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Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9–24), 4 years for FTC (range 2.1–41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8–57), 26 months for FTC (range 3.9–188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy.

Purpose: HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non–small cell lung cancer (NSCLC) as the basis for future clinical trial design. Experimental Design: We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. Results: A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. Conclusions: HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody–drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted.

While colorectal and gastroesophageal cancer represent the two gastrointestinal (GI) tumor entities with the highest incidence of brain metastatic (BM) disease, data on the clinical course of BM patients from hepatopancreatobiliary malignancies are rare. Patients with cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC) and gastroenteropancreatic neuroendocrine neoplasms (GEP NEN). Treated for BM between 1991 and 2017 at an academic care center were included. Brain metastases-free survival (BMFS) was defined as interval from first diagnosis until BM development. Overall survival (OS) was defined as interval from diagnosis of BM until death or last date of follow-up. Outcome was correlated with clinical and treatment factors. 29 patients from overall 6102 patients (0.6%) included in the Vienna Brain Metastasis Registry presented with BM from hepatopancreatobiliary primaries including 9 (31.0%) with CCA, 10 (34.5%) with HCC, 7 (24.1%) with PDAC and 3 (10.3%) with GEP NEN as primary tumor. Median BMFS was 21, 12, 14 and 7 months and median OS 4, 4, 6 and 4 months, respectively. Karnofsky Performance Status (KPS) below 80% (p = 0.08), age above 60 years (p = 0.10) and leptomeningeal carcinomatosis (LC) (p = 0.09) diagnosed concomitant to solid BM showed an inverse association with median OS (Cox proportional hazards model). In this cohort of patients with BM from hepatopancreatobiliary tumor entities, prognosis was shown to be very limited. Performance status, age and diagnosis of LC were identified as negative prognostic factors.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

Discrimination; Gender equity; Oncology Discriminació; Equitat de gènere; Oncologia Discriminación; Equidad de género; Oncología Background Following a European Society for Medical Oncology Women for Oncology (ESMO W4O) survey in 2016 showing severe under-representation of female oncologists in leadership roles, ESMO launched a series of initiatives to address obstacles to gender equity. A follow-up survey in October 2021 investigated progress achieved. Materials and methods The W4O questionnaire 2021 expanded on the 2016 survey, with additional questions on the impact of ethnicity, sexual orientation and religion on career development. Results were analysed according to respondent gender and age. Results The survey sample was larger than in 2016 (n = 1473 versus 482), especially among men. Significantly fewer respondents had managerial or leadership roles than in 2016 (31.8% versus 51.7%). Lack of leadership development for women and unconscious bias were considered more important in 2021 than in 2016. In 2021, more people reported harassment in the workplace than in 2016 (50.3% versus 41.0%). In 2021, ethnicity, sexual orientation and religion were considered to have little or no impact on professional career opportunities, salary setting or related potential pay gap. However, gender had a significant or major impact on career development (25.5% of respondents), especially in respondents ≤40 years of age and women. As in 2016, highest ranked initiatives to foster workplace equity were promotion of work–life balance, development and leadership training and flexible working. Significantly more 2021 respondents (mainly women) supported the need for culture and gender equity education at work than in 2016. Conclusions Gender remains a major barrier to career progression in oncology and, although some obstacles may have been reduced since 2016, we are a long way from closing the gender gap. Increased reporting of discrimination and inappropriate behaviour in the workplace is a major, priority concern. The W4O 2021 survey findings provide new evidence and highlight the areas for future ESMO interventions to support equity and diversity in oncology career development. This work was supported by the European Society for Medical Oncology (no grant number).

Purpose: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. Experimental Design: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. Results: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. Conclusions: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.

MET exon 14 ( MET ex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of patients with MET ex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib). To support optimal management of MET ex14 skipping NSCLC in this typically older patient population, the safety profiles of these treatment options are reviewed here. Published safety data from prospective clinical trials with MET TKIs in patients with MET ex14 skipping NSCLC were reviewed. Treatmentrelated adverse events (TRAEs) occurring in > 10% of patients were reported where feasible. Guidance on clinical monitoring and management of key MET TKI TRAEs and dr ug-dr ug interactions is provided. Across the clinical trials, safety data for MET TKIs were reported for 442 patients with MET ex14 skipping. Peripheral edema was the most reported TRAE (50%-63% of patients; grade > 3: 1%-11%), followed by nausea (26%-46% of patients; grade > 3: 0%1%). TRAEs led to dose reductions in 33% to 38% of patients and to discontinuation in 7% to 14% of patients, across the MET TKIs. Considerations on interpreting available safety data are provided, along with insights into monitoring and managing specific MET TKI TRAEs of interest and dr ug-dr ug interactions. Overall, MET TKIs are tolerable treatment options for patients with MET ex14 skipping NSCLC, an older population for whom chemo- or immuno-therapy may not be an effective nor tolerable option. More data regarding the effectiveness of safety interventions and management strategies are needed.

