 1;153(2):283-291. Epub 2021 May 1.

Department of Neurosurgery, Medical Center of the University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.

Introduction: The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy.

Methods: Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed.

Results: PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS.

Conclusions: PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.
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http://dx.doi.org/10.1007/s11060-021-03765-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211617PMC
June 2021

Distinct Cerebrovascular Reactivity Patterns for Brain Radiation Necrosis.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Department of Neurosurgery, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.

Current imaging-based discrimination between radiation necrosis versus recurrent glioblastoma contrast-enhancing lesions remains imprecise but is paramount for prognostic and therapeutic evaluation. We examined whether patients with radiation necrosis exhibit distinct patterns of blood oxygenation-level dependent fMRI cerebrovascular reactivity (BOLD-CVR) as the first step to better distinguishing patients with radiation necrosis from recurrent glioblastoma compared with patients with newly diagnosed glioblastoma before surgery and radiotherapy. Eight consecutive patients with primary and secondary brain tumors and a multidisciplinary clinical and radiological diagnosis of radiation necrosis, and fourteen patients with a first diagnosis of glioblastoma underwent BOLD-CVR mapping. For all these patients, the contrast-enhancing lesion was derived from high-resolution T1-weighted MRI and rendered the volume-of-interest (VOI). From this primary VOI, additional 3 mm concentric expanding VOIs up to 30 mm were created for a detailed perilesional BOLD-CVR tissue analysis between the two groups. Receiver operating characteristic curves assessed the discriminative properties of BOLD-CVR for both groups. Mean intralesional BOLD-CVR values were markedly lower in radiation necrosis than in glioblastoma contrast-enhancing lesions (0.001 ± 0.06 vs. 0.057 ± 0.05; = 0.04). Perilesionally, a characteristic BOLD-CVR pattern was observed for radiation necrosis and glioblastoma patients, with an improvement of BOLD-CVR values in the radiation necrosis group and persisting lower perilesional BOLD-CVR values in glioblastoma patients. The ROC analysis discriminated against both groups when these two parameters were analyzed together (area under the curve: 0.85, 95% CI: 0.65-1.00). : In this preliminary analysis, distinctive intralesional and perilesional BOLD-cerebrovascular reactivity patterns are found for radiation necrosis.
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http://dx.doi.org/10.3390/cancers13081840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069508PMC
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

Neurological complications of cancer immunotherapy.

Cancer Treat Rev 2021 Jun 23;97:102189. Epub 2021 Mar 23.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria.

Immunotherapy has emerged as a powerful therapeutic approach in many areas of clinical oncology and hematology. The approval of ipilimumab, a monoclonal antibody targeting the immune cell receptor CTLA-4, has marked the beginning of the era of immune checkpoint inhibitors. In the meantime, numerous antibodies targeting the PD-1 pathway have expanded the class of clinically approved immune checkpoint inhibitors. Furthermore, novel antibodies directed against other immune checkpoints are currently in clinical evaluation. More recently, bispecific antibodies, which link T cells directly to tumor cells as well as adoptive T cell transfer with immune cells engineered to express a chimeric antigen receptor, have been approved in certain indications. Neurological complications associated with the use of these novel immunotherapeutic concepts have been recognized more and more frequently. Immune checkpoint inhibitors may cause various neurological deficits mainly by alterations of the peripheral nervous system's integrity. These include radiculopathies, neuropathies, myopathies as well as myasthenic syndromes. Side effects involving the central nervous system are less frequent but may result in severe clinical symptoms and syndromes. The administration of chimeric antigen receptor (CAR) T cell is subject to rigorous patient selection and their use is frequently associated with neurological complications including encephalopathy and seizures, which require immediate action and appropriate therapeutic measures. Close clinical monitoring for neurological symptoms is key for early recognition of immunotherapy-related side effects. Comprehensive diagnostic work-up and adequate therapeutic measures are essential to avoid further clinical deterioration and residual neurological deficits.
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http://dx.doi.org/10.1016/j.ctrv.2021.102189DOI Listing
June 2021

HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy.

