Publications by authors named "Matthias Preusser"

324 Publications

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

Eur J Cancer 2021 Aug 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
August 2021

SARS-CoV-2 screening in cancer outpatients during the second wave of the COVID-19 pandemic : Conclusions for crisis response at a high-volume oncology center.

Wien Klin Wochenschr 2021 Sep 19;133(17-18):909-914. Epub 2021 Aug 19.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: During the second wave of the coronavirus disease 2019 (COVID-19) pandemic Austria suffered one of the highest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rates worldwide. We report performance parameters of a SARS-CoV‑2 screening program established for cancer outpatients at our center.

Methods: Institutional policy recommended routine biweekly SARS-CoV‑2 testing. Adherence to the testing recommendation during the second wave of the COVID-19 pandemic between 1 October and 30 November 2020 was analyzed. The SARS-CoV‑2 infection rate during first wave period (21 March to 4 May 2020) was compared to the one during second wave.

Results: A total of 1577 cancer patients were seen at our outpatient clinic during the second wave. In 1079/1577 (68.4%) patients, at least 1 SARS-CoV2 test was performed. Overall 2833 tests were performed, 23/1577 (1.5%, 95% confidence interval, CI 1.0-2.2%) patients were tested positive for SARS-CoV‑2, which indicates a significant increase compared to the first wave (4/1016; 0.4%, 95% CI 0.1-1.0%) with an odds ratio of 3.9 (95% CI 1.5-10.1; p < 0.005). Patients undergoing active anticancer treatment (172/960; 17.9% not tested) were more likely to have undergone a SARS-CoV‑2 test than patients in follow-up or best supportive care (326/617; 52.8% not tested p < 0.001). Furthermore, patients with only 1 visit within 4 weeks were more likely to not have undergone a SARS-CoV‑2 test (386/598; 64.5%) compared to patients with 2 or more visits (112/979; 11.4%; p < 0.001). The projected number of patients with undetected SARS-CoV‑2 infection during the study period was 5.

Conclusion: We identified clinical patient parameters influencing SARS-CoV‑2 testing coverage in cancer outpatients. Our data can provide information on generation of standard operating procedures and resource allocation during subsequent infection waves.
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http://dx.doi.org/10.1007/s00508-021-01927-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375465PMC
September 2021

Expression of programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand (PD-L1) in adenocarcinomas of the gastroesophageal junction change significantly after neoadjuvant treatment.

Eur J Surg Oncol 2021 Aug 11. Epub 2021 Aug 11.

Department of Surgery, Comprehensive Cancer Center Vienna, Upper-GI-Service, GET-Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria. Electronic address:

Background: The effects of cytotoxic chemotherapy on the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in cancer cells and peritumoral cells are unclear. The aim of this study was to investigate the impact of neoadjuvant chemotherapy on PD-1 and PD-L1 expression in adenocarcinomas of the gastroesophageal junction.

Methods: PD-1 and PD-L1 expression in cancer cells and tumor-infiltrating lymphocytes in paired diagnostic biopsies and surgical specimens from patients with pretreated and curatively resected adenocarcinomas of the gastroesophageal junction were evaluated by immunohistochemistry.

Results: Paired tumor samples were available from 40 patients. PD-1 expression in cancer cells (p < 0.001; Exact Symmetry Test) and tumor-infiltrating lymphocytes (p < 0.001; Exact Symmetry Test) increased significantly after neoadjuvant therapy. Furthermore, we observed a significant decrease in PD-L1 expression in cancer cells (p = 0.003) after neoadjuvant therapy was observed.

Conclusion: In this study we could show that tumor-cell expression of PD-1 and PD-L1 was significantly altered in patients with adenocarcinomas of the gastroesophageal junction after receiving neoadjuvant chemotherapy. Based on these observations, patients might profit from the combined use of cytotoxic chemotherapy and the blockade of the PD-1 axis.
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http://dx.doi.org/10.1016/j.ejso.2021.08.016DOI Listing
August 2021

Frequency of actionable molecular drivers in lung cancer patients with precocious brain metastases.