An accurate classification of patients with brain metastases (BMs) is an important foundation to guide individualised treatment decisions and to formulate BM cohorts for modern clinical trials.Six thousand and thirty-one patients with newly diagnosed BM from different solid tumours treated between 1986 and 2020 were identified from the Vienna Brain Metastasis Registry.A rising fraction of patients presented with asymptomatic BM during the observation period (1986-1999: 20.2% vs 2010-2020: 30.6%; p 0.001). Especially, oncogene-addicted non-small-cell lung cancer (NSCLC) and BRAF (v-Raf murine sarcoma viral oncogene homolog)-positive melanoma had a higher rate of asymptomatic BM presentation compared with wild-type tumours (p 0.05). Significant changes of initial BM treatment approaches were observed with a decrease of neurosurgical procedures (1986-1999: 30.8% vs 2010-2020: 19.5%) and an increase of radiation treatments (1986-1999: 65.0% vs 2010-2020: 73.3%) and systemic therapies (1986-1999: 1.0% vs 2010-2020: 2.0%; p 0.001). Median overall survival (OS) was heterogeneous between primary tumour entities but with an overall increase over the decades (median OS 1986-1999: 5 months vs 2010-2020: 7 months; p = 0.001). Survival times were longer in patients with oncogene-addicted NSCLC, BRAF-positive melanoma and hormone receptor-positive breast cancer compared with the other cancer subtypes (p 0.05).Our data highlight shifting trends in the symptomatic presentation and in treatment strategies of patients with BM over the last decades. Entity specific aspects and, in particular, the presence of targetable driver mutation impact the clinical presentation and prognosis. Future BM specific trials need to address the modern composition of BM cohorts and the distinct clinical course of patients with targetable driver mutations.

Background Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial. Methods This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation. Results In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III–IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios. Conclusion Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients. ClinicalTrials.gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.

Crossing the blood–brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it. Significance: Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell–derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167

PURPOSE Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established ( CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS Both CNV- and methylation family–based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

Purpose Meningiomas are the most frequently diagnosed intracranial neoplasms. Usually, they are treated by surgical resection in curative intent. Radiotherapy and stereotactic radiosurgery are commonly applied in the adjuvant setting in newly diagnosed atypical (CNS WHO grade 2), and anaplastic (CNS WHO grade 3) meningioma, especially if gross total resection is not feasible, and in recurrent cases. Conversely, the evidence for pharmacotherapy in meningioma is scarce. Methods The available literature of systemic treatment in meningioma was screened using PubMed, and ongoing clinical trials were explored using ClinicalTrials.gov. Results Classical cytotoxic agents, somatostatin analogs, and antihormone treatments have shown only limited efficacy. In contrast, tyrosine kinase inhibitors and monoclonal antibodies, especially those targeting angiogenic signaling such as sunitinib and bevacizumab, have shown promising antitumoral activity in small phase 2 trials. Moreover, results of recent landmark studies on (epi-)genetic alterations in meningioma revealed potential therapeutic targets which are currently under investigation. These include inhibitors of mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK), cyclin-dependent kinases (CDK), phosphoinositide-3-kinase (PI3K), sonic hedgehog signaling, and histone deacetylases. In addition, clinical trials evaluating immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab and avelumab are currently being conducted and early results suggest clinically meaningful responses in a subset of patients. Conclusions There is a paucity of high-level evidence on systemic treatment options in meningioma. However, interesting novel treatment targets have been identified in the last decade. Positive signals of anti-angiogenic agents, genomically targeted agents and immunotherapy in early phase trials should be confirmed in large prospective controlled trials.

Edema; Nausea; Non-small cell lung cancer Edema; Náuseas; Cáncer de pulmón de células no pequeñas Edema; Nàusees; Càncer de pulmó de cèl·lules no petites Introduction The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. Patients and Methods Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. Results Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. Conclusion Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). Results In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. Trial registration ClinicalTrials.gov NCT01988493.

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.

Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.

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 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.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG\(_{35-55}\)‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2\(^{ind-/-}\)) was achieved by application of tamoxifen; EAE was induced using the MOG\(_{35-55}\) peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2\(^{ind-/-}\) mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2\(^{ind-/-}\) mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2\(^{ind-/-}\) mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2\(^{ind-/-}\) mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2\(^{ind-/-}\) mice than controls. Fgfr2ind−/− mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS.