J Immunother Cancer 2021 04;9(4)

Clinical Neuroscience Center and Department of Neurosurgery, University Hospital and University of Zurich, Zurich, Switzerland.

Background: The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level.

Methods: Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing.

Results: The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference.

Conclusion: Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at .
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http://dx.doi.org/10.1136/jitc-2020-002071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054196PMC
April 2021

Evidence-based recommendations on categories for extent of resection in diffuse glioma.

Eur J Cancer 2021 May 2;149:23-33. Epub 2021 Apr 2.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Surgical resection represents the standard of care in diffuse glioma, and more extensive tumour resection appears to be associated with favourable outcome. Up to now, terminology to describe extent of resection has been inconsistently applied across clinical trials which hampers comparative analysis of cohorts between different studies. Based on a comprehensive literature review, we developed evidence-based expert recommendations on categories for extent of resection. Recommendations are formulated for the categories 'biopsy', 'partial resection', 'subtotal resection', 'near total resection', 'complete resection' and 'supramaximal resection'. Definitions rest on reduction of contrast- and non-contrast-enhancing tumour in glioblastoma, and on reduction of T2/FLAIR-hyperintense tumour in gliomas WHO grade 2 or 3. Both relative reduction of tumour volume (in percentage) as a measurement of surgical efficacy and absolute residual tumour volume (in cm) as a measurement of remaining tumour burden are incorporated into the categories for extent of resection. Class of evidence for the proposed categories ranges from class IIB to IV. Limitations of the suggested categories are discussed. The proposed categories on extent of resection offer a framework to standardize nomenclature based on previous studies, and will need to be evaluated in prospective, molecularly well-defined cohorts. Our categories may eventually help as a stratification factor for future clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2021.03.002DOI Listing
May 2021

A tumor-promoting role for soluble TβRIII in glioblastoma.

Mol Cell Biochem 2021 Aug 26;476(8):2963-2973. Epub 2021 Mar 26.

Laboratory of Molecular Neuro-Oncology, Department of Neurology & Brain Tumor Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

Purpose: Members of the transforming growth factor (TGF)-β superfamily play a key role in the regulation of the malignant phenotype of glioblastoma by promoting invasiveness, angiogenesis, immunosuppression, and maintaining stem cell-like properties. Betaglycan, a TGF-β coreceptor also known as TGF-β receptor III (TβRIII), interacts with members of the TGF-β superfamily and acts as membrane-associated or shed molecule. Shed, soluble TβRIII (sTβRIII) is produced upon ectodomain cleavage of the membrane-bound form. Elucidating the role of TβRIII may improve our understanding of TGF-β pathway activity in glioblastoma METHODS: Protein levels of TβRIII were determined by immunohistochemical analyses and ex vivo single-cell gene expression profiling of glioblastoma tissue respectively. In vitro, TβRIII levels were assessed investigating long-term glioma cell lines (LTCs), cultured human brain-derived microvascular endothelial cells (hCMECs), glioblastoma-derived microvascular endothelial cells, and glioma-initiating cell lines (GICs). The impact of TβRIII on TGF-β signaling was investigated, and results were validated in a xenograft mouse glioma model RESULTS: Immunohistochemistry and ex vivo single-cell gene expression profiling of glioblastoma tissue showed that TβRIII was expressed in the tumor tissue, predominantly in the vascular compartment. We confirmed this pattern of TβRIII expression in vitro. Specifically, we detected sTβRIII in glioblastoma-derived microvascular endothelial cells. STβRIII facilitated TGF-β-induced Smad2 phosphorylation in vitro and overexpression of sTβRIII in a xenograft mouse glioma model led to increased levels of Smad2 phosphorylation, increased tumor volume, and decreased survival CONCLUSIONS: These data shed light on the potential tumor-promoting role of extracellular shed TβRIII which may be released by glioblastoma endothelium with high sTβRIII levels.
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http://dx.doi.org/10.1007/s11010-021-04128-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263459PMC
August 2021
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