Clin Neurol Neurosurg 2021 Sep 24;208:106841. Epub 2021 Jul 24.

Department of Neuropathology, Otto-von-Guericke University Magdeburg, Germany. Electronic address:

Brain metastases frequently occur during the course of disease in patients suffering from lung cancer. Occasionally, neurological symptoms caused by brain metastases (BM) might represent the first sign of systemic tumor disease (so called precocious metastases), leading to the detection of the primary lung tumor. The biological basis of precocious BM is largely unknown, and treatment options are not well established for this subgroup of patients. Therefore, we retrospectively analyzed 33 patients (24 non-small cell lung cancer (NSCLC)), 9 small cell lung cancer (SCLC)) presenting with precocious BM focusing on molecular alterations potentially relevant for the tumor's biology and treatment. We found five FGFR1 amplifications (4 adenocarcinoma, 1 SCLC) among 31 analyzed patients (16.1%), eight MET amplifications among 30 analyzed tumors (7 NSCLC, 1 SCLC; 26.7%), three EGFR mutations within 33 patients (all adenocarcinomas, 9.1%), and five KRAS mutations among 32 patients (all adenocarcinomas; 15.6%). No ALK, ROS1 or RET gene rearrangements were detected. Our findings suggest that patients with precocious BM of lung cancer harbor EGFR mutations, MET amplifications or FGFR1 amplifications as potential targeted treatment options.
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http://dx.doi.org/10.1016/j.clineuro.2021.106841DOI Listing
September 2021

Prognostic factors in adult brainstem glioma: a tertiary care center analysis and review of the literature.

J Neurol 2021 Aug 3. Epub 2021 Aug 3.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Introduction: Adult brainstem gliomas (BSGs) are rare central nervous system tumours characterized by a highly heterogeneous clinical course. Median survival times range from 11 to 84 months. Beyond surgery, no treatment standard has been established. We investigated clinical and radiological data to assess prognostic features providing support for treatment decisions.

Methods: 34 BSG patients treated between 2000 and 2019 and aged ≥ 18 years at the time of diagnosis were retrospectively identified from the databases of the two largest Austrian Neuro-Oncology centres. Clinical data including baseline characteristics, clinical disease course, applied therapies, the outcome as well as neuroradiological and neuropathological findings were gathered and analysed. The tumour apparent diffusion coefficient (ADC), volumetry of contrast-enhancing and non-contrast-enhancing lesions were determined on magnetic resonance imaging scans performed at diagnosis.

Results: The median age at diagnosis was 38.5 years (range 18-71 years). Tumour progression occurred in 26/34 (76.5%) patients after a median follow up time of 19 months (range 0.9-236.2). Median overall survival (OS) and progression-free survival (PFS) was 24.1 months (range 0.9-236.2; 95% CI 18.1-30.1) and 14.5 months (range 0.7-178.5; 95% CI 5.1-23.9), respectively. Low-performance status, high body mass index (BMI) at diagnosis and WHO grading were associated with shorter PFS and OS at univariate analysis (p < 0.05, log rank test, respectively). ADC values below the median were significantly associated with shorter OS (14.9 vs 44.2 months, p = 0.018).

Conclusion: ECOG, BMI, WHO grade and ADC values were associated with the survival prognosis of BSG patients and should be included in the prognostic assessment.
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http://dx.doi.org/10.1007/s00415-021-10725-0DOI 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

PSMA Expression in 122 Treatment Naive Glioma Patients Related to Tumor Metabolism in C-Methionine PET and Survival.

J Pers Med 2021 Jun 30;11(7). Epub 2021 Jun 30.

Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Apart from its expression in benign and malignant prostate tissue, prostate specific membrane antigen (PSMA) was shown to be expressed specifically in the neovasculature of solid tumors. For gliomas only little information exists. Therefore, we aimed to correlate PSMA expression in gliomas to tumor metabolism by L-[S-methyl-C]methionine (MET) PET and survival. Therefore, immunohistochemical staining (IHC) for isocitrate dehydrogenase 1-R132H (IDH1-R132H) mutation and PSMA expression was performed on the paraffin embedded tissue samples of 122 treatment-naive glioma patients. The IHC results were then related to the pre-therapeutic semiquantitative MET PET data and patients' survival. Vascular PSMA expression was observed in 26 of 122 samples and was rather specific for high-grade gliomas ([HGG] 81% of glioblastoma multiforme, 10% of WHO grade III and just 2% of grade II gliomas). Significantly higher amounts of gliomas without verifiable IDH1-R132H mutation showed vascular PSMA expression. Significantly shorter median survival times were seen for patients with vascular PSMA staining in all tumors as well as HGG only. Additionally, significantly higher numbers of PSMA staining vessels were found in tumors with high amino acid metabolic rates. Vascular PSMA expression in gliomas was seen as a high-grade specific feature associated with elevated amino acid metabolism and short survival.
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http://dx.doi.org/10.3390/jpm11070624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305688PMC
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

Androgen Receptor is Expressed in Breast Cancer Brain Metastases.

Appl Immunohistochem Mol Morphol 2021 Jun 14. Epub 2021 Jun 14.

Department of Medicine I, Division of Oncology Departments of Neurosurgery Pathology Surgery Radiooncology, Medical University of Vienna, Vienna, Austria.

Background: Androgen receptor (AR) expression is a potential therapeutic target in breast cancer (BC) as it is frequently expressed in the luminal A and B subtypes and in approximately one third of basal-like cancers. As AR-positive BC displays a distinct biological behavior, we aimed to analyze AR expression in the particular context of BC brain metastases (BM).

Materials And Methods: Patients with newly diagnosed BC BM treated with neurosurgical resection were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, biological tumor subtypes and overall survival were obtained by retrospective chart review. Formalin-fixed and paraffin-embedded specimen containing BM tissue were retrieved from the Neuro-Biobank. Immunohistochemical staining of AR was performed and AR expression in the tumor-cell nucleus was evaluated.

Results: Fifty-seven BM samples from 57 individual patients with BC were available for this analysis. AR expression of ≥1% tumor cells was evident in 20/57 (35.1%) BM specimens; the median AR-expression rate was 10% (range: 1% to 60%). AR expression was observed in 11/21 (52.4%) BM of the luminal/human epidermal growth factor receptor 2 (HER2)-negative subtype, 3/13 (23.1%) of the luminal/HER2-positive subtype, 2/7 (28.6%) of the HER2-positive subtype and 4/16 (25.0%) of the triple-negative subtype (P=0.247). Median survival from diagnosis of BM was 10 months (range: 0 to 104 mo) in the entire cohort. No significant association of overall survival and AR expression ≥1% was observed (15 vs. 13 mo; P>0.05).

Conclusion: AR is expressed in more than one third of BC BM with the highest rates among the luminal/HER2-negative BC subtype and may therefore be a potential prognostic and predictive biomarker in this particular BC population.
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http://dx.doi.org/10.1097/PAI.0000000000000952DOI Listing
June 2021

Impact of COVID-19 lockdown on routine oncology versus emergency care at a high volume cancer centre.

Eur J Clin Invest 2021 Aug 4;51(8):e13623. Epub 2021 Jun 4.

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

Background: We investigated the influence of population-wide COVID-19 lockdown measures implemented on 16, March 2020 on routine and emergency care of cancer outpatients at a tertiary care cancer centre in Vienna, Austria.

Methods: We compared the number/visits of cancer outpatients receiving oncological therapies at the oncologic day clinic (DC) and admissions at the emergency department (ED) of our institution in time periods before (pre-lockdown period: 1 January - 15 March 2020) and after (post-lockdown period: 16 March- 31 May 2020) lockdown implementation with the respective reference periods of 2018 and 2019. Additionally, we analysed Emergency Severity Index (ESI) score of unplanned cancer patient presentations to the ED in the same post-lockdown time periods. Patient outcome was described as 3-month mortality rate (3-MM).