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods: Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration: NCT02316197, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Oligodendrogliomas are glial tumors with a relatively favorable survival prognosis of >10 years. While immediate postoperative treatment prolongs survival, long-term toxicities of adjuvant radio-chemotherapy remain a concern. Predictive biomarkers guiding postoperative treatment decisions are limited. Material and Methods In this retrospective study, we included patients treated for a newly diagnosed oligodendroglioma (isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted, CNS WHO grades 2 and 3) in 1992 - 2019 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria). Early treatment was defined as radiotherapy, chemotherapy, or both within 6 months after resection, whereas benefit from early treatment was defined as progression-free survival (PFS) above the median in the overall cohort. DNA methylation analysis was performed using Illumina MethylationEPIC 850k microarrays. Results Of all 201 eligible patients, sufficient tumor tissue for DNA methylation analysis was available in 46 patients. Of these, 25/46 (54.3%) were diagnosed with CNS WHO grade 2 and 21/46 (45.6%) with grade 3 oligodendroglioma. Median age at diagnosis was 41 years (range: 23-70). In total, 21/46 (45.6%) patients received early treatment, of whom 13/21 (61.9%) received radio-chemotherapy, 6/21 (28.6%) radiotherapy only and 2/21 (9.5%) chemotherapy only. Median PFS was 134.0 months (95%CI: 78.3 - not reached) in patients receiving early treatment versus 87.2 months (95%CI: 66.8 - 150) in patients who did not. In patients receiving early treatment, differences in DNA methylation profiles could be detected between patients who drew benefit from postoperative treatment (group 1) versus those who did not (group 2). Based on the top 1000 differentially methylated CpG sites between both groups, two clusters were detected which comprised either patients of group 1 or 2. Clustering was independent from gender, WHO grade, extent of resection, type of postoperative treatment, treating center, and O6-methylguanine-methyltransferease (MGMT) promoter methylation status. Gene set enrichment analysis of the top 1000 differentially methylated gene sites mapped to 694 genes showed differential methylation in genes involved in fibroblast growth receptor 1 (FGFR1) signaling, Wnt signaling, integrin signaling, and actin cytoskeleton regulation. Conversely, in patients not receiving early treatment, PFS did neither correlate with DNA methylation clustering nor with MGMT promoter methylation. Conclusion In our cohort, whole genome DNA methylation was associated with PFS in patients who received early postoperative treatment, suggesting a predictive but not prognostic role. As the predictive value of MGMT promoter methylation is limited in oligodendroglioma, whole genome DNA methylation should be considered in future clinical trials.

Background Glioblastoma is associated with a high risk of epileptic seizures ranging from 40% to 60%. Before the advent of modern imaging techniques, electroencephalography (EEG) was a critical component in evaluating patients with space-occupying lesions. In this retrospective single-center study, we aimed (1) to characterize a cohort of patients with glioblastoma with regards to EEG monitoring, seizure frequency and the frequency of prescribed anti-seizure medications (ASM) and (2) to assess the value of EEG as a localizing technique in patients with glioblastoma. Material and Methods We reviewed the charts of 179 patients with glioblastomas between January 1st, 2020 and January 1st, 2022, treated at the Medical University of Vienna. The diagnosis was based on MRI and/or confirmed by biopsy according to the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Patients who received an in-house EEG as part of their diagnostic work-up were included if an MRI/CT scan was available (within an average time of +/-60 days). For localization, focal slowing (theta/delta activity) and/or epileptiform discharges were considered. EEG rating was performed by a board-certified electrophysiologist blinded for the diagnosis and MRI/biopsy findings. Results We included 52 patients (29.05% of screened cohort) with at least one EEG and MRI or CT scan performed before or after EEG, following inclusion criteria (median: 2 days; mean: 6 days; range: -29 to 52), in the final analysis. Clinical seizure activity and/or epileptiform discharges on EEG were detected in 46 patients (88.46%), and 48 patients (92.31%) were on ASM. An IDH-wildtype glioblastoma was diagnosed in 45 patients (86.54%), 4 had an IDH-mutant glioblastoma (7.69%), and in 3 patients, IDH-status was unknown (5.77%). In 22 patients (42.31%), biopsy revealed a positive MGMT promoter methylation status, while 28 were unmethylated (53.84%), and two patients had an unknown MGMT promoter methylation status (3.85%). Intermittent and/or continuous focal slow-wave activity was registered in 45 patients (86.54%). In comparison, epileptiform discharges could only be found in 13 patients (25%). When compared to MRI/CT scans, the hemispheric tumor localization could be determined in 42 cases (80.77%). Moreover, the affected brain lobe was accurately predicted in 35 patients (67.31%). Three patients had diffuse EEG changes (5.77%), and EEG was unremarkable in 7 patients (13.46%). Conclusion Overall, our presented data indicate that the hemispheric localization of glioblastoma can be reliably predicted by EEG recordings, while a precise (brain lobe-specific) localization was only possible in around two-thirds of cases.

BackgroundAccounting for 15–20% of all meningiomas, WHO grade II meningiomas represent an intermediate group regarding risk of tumor recurrence. However, even within this subgroup varying clinical courses are observed with potential occurrence of multiple recurrences. Recently, DNA methylation profiles showed their value for distinguishing biological behaviors in meningiomas. Therefore, aim of this study was to investigate DNA methylation profiles in WHO grade II meningiomas.MethodsAll patients that underwent resection of WHO grade II meningiomas between 1993 and 2015 were screened for a dismal course clinical course with ≥2 recurrences. These were matched to control cases with benign clinical courses without tumor recurrence. DNA methylation was assessed using the Infinium Methylation EPIC BeadChip microarray. Unsupervised hierarchical clustering was performed for identification of DNA methylation profiles associated with such a dismal clinical course.ResultsOverall, 11 patients with WHO grade II meningiomas with ≥2 recurrences (Group dismal) and matched 11 patients without tumor recurrence (Group benign) were identified. DNA methylation profiles revealed 3 clusters—one comprising only patients of group dismal, a second cluster comprising mainly patients from group benign and a third cluster comprising one group dismal and one group benign patient. Based on differential methylation pattern associations with the Wnt and the related cadherin signaling pathway was observed.ConclusionDNA methylation clustering showed remarkable differences between two matched subgroups of WHO grade II meningiomas. Thus, DNA methylation profiles may have the potential to support prognostic considerations regarding meningioma recurrence and radiotherapeutic treatment allocation after surgical resection.

BackgroundBiomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI.MethodsWe identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI.Results37 patients with HNSCC (median age of 62 years; range 49–83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1–4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0–22.9) and 9.0 months (range 0–38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with ‘Axon guidance’, ‘Hippo signaling’, ‘Pathways in cancer’ and ‘MAPK signaling’. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498).ConclusionsOur findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.

Background/aim To compare the GeneXpert® O6-methylguanine DNA methyltransferase (MGMT) methylation prototype (GX MGMT) assay with pyrosequencing in glioblastomas. Materials and methods The MGMT methylation status was retrospectively assessed in formalin-fixed paraffin embedded (FFPE) tumor blocks from 262 glioblastoma patients obtained from three independent cohorts using either a standard of care pyrosequencing laboratory developed test or the GX MGMT assay. Results The concordance rate was 92.1% (58/63) for Oregon Health and Science University (OSHU) samples, 91.7% (88/96) for Medical University of Vienna (MUV) samples, and 82.5% (85/103) for Kepler University Hospital (KUH) samples. Patients with MGMT promoter hypermethylation assessed by pyrosequencing or the GX MGMT test had a significantly longer overall survival compared to patients without hypermethylation (HR=0.43, 95%CI=0.26-0.72, p=0.001 and HR=0.51, 95%CI=0.31-0.84, p=0.008, respectively). Conclusion Standardized, simplified, and on-demand testing of MGMT promoter methylation by the GX MGMT assay is feasible.

Background Brain metastases (BM) are a frequent complication of advanced cancer and are characterized by a variety of neurological symptoms. Although the presence of neurological symptoms is included in the response assessment in patients with primary brain tumors, to the authors' knowledge little is known regarding the prognostic impact of neurological symptoms in patients with BM. Methods Patients with newly diagnosed BM from non–small cell lung cancer were identified from the Vienna Brain Metastasis Registry and were evaluated according to the incidence, distribution, and prognostic impact of neurological symptoms at the time of diagnosis of BM. Results A total of 1608 patients (57.3% male and 42.7% female; median age, 62 years) were available for further analyses. Neurological symptoms including focal deficits (985 patients; 61.3%), signs of increased intracranial pressure (483 patients; 30.0%), epileptic seizures (224 patients; 13.9%), and neuropsychological symptoms (233 patients; 14.5%) were documented in 1186 of the 1608 patients (73.8%). Patients with asymptomatic BM presented with a longer median overall survival after the diagnosis of BM compared with patients with symptomatic BM (11 months vs 7 months; P, Neurological symptoms at the time of diagnosis of brain metastases demonstrate a strong, independent prognostic impact on prognosis. The current study highlights the integration of neurological symptom burden into the prognostic assessment of patients with brain metastases from non–small cell lung cancer.

Introduction Pilocytic astrocytoma (PA) is the most common primary brain neoplasm in children and treated in curative intent with gross total resection (GTR). However, PA is rare in adults, resulting in limited knowledge on the natural clinical course. This study aimed to describe the clinical course and identify prognostic factors of adult patients with PA. Methods 46 patients ≥ 18 years at diagnosis of PA and neurosurgical resection or biopsy between 2000 and 2018 were identified from the Neuro-Biobank of the Medical University of Vienna. In two cases with differing histopathological diagnosis at recurrence, DNA methylation analysis was performed using Illumina Infinium HumanMethylation850 BeadChip (850 k) arrays and the Molecular Neuropathology classifier. Clinico-pathological features were correlated with patient outcomes. Results Median age at diagnosis was 32.5 years (range: 19–75) and median Ki67 proliferation index was 2.8% (0.5–13.4%). Tumor location significantly correlated with resectability (p 40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p Conclusions Tumor recurrence or progression in adult PA patients was higher than the one reported in pediatric patients. Higher age and BMI were associated with impaired prognosis.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Rationale: Glioblastoma is the most frequent, primary brain tumor that is characterized by a highly immunosuppressive tumor microenvironment (TME). The TME plays a key role for tumor biology and the effectiveness of immunotherapies. Composition of the TME correlates with overall survival and governs therapy response. Non invasive assessment of the TME has been notoriously difficult. Methods: We have designed an in vivo imaging approach to non invasively visualize innate immune cell dynamics in the TME in a mouse glioma model by correlated MRI and multiphoton microscopy (MR-MPM) using a bimodal, fluorescently labeled iron oxide nanoparticle (NP). The introduction of Teflon cranial windows instead of conventional Titanium rings dramatically reduced susceptibility artifacts on MRI and allowed longitudinal MR-MPM imaging for innate immune cell tracking in the same animal. Results: We visualized tumor associated macrophage and microglia (TAM) dynamics in the TME and dissect the single steps of NP uptake by blood-born monocytes that give rise to tumor-associated macrophages. Next to peripheral NP-loading, we identified a second route of direct nanoparticle uptake via the disrupted blood-brain barrier to directly label tissue resident TAMs. Conclusion: Our approach allows innate immune cell tracking by MRI and multiphoton microscopy in the same animal to longitudinally investigate innate immune cell dynamics in the TME.

In pre-clinical and clinical settings, active immunization with a Her-2/neu vaccine (HerVaxx), comprising B-cell peptide from Trastuzumab binding site, has been shown to reduce primary tumor growth via induction of polyclonal anti-tumor immune responses and immunological memory. Here, we tested the combination of HerVaxx and the recently identified B-cell epitope/mimotope of Pertuzumab, i.e. a multi-peptide B-cell vaccine, for preventing Her-2/neu lung metastases formation in a mouse model. Active immunization with the multi-peptide vaccine was associated with decreased lung weights, and histological evaluation of the lungs showed that the significant reduction of lung metastases was associated with increased CD4+ and CD8+ T cell infiltration. Notably, along with the overall reduction of lungs weights and Her-2 positive metastases, a formation of Her-2/neu-negative tumors but with increased PD-L1 expression was observed. Our results might pave the way to a multi-peptide B-cell Her-2/neu vaccine serving as a secondary intervention in adjuvant settings to prevent tumor recurrence and spread. Moreover, combination therapy targeting PD-L1 may result in total remission of metastases. Such a therapy may be used clinically to alternately target Her-2/neu and PD-L1 in metastatic breast cancer.

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

Background Due to potentially immune-escaping virus variants and waning immunity, a third SARS-CoV-2 vaccination dose is increasingly recommended. However, data in patients with cancer are limited. Patients and methods We measured anti-SARS-CoV-2 spike protein antibody levels after the third vaccination dose in 439 patients with cancer and 41 health care workers (HCW) at an academic center in Austria and a rural community hospital in Italy. Adverse events were retrieved from questionnaires. Results Overall, 439 patients and 41 HCW were included. SARS-CoV-2 infections were observed in 62/439 (14.1%) patients before vaccination and in 5/439 (1.1%) patients after ≥1 dose. Longitudinal analysis revealed a decrease of antibody levels between 3 and 6 months after second vaccination in patients with solid tumors (p

Simple Summary In the next decades, the incidence of patients with glioblastoma (GBM) will markedly increase due to the growth of the elderly population. Despite the increasing incidence of GBM, elderly patients are frequently excluded from clinical studies and thus, only few data are available specifically focusing on the elderly population. In the current study, we aimed to investigate the efficacy, outcome, and safety of surgically-treated GBM including resections and biopsies in the 5-ALA era in a large elderly cohort of altogether 272 patients. Our data of this large elderly cohort demonstrate for the first time the clinical utility and safety of 5-ALA fluorescence in GBM for improved tumor visualization in both resections as well as biopsies. Therefore, we recommend the use of 5-ALA not only in resections, but also in open/stereotactic biopsies to optimize the neurosurgical management of elderly GBM patients. Abstract Background: In the next decades, the incidence of patients with glioblastoma (GBM) will increase due to the growth of the elderly population. Fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) is widely applied to achieve maximal safe resection of GBM and is identified as a novel intraoperative marker for diagnostic tissue during biopsies. However, detailed analyses of the use of 5-ALA in resections as well as biopsies in a large elderly cohort are still missing. The aim of this study was thus to investigate the efficacy, outcome, and safety of surgically- treated GBM in the 5-ALA era in a large elderly cohort. Methods: All GBM patients aged 65 years or older who underwent neurosurgical intervention between 2007 and 2019 were included. Data on 5-ALA application, intraoperative fluorescence status, and 5-ALA-related side effects were derived from our databank. In the case of resection, the tumor resectability and the extent of resection were determined. Potential prognostic parameters relevant for overall survival were analyzed. Results: 272 GBM patients with a median age of 71 years were included. Intraoperative 5-ALA fluorescence was applied in most neurosurgical procedures (n = 255/272, 88%) and visible fluorescence was detected in most cases (n = 252/255, 99%). In biopsies, 5-ALA was capable of visualizing tumor tissue by visible fluorescence in all but one case (n = 91/92, 99%). 5-ALA administration did not result in any severe side effects. Regarding patient outcome, smaller preoperative tumor volume (

Purpose Tepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes. Methods Exposure–efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure–safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30–1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia’s method (QTcF). Results Tepotinib exhibited flat exposure–efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure–safety relationships for all endpoints within the exposure range observed with 30–1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses. Conclusions These analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations. Registration Numbers NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

PURPOSE Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from cases with benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for the individual patient is of pivotal importance in clinical management. However, only biomarkers for highly aggressive tumors are established at present (CDKN2A/B and TERT), while no molecularly-based stratification exists for the broad spectrum of low- and intermediate-risk meningioma patients. PATIENTS AND METHODS DNA methylation data and copy-number information were generated for 3,031 meningiomas of 2,868 individual patients, with mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNV), mutations and WHO grading were comparatively analyzed. Prediction power for outcome of these parameters was assessed in an initial retrospective cohort of 514 patients, and validated on a retrospective cohort of 184, and on a prospective cohort of 287 multi-center cases, respectively. RESULTS Both CNV and methylation family- (MF)-based subgrouping independently resulted in an increase in prediction accuracy of risk of recurrence compared to the WHO classification (c-indexes WHO 2016, CNV, and MF 0.699, 0.706 and 0.721, respectively). Merging all independently powerful risk stratification approaches into an integrated molecular-morphological score resulted in a further, substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference p=0.005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (HR 4.56 [2.97;7.00], 4.34 [2.48;7.57] and 3.34 [1.28; 8.72] for discovery, retrospective, and prospective validation cohort, respectively). CONCLUSIONS Merging these layers of histological and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision-making for meningioma patients on the basis of robust outcome prediction.