Results: In total, 16 703 visits at the DC and 2664 patient visits for the respective time periods were recorded at the ED. No decrease in patient visits was observed at the DC after lockdown implementation (P = .351), whereas a substantial decrease in patient visits at the ED was seen (P < .001). This translates into a 26%-31% reduction of cancer-related patient visits per half month after the lockdown at the ED (P < .001 vs. 2018 + 2019). There was no difference in the distribution of ESI scores at ED presentation (P = .805), admission rates or 3-MM in association with lockdown implementation (P = .086).

Conclusion: We demonstrate the feasibility of maintaining antineoplastic therapy administration during the COVID-19 pandemic. However, our data underline the need for adapted management strategies for emergency presentations of cancer patients.
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http://dx.doi.org/10.1111/eci.13623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209914PMC
August 2021

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab.

Ther Adv Med Oncol 2021 22;13:17588359211009002. Epub 2021 Apr 22.

Division of Oncology, Department of Medicine 1, Medical University of Vienna, Austria.

Background: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown.

Methods: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into 'TP', 'other-HER2-targeted therapy' and 'no-HER2-targeted therapy' according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM).

Results: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 17 3 months,  < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%.

Conclusion: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.
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http://dx.doi.org/10.1177/17588359211009002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072867PMC
April 2021

Circulating PD-L1 levels change during bevacizumab-based treatment in recurrent glioma.

Cancer Immunol Immunother 2021 May 6. Epub 2021 May 6.

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

Purpose: In primary brain tumors, the efficacy of immune-modulating therapies is still under investigation as inflammatory responses are restricted by tight immunoregulatory mechanisms in the central nervous system. Here, we measured soluble PD-L1 (sPD-L1) in the plasma of patients with recurrent glioblastoma (GBM) and recurrent WHO grade II-III glioma treated with bevacizumab-based salvage therapy.

Methods: Thirty patients with recurrent GBM and 10 patients with recurrent WHO grade II-III glioma were treated with bevacizumab-based salvage therapy at the Medical University of Vienna. Prior to each treatment cycle, EDTA plasma was drawn and sPD-L1 was measured applying a sandwich ELISA with a lower detection limit of 0.050 ng/ml. Leukocyte counts and C-reactive protein (CRP) levels were measured according to institutional practice.

Results: Median number of sPD-L1 measurements was 6 per patient (range: 2-24). At baseline, no significant difference in sPD-L1 concentrations was observed between WHO grade II-III glioma and GBM. Intra-patient variability of sPD-L1 concentrations was significantly higher in WHO grade II-III glioma than in GBM (p = 0.014) and tendentially higher in IDH-mutant than in IDH-wildtype glioma (p = 0.149) In WHO grade II-III glioma, sPD-L1 levels were significantly lower after one administration of bevacizumab than at baseline (median: 0.039 ng/ml vs. 0.4855 ng/ml, p = 0.036). In contrast, no significant change could be observed in patients with GBM.

Conclusions: Changes in systemic inflammation markers including sPD-L1 are observable in patients with recurrent glioma under bevacizumab-based treatment and differ between WHO grade II-III glioma and GBM.
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http://dx.doi.org/10.1007/s00262-021-02951-2DOI Listing
May 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

Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients.

J Immunother Cancer 2021 03;9(3)

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

Background: Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.

Patients And Methods: We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.

Results: 35 patients (median age of 50 (23-81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)-receptor interaction.

Conclusions: Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.
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http://dx.doi.org/10.1136/jitc-2020-001458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993298PMC
March 2021

LAG-3 expression in the inflammatory microenvironment of glioma.

J Neurooncol 2021 May 2;152(3):533-539. Epub 2021 Mar 2.

Division of Oncology and Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Purpose: Immune modulatory therapies including immune checkpoint inhibitors have so far failed to result in clinically meaningful efficacy in glioma. We aimed to investigate lymphocyte activation gene 3 (LAG-3), an inhibitory receptor on immune cells and target of second-generation immune checkpoint inhibitors, in glioma.

Methods: 97 patients with diffuse glioma (68 with glioblastoma, 29 with WHO grade II-III glioma) were identified from the Neuro-Biobank of the Medical University of Vienna. LAG-3 expression in the inflammatory microenvironment was assessed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4) and correlated to CD3+ , CD8+ , CD20+ and PD-1+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells.

Results: LAG-3+ TILs could be observed in 10/97 (10.3%) IDH-wildtype samples and in none of the included IDH-mutant glioma samples (p = 0.057). Further, LAG-3+ TILs were only observed in WHO grade IV glioblastoma, while none of the investigated WHO grade II-III glioma presented with LAG-3+ TILs (p = 0.03). No association of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and presence of LAG-3+ TILs was observed (p = 0.726). LAG-3 expression was associated with the presence of CD3+ (p = 0.029), CD8+ (p = 0.001), PD-1+ (p < 0.001) TILs and PD-L1+ tumor cells (p = 0.021), respectively. No association of overall survival with LAG-3+ TIL infiltration was evident (median OS 9.9 vs. 14.2 months, p = 0.95).

Conclusions: LAG-3 is only rarely expressed on TILs in IDH-wildtype glioma and associated with active inflammatory milieu as defined by higher TIL density. Immune microenvironment diversity should be considered in the design of future immunotherapy trials in glioma.
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http://dx.doi.org/10.1007/s11060-021-03721-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084780PMC
May 2021

Degradation of BRD4 - a promising treatment approach not only for hematologic but also for solid cancer.

Am J Cancer Res 2021 1;11(2):530-545. Epub 2021 Feb 1.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna Austria.

Bromodomain (BRD) and extra-terminal (BET) proteins are epigenetic readers that regulate gene expression and promote cancer evolution. Pharmacological inactivation of BRD4 has recently been introduced as a promising anti-neoplastic approach that targets MYC oncogene expression. However, resistance against BRD4-targeting drugs has been described. We compared the efficacy of the small-molecule-type BET BRD inhibitor JQ1 with the recently developed BET protein degraders dBET1 and dBET6 in colon, breast, melanoma, ovarian, lung and prostate cancer cell lines. As determined by qPCR, all BRD4 targeting drugs dose-dependently decreased MYC expression, with dBET6 introducing the strongest downregulation of MYC. This correlated with the anti-proliferative activity of these drugs, which was at least one order of magnitude higher for dBET6 (IC 0.001-0.5 µM) than for dBET1 or JQ1 (IC 0.5-5 µM). Interestingly, when combined with commonly used cytotoxic therapeutics, dBET6 was found to promote anti-neoplastic effects and to counteract chemoresistance in most cancer cell lines. Moreover, JQ1 and both BET degraders strongly downregulated baseline and interferon-gamma induced expression of the immune checkpoint molecule PD-L1 in all cancer cell lines. Together, our data suggest that dBET6 outperforms first-generation BRD4 targeting drugs like dBET1 and JQ1, and decreases chemoresistance and immune resistance of cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868748PMC
February 2021

Prognostic Value of 5-ALA Fluorescence, Tumor Cell Infiltration and Angiogenesis in the Peritumoral Brain Tissue of Brain Metastases.

Cancers (Basel) 2021 Feb 3;13(4). Epub 2021 Feb 3.