Introduction: As thyroid hormones modulate proliferative pathways it is surmised that they can be associated with cancer development. Since the potential association of gastroesophageal cancer and thyroid disorders has not been addressed so far, the aim of this study was to investigate the association of thyroid hormone parameters with the outcome of these patients, so novel prognostic and even potentially therapeutic markers can be defined. Material and Methods: Clinical and endocrinological parameters of patients with resectable gastroesophageal cancer treated between 1990 and 2018 at the Vienna General Hospital, Austria, including history of endocrinological disorders and laboratory analyses of thyroid hormones at first cancer diagnosis were investigated and correlated with the overall survival (OS). Results: In a total of 865 patients, a tendency towards prolonged OS in hypothyroid patients (euthyroid, n = 647: median OS 29.7 months, hyperthyroid, n = 50: 23.1 months, hypothyroid, n = 70: 47.9 months, p = 0.069) as well as a significant positive correlation of thyroid hormone replacement therapy with the OS was observed (without, n = 53: median OS 30.6 months, with, n = 67: 51.3 months, p = 0.017). Furthermore, triiodothyronine (T3) levels were also associated with the OS (median OS within the limit of normal: 23.4, above: 32.4, below: 9.6 months, p = 0.045). Conclusions: Thyroid disorders and their therapeutic interventions might be associated with the OS in patients with resectable gastroesophageal cancer. As data on the correlation of these parameters is scarce, this study proposes an important impulse for further analyses concerning the association of thyroid hormones with the outcome in patients with gastroesophageal tumors.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

BACKGROUND Oligodendrogliomas are rare, slow-growing brain tumors with a survival prognosis of >10 years. Although adjuvant radio-chemotherapy has been shown to prolong survival, aggressive treatment comes at the cost of increased toxicity. Systematic data on the optimal timing of adjuvant treatment in oligodendroglioma are lacking. MATERIAL AND METHODS Patients treated for a newly diagnosed IDH-mutated, 1p/19q-codeleted oligodendroglioma (WHO grades II/III) in 2000 - 2018 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria) were included in this retrospective study. Adjuvant treatment was defined as radiotherapy (RT), chemotherapy (CHT) or radio-chemotherapy (R-CHT) within 6 months after resection in the absence of progression. “Wait and see” was defined as regular follow up with magnetic resonance imaging and treatment at progression. RESULTS 185 patients were identified, comprising 123/185 (66.5%) WHO grade II and 62/185 (33.5%) WHO grade III oligodendrogliomas. Median age at diagnosis was 42 years (range: 20–82). Gross total resection (GTR) could be achieved in 77/178 (42.3%) evaluable patients. Adjuvant treatment was applied in 63/185 (38.2%) patients, of whom 43/63 (68.3%) underwent R-CHT, 9/63 (14.3%) CHT only and 11/63 (17.5%) RT only. 43/52 (82.7%) received temozolomide-based treatment, 1/52 (1.9%) procarbazine, lomustine and vincristine (PCV), 1/52 dacarbazine/fotemustine and in 7/52 (13.5%) patients, no data on used regimens was available. Adjuvant treatment was more frequently applied in WHO grade 3 tumors (p CONCLUSION The application of adjuvant therapy was associated with favorable PFS in patients who underwent resection of newly diagnosed oligodendroglioma in this retrospective study. Prospective clinical trials should investigate the risks and benefits of adjuvant treatment versus initial observation in patients with oligodendroglioma.

Background Brain metastases (BM) constitute the most common central nervous system tumors. The treatment options of BM consist of surgery, radiotherapy, radiosurgery, chemotherapy, and immunotherapy. Regarding surgery in BM, the extent of resection (EOR) represents a crucial factor for patient prognosis. However, first studies using postoperative MRI demonstrated that an unexpected residual tumor after surgery of BM is not uncommon despite these tumors were considered to be well-demarcated. The aim of this study was thus to investigate in a large cohort including multiple neurosurgical centers the EOR following BM resection, potential risk factors for incomplete resection and postsurgical follow-up data. Material and Methods In the current retrospective study conducted at 5 specialized neurosurgical centers in Austria, we included patients with BM resection and available postoperative MRI. The EOR following BM resection was determined by postoperative MRI (complete vs incomplete resection). Additionally, the data on the intraoperative judgement of the EOR of the performing neurosurgeon were collected. Moreover, potential factors for incomplete resection including tumor localization, tumor volume, primary tumor, pattern of contrast media enhancement on imaging and tumor eloquence were investigated. Finally, the rate of local progression of BM after initial surgery was analyzed in the follow-up period and overall survival data were collected. Results Altogether, 548 patients with 649 surgically treated BM were included. According to postoperative MRI, complete resection was achieved in 407 (66%) of 649 BM and incomplete resection in 176 (29%) of 649 BM. Misjudgment of the EOR by the neurosurgeon was found in 25% of cases and resulted in an unexpected residual tumor which was evident on postoperative MRI in 122 (22%) BM. Preoperative tumor volume was significantly larger in incompletely resected BM. Moreover, local progression was significantly more common in cases with incompletely resected BM and was also associated with shorter overall survival. Conclusion Our data of this study including multiple centers indicate that postoperative MRI is capable to detect a relatively high rate of unexpected residual tumors following resection of BM. Since local progression was more common in BM with residual tumors and this was associated with shorter survival, special attention should be paid to achieve a complete tumor resection.