Department of Neurosurgery, Medical University Vienna, Vienna General Hospital, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Complete resection is an indispensable treatment option in the management of brain metastases (BM). 5-aminolevulinic acid (5-ALA) fluorescence is used for improved intraoperative visualization of tumor tissue in gliomas and was recently observed in BM. We investigated the potential of 5-ALA fluorescence to visualize the infiltrative growth of BM in the peritumoral brain tissue and its histopathological correlate. Patients with BM resection after 5-ALA administration and collection of tissue samples from peritumoral brain tissue were included. Each tissue sample was histopathologically investigated for tumor cell infiltration and angiogenesis. Altogether, 88 samples were collected from the peritumoral brain tissue in 58 BM of 55 patients. Visible 5-ALA fluorescence was found in 61 (69%) of the samples, tumor infiltration in 19 (22%) and angiogenesis in 13 (15%) of samples. Angiogenesis showed a significant correlation with presence of fluorescence ( = 0.008). Moreover, angiogenesis was related to visible 5-ALA fluorescence and showed an association with patient prognosis since it was significantly correlated to shorter time to local progression/recurrence ( = 0.001) and lower one-year survival ( = 0.031). Consequently, angiogenesis in the peritumoral brain tissue of BM might be a novel prognostic marker for individualized perioperative treatment concepts in the future.
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http://dx.doi.org/10.3390/cancers13040603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913757PMC
February 2021

Evaluation of the Temporal Muscle Thickness as an Independent Prognostic Biomarker in Patients with Primary Central Nervous System Lymphoma.

Cancers (Basel) 2021 Feb 2;13(3). Epub 2021 Feb 2.

Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient's frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2-097-4.848, < 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608-3.911, < 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker.
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http://dx.doi.org/10.3390/cancers13030566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867149PMC
February 2021

Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases.

Br J Cancer 2021 03 21;124(7):1294-1300. Epub 2021 Jan 21.

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

Background: Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer.

Methods: One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry.

Results: PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; p < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32-1.59; p = 1.62e - 13, NLR (HR 1.55; 95% CI: 1.38-1.75; p = 1.92e - 11), LLR (HR 1.57; 95% CI: 1.39-1.77; p = 1.96e - 11, PLR (HR 1.60; 95% CI: 1.39-1.85; p = 2.87955e - 9), MLR (HR 1.41; 95% CI: 1.14-1.75; p = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54-2.18; p = 2.73e - 10) remained independent factors associated with OS at BM diagnosis.

Conclusions: Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.
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http://dx.doi.org/10.1038/s41416-020-01254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007827PMC
March 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

Prognostic validation and clinical implications of the EANO ESMO classification of leptomeningeal metastasis from solid tumors.

Neuro Oncol 2021 07;23(7):1100-1112

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

Background: The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) from solid cancers based on clinical, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cytology presentation. MRI patterns are classified as linear, nodular, both, or neither. Type I LM is defined by positive CSF cytology (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these LM subtypes.

Patients And Methods: We retrospectively assembled data from 254 patients with newly diagnosed LM from solid tumors. Survival curves were derived using the Kaplan-Meier method and compared by Log-rank test.

Results: Median age at LM diagnosis was 56 years. Typical clinical LM features were noted in 225 patients (89%); 13 patients (5%) were clinically asymptomatic. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 patients (9.5%) and negative in 44 patients (17.5%). Patients with confirmed LM had inferior outcome compared with patients with probable or possible LM (P = 0.006). Type I patients had inferior outcome than type II patients (P = 0.002). Nodular disease on MRI was a negative prognostic factor in type II LM (P = 0.014), but not in type I LM. Administration of either intrathecal pharmacotherapy (P = 0.020) or systemic pharmacotherapy (P = 0.0004) was associated with improved outcome in type I LM, but not in type II LM.

Conclusion: The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.
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http://dx.doi.org/10.1093/neuonc/noaa298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301235PMC
July 2021

A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?

Cancers (Basel) 2020 Dec 15;12(12). Epub 2020 Dec 15.

Department of Neurology, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients [...].
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http://dx.doi.org/10.3390/cancers12123775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765319PMC
December 2020

EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood.

Nat Rev Clin Oncol 2021 03 8;18(3):170-186. Epub 2020 Dec 8.

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

In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
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http://dx.doi.org/10.1038/s41571-020-00447-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904519PMC
March 2021

Prevalence of pain and its association with symptoms of post-traumatic stress disorder, depression, anxiety and distress in 846 cancer patients: A cross sectional study.

Psychooncology 2021 04 3;30(4):504-510. Epub 2020 Dec 3.

Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Objective: Pain depicts a severe physical symptom but its relationship to mental health problems is not well studied in cancer patients. The aim of this study was to investigate the prevalence of pain and its correlation with symptoms of post-traumatic stress disorder (PTSD), depression, anxiety and psychological distress in a large sample of cancer patients.

Methods: From 2010 to 2019, cancer patients who received outpatient treatment at the Medical University of Vienna were assessed with the Post-Traumatic Symptom Scale (PTSS-10) and the Hospital Anxiety and Depression Scales. A visual analogue scale was used to assess pain perception. For statistical analysis, linear regression models were applied to log-transformed data.

Results: Of the 846 cancer patients included in the study, 63.5% experienced pain (mild 43.5%, moderate 13.6%, severe 6.4%). About a third (31.2%) of the total sample presented with significant PTSD symptoms. Significant symptoms of depression, anxiety and distress were present in 13.9%, 15.1% and 25.3%, respectively. Women more often reported symptoms of PTSD, anxiety and distress. Pain scores were significantly related to symptoms of PTSD, depression and psychological distress (all with p < .001), but not to anxiety.

Conclusions: Results show a high prevalence of experienced pain and indicate a clear association of elevated pain levels with psychiatric symptoms in oncological patients in a large Austrian sample. In order to decrease experienced pain and to enable better treatment of mental health problems in cancer patients, diagnostic procedures and interventions based on a biopsychosocial model need to be intensified.
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http://dx.doi.org/10.1002/pon.5595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049050PMC
April 2021

Assessment of Central Nervous System Lymphoma Based on CXCR4 Expression In Vivo Using 68Ga-Pentixafor PET/MRI.

Clin Nucl Med 2021 Jan;46(1):16-20

From the Division of Oncology, Department of Medicine I.

Purpose Of The Report: F-FDG PET is limited for assessment of central nervous system lymphoma (CNSL) due to physiologic tracer accumulation in the brain. We prospectively evaluated the novel PET tracer Ga-pentixafor, which targets the C-X-C chemokine receptor 4 (CXCR4), for lesion visualization and response assessment of CNSL.

Materials And Methods: Seven CNSL patients underwent Ga-pentixafor PET/MRI with contrast enhancement (CE-MRI) and diffusion-weighted sequences. The accuracy of Ga-pentixafor PET for CNSL lesion detection relative to the CE-MRI reference standard was determined. Standardized uptake values (SUVmean and SUVmax), PET-based (PTV) and MRI-based (VOLMRI) tumor volumes, and apparent diffusion coefficients (ADCs) were assessed, and correlation coefficients were calculated. Three SUVmax thresholds (41%, 50%, and 70%) were evaluated for PTV definitions (PTV41%, PTV50%, and PTV70%) and tested against VOLMRI using paired sample t tests.

Results: Twelve Ga-pentixafor PET/MRI examinations (including 5 follow-up scans) of 7 patients were evaluated. Ga-pentixafor PET demonstrated 18 lesions, all of which were confirmed by CE-MRI; there were no false-positive lesions on PET (accuracy, 100%). PTV41% showed the highest concordance with lesion morphology, with no significant difference compared with VOLMRI (mean difference, -0.24 cm; P = 0.45). The correlation between ADCmean and SUVmean41% (r = 0.68) was moderate. Changes in PTV41% on follow-up PET/MRI showed the same trend as VOLMRI changes, including progression of 1 lesion each in patient 1 (+456.0% PTV41% and +350.8% VOLMRI) and patient 3 (+110.4% PTV41% and +85.1% VOLMRI).