Background T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100. Material and Methods We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05. Results At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point. Conclusion In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.

Background The intraoperative visualization of adult-type diffuse gliomas with 5-aminolevulinic acid (5-ALA) induced fluorescence is widely used in the neurosurgical field. While visible 5-ALA induced fluorescence is found in the majority of high-grade gliomas, most low-grade gliomas lack visible fluorescence during surgery. Recently, the heme biosynthesis pathway was identified as crucial influencing factor for presence of visible fluorescence since it metabolizes 5-ALA to fluorescing Protoporphyrin IX (PpIX). However, the exact alterations within the heme biosynthesis pathway resulting in visible 5-ALA induced fluorescence in gliomas are still unclear. The aim of the present study was thus to compare the mRNA and protein expression of promising intramitochondrial heme biosynthesis enzymes/transporters in glioma tissue samples of different fluorescence behavior. Material and Methods A total of 19 strongly fluorescing and 21 non-fluorescing tissue samples from neurosurgical adult-type diffuse gliomas (WHO grades II-IV) were included in the current analysis. In these samples, we investigated the mRNA expression by quantitative real time PCR and protein expression using immunohistochemistry of the intramitochondrial heme biosynthesis enzymes Coproporphyrinogen Oxidase (CPOX), Protoporphyrinogen Oxidase (PPOX), Ferrochelatase (FECH) and the transporter ATP-binding Cassette Subfamily B Member 2 (ABCG2). Results Regarding mRNA expression analysis, we found a significantly decreased ABCG2 expression in fluorescing specimens compared to non-fluorescing samples (p=0.001), whereas no difference in CPOX, PPOX and FECH was present. With respect to protein expression, significantly higher levels of CPOX (p=0.005), PPOX (p Conclusion Distinct alterations of the analyzed heme biosynthesis factors were found primarily on protein level. Our data indicate that heme biosynthesis pathway activity in general is enhanced in fluorescing gliomas with upregulation of PpIX generating enzymes and decreased ABCG2 mediated PpIX efflux outweighing the also increased further metabolization of PpIX to heme. Intramitochondrial heme biosynthesis factors thus constitute promising pharmacological targets to optimize intraoperative 5-ALA fluorescence visualization of usually non-fluorescing tumors such as low-grade gliomas.

Background The incidence of brain metastases (BM) in patients with thyroid cancer (TC) depends on the histological subtype. About 1% of patients with differentiated (DTC), 3% with medullary (MTC) and up to 10% with anaplastic thyroid cancer (ATC) develop BM. The diagnosis of BM drastically worsens the prognosis of TC. Given the rare incidence, little is known about the presentation and outcome of this cohort. Material and Methods Patients with a histologically verified diagnosis of TC and BM were identified from the Vienna Brain Metastasis Registry, a comprehensive database managed by the Division of Oncology, Medical University of Vienna, including patients with cerebral metastasis since 1990. Data were obtained from medical records comprising clinicopathological features, treatment, BM-specific characteristics and outcome. Results 20/6074 patients included in the registry had a diagnosis of TC and radiologically verified BM. 13/20 (65%) were female and the median age at diagnosis of TC and manifestation of BM was 56 years (range 21-75) and 68 years (range 45-75), respectively. In terms of histology, 18/20 (90%) had DTC, one MTC and one ATC. Interestingly, 10/18 DTC presented with follicular histology which underlines the more aggressive course of this rare subtype. 6/20 (30%) had BM at primary diagnosis (DTC n=5, ATC n=1), while the remaining developed BM during follow-up. The median time to diagnosis of BM was 2.6 years for DTC (range 0-42), 22 years in the MTC patient and 2 months for ATC. Regarding BM-specific characteristics, all but one patient had symptoms due to BM (neurological deficits n=11, increased intracranial pressure n=5, seizures n=3). Most patients (13/20) had a singular BM, commonly located in the left hemisphere (8/13), and only one had more than three BMs. Upfront treatment for BM was local therapy (resection n=9, stereotactic radiosurgery n=7, whole brain radiotherapy n=3); one patient received supportive care only. The median overall survival (mOS) from diagnosis of TC was 6 years for DTC (range 2.5 months-42 years), 33 years for the MTC and 9 months for the ATC. The mOS from diagnosis of BM was 14 months for DTC (1.8 months-16 years), 22 years for the MTC and 3 months for the ATC. Conclusion Few patients with TC develop BM, which present commonly as single lesion. While in general BM constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. More information about the optimal management of BM in TC is needed to enable guideline recommendations.