Conclusions: Ga-pentixafor PET may be feasible for assessment and follow-up of CNSL. Future studies need to focus on testing its clinical value to distinguish between glioma and CNSL, and between radiation-induced inflammation and viable residual tumor.
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http://dx.doi.org/10.1097/RLU.0000000000003404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385649PMC
January 2021

Soluble PD-L1 is associated with local and systemic inflammation markers in primary and secondary brain tumours.

ESMO Open 2020 11;5(6):e000863

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

Background: Immune-modulatory treatments have so far shown limited clinical activity in primary brain tumours. We aimed to investigate soluble programmed death receptor ligand 1 (sPD-L1) as systemic inflammation parameter in patients with brain tumour.

Methods: EDTA plasma was collected from 81 glioma (55 glioblastoma (GBM), 26 lower-grade glioma (LGG)), 17 meningioma and 44 brain metastasis (BM) patients and 24 controls. sPD-L1 concentrations were determined by ELISA. Correlations with the local tumour microenvironment were assessed by immunohistochemical analysis for PD-L1, CD3 and CD8.

Results: sPD-L1 was detected in 62 out of 166 (37.7%) patients (glioma: 41/81, 50.6%; meningioma: 5/17, 29.4%; BM: 7/44, 15.9%; controls: 9/24, 37.5%; p=0.002). sPD-L1 concentrations were lower in BM than in LGG (p=0.003) or GBM (p<0.001). Membranous PD-L1 expression on tumour cells was not associated with sPD-L1 concentrations (p=0.953). sPD-L1 concentration was inversely correlated with the density of CD8+ (r=-0.713, p=0.001) and CD3+ (r=-0.484, p=0.042) tumour-infiltrating lymphocytes in LGG. sPD-L1 is correlated with neutrophil counts (r=-0.318, p=0.045) and C reactive protein levels (r=-0.363, p=0.008) in GBM. sPD-L1+ patients had longer overall survival in GBM (p=0.006) and worse OS in LGG (p=0.028).

Conclusions: sPD-L1 is detectable in a fraction of patients with brain tumour. Although it is not correlated with tissue PD-L1 expression, correlations with other local and systemic inflammation parameters could be detected in LGG and GBM.
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http://dx.doi.org/10.1136/esmoopen-2020-000863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662140PMC
November 2020

p53 Loss Mediates Hypersensitivity to ETS Transcription Factor Inhibition Based on PARylation-Mediated Cell Death Induction.

Cancers (Basel) 2020 Oct 30;12(11). Epub 2020 Oct 30.

Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria.

The small-molecule E26 transformation-specific (ETS) factor inhibitor YK-4-279 was developed for therapy of ETS/EWS fusion-driven Ewing's sarcoma. Here we aimed to identify molecular factors underlying YK-4-279 responsiveness in ETS fusion-negative cancers. Cell viability screenings that deletion of induced hypersensitization against YK-4-279 especially in the BRAF-mutated colon cancer model RKO. This effect was comparably minor in the BRAF wild-type HCT116 colon cancer model. Out of all ETS transcription factor family members, especially ETS1 overexpression at mRNA and protein level was induced by deletion of specifically under BRAF-mutated conditions. Exposure to YK-4-279 reverted ETS1 upregulation induced by knock-out in RKO cells. Despite upregulation of p53 by YK-4-279 itself in RKOp53 wild-type cells, YK-4-279-mediated hyperphosphorylation of histone histone H2A.x was distinctly more pronounced in the knock-out background. YK-4-279-induced cell death in RKOp53-knock-out cells involved hyperPARylation of PARP1, translocation of the apoptosis-inducible factor AIF into nuclei, and induction of mitochondrial membrane depolarization, all hallmarks of parthanatos. Accordingly, pharmacological PARP as well as BRAF inhibition showed antagonistic activity with YK-4-279 especially in the knock-out background. Taken together, we identified ETS factor inhibition as a promising strategy for the treatment of notoriously therapy-resistant p53-null solid tumours with activating MAPK mutations.
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http://dx.doi.org/10.3390/cancers12113205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693367PMC
October 2020
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