Background Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms. Material and Methods Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO). Results Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort. Conclusion Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.

Background Based on the the rising detection of asymptomatic brain metastases (BM) and the remarkable intracranial responses of targeted- and immunotherapy in specific subgroups of asymptomatic BM patients, we aimed to evaluate the clinical characteristics and prognostic value of neurological symptoms in BM from melanoma. Material and Methods 670 patients with newly diagnosed melanoma BM were identified from the Vienna Brain Metastasis Registry. We performed retrospective chart review and statistical outcome analyses. Results 370/670 (55.2%) patients presented with neurological symptoms including neurological deficits (316/370; 85.4%), signs of increased intracranial pressure (126/370; 34.1%) and epileptic seizures (53/370; 14.3%). 57.6% (80/139) of patients with BRAF mutated melanoma presented with asymptomatic BM at diagnosis. Absence of neurological symptoms at BM diagnosis was associated with a longer median overall survival after time of BM diagnosis (7 vs. 5 months; p< 0.001; log-rank test). In multivariate analysis with the diagnosis-specific graded prognostic assessment (DS-GPA: HR:1.4; 95% CI, 1.25-1.48; p Conclusion: Neurological symptoms at the time of BM diagnosis are an independent and strong prognostic factor in melanoma BM patients. Our results argue for the integration of neurological symptoms into the prognostic assessment of patients with BM from melanoma.

Background Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) is a widely used technique to conduct maximum safe resection of high-grade gliomas (HGG). 5-ALA accumulates in malignant tumor tissue where it is metabolized to Protoporphyrin IX (PpIX), an agent with fluorescence properties. It helps neurosurgeons to distinguish between tumor-infiltrated tissue and healthy brain parenchyma. Even though fluorescence-guided surgery is clinically well established, the biological properties of different fluorescence levels are not comprehensively studied yet. A relevant current gap in that respect is the pattern of immune cell infiltration in fluorescent versus non-fluorescent tissue samples. In light of future research, reliable, standardized histopathology methods that allow high-throughput analysis are desirable and digital pathology with automated image analysis is an attractive option to explore. Material and Methods 128 formalin-fixed paraffin-embedded (FFPE) tissue blocks of 39 patients who underwent fluorescence-guided surgery of a HGG were included. Samples were selected based on their documented 5-ALA fluorescence intensity status (strong, vague, negative). Microtome-cut sections of the tissue were stained with antibodies against CD8, CD68, CD163 and FOX P3, representing immune cell populations of specific interest (cytotoxic T cells, glioma-associated macrophages, regulatory T cells). A total of 512 stained slides were then available for assessment. In addition to a classical, semi-quantitative analysis by two independent human reviewers, the immune infiltration intensity was measured via automated image analysis with the digital pathology software QuPath Version 0.3.2. Results Across all stained FFPE samples CD68 showed the overall highest intensity, followed by CD163. CD8 and FoxP3 showed generally lower average intensities. In 5-ALA negative and positive high-grade glioma samples the immune cell infiltration pattern was the same. Quantitative automatic digital pathology correlated well with the classical human histopathological analysis for the majority of markers evaluated. Conclusion We successfully explored and established novel digital pathology technologies for the study of immune cell infiltration patterns in neurooncology, specifically in the context of fluorescence-guided resection. Leveraging this platform could allow parallelized and high-throughput analysis of immune cell infiltration also in other contexts.

Background Neurosurgical resection represents an important treatment option in the modern, multimodal therapy approach of brain metastases (BM). Guidelines for perioperative imaging exist for primary brain tumors to guide postsurgical treatment. Optimal perioperative imaging of BM patients is so far a matter of debate as no structured guidelines exist. Methods A comprehensive questionnaire about perioperative imaging was designed by the European Association of Neuro-Oncology (EANO) Youngsters Committee. The survey was distributed to physicians via the EANO network to perform a descriptive overview on the current habits and their variability on perioperative imaging. Chi square test was used for dichotomous variables. Results One hundred twenty physicians worldwide responded to the survey. MRI was the preferred preoperative imaging method (93.3%). Overall 106/120 (88.3%) physicians performed postsurgical imaging routinely including MRI alone (62/120 [51.7%]), postoperative CT (29/120 [24.2%]) and MRI + CT (15/120 [12.5%]). No correlation of postsurgical MRI utilization in academic vs. non-academic hospitals (58/89 [65.2%] vs. 19/31 [61.3%], p = 0.698) was found. Early postoperative MRI within ≤72 h after resection is obtained by 60.8% of the participants. The most frequent reason for postsurgical imaging was to evaluate the extent of tumor resection (73/120 [60.8%]). In case of residual tumor, 32/120 (26.7%) participants indicated to adjust radiotherapy, 34/120 (28.3%) to consider re-surgery to achieve complete resection and 8/120 (6.7%) to evaluate both. Conclusions MRI was the preferred imaging method in the preoperative setting. In the postoperative course, imaging modalities and timing showed high variability. International guidelines for perioperative imaging with special focus on postoperative MRI to assess residual tumor are warranted to optimize standardized management and adjuvant treatment decisions for BM patients.