Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts ( < .001) and higher D-dimer levels ( < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens ( < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; 010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.

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Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging.Patients with IDH1 wildtype and high podoplanin expression have a 6‐month VTE risk of 18.2%.Patients with IDH1 mutation and no podoplanin expression have a 6‐month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SummaryBackgroundVenous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk.ObjectivesTo investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development.Patients/MethodsIn a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2‐year follow‐up.ResultsAll brain tumors that expressed podoplanin to a medium‐high extent showed also an IDH1 wild‐type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild‐type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6‐month risk 18.2% vs. 0%).Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild‐type tumors is strongly linked to podoplanin expression levels.

A tight interplay between inflammation and hemostasis has been described as a potential driver for developing venous thromboembolism (VTE). Here, we investigated the association of systemic cytokine levels and risk of VTE in patients with glioma. This analysis was conducted within the prospective, observational Vienna Cancer and Thrombosis Study. Patients with glioma were included at time of diagnosis or progression and were observed for a maximum of two years. Primary endpoint was objectively confirmed VTE. At study entry, a single blood draw was performed. A panel of nine cytokines was measured in serum samples with the xMAP technology developed by Luminex. Results: Overall, 76 glioma patients were included in this analysis, and 10 (13.2%) of them developed VTE during the follow-up. Chemokine C-C motif ligand 3 (CCL3) levels were inversely associated with risk of VTE (hazard ratio [HR] per double increase, 95% confidence interval [CI]: 0.385, 95% CI: 0.161–0.925, p = 0.033), while there was no association between the risk of VTE and serum levels of interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-11, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF), respectively. In conclusion, low serum levels of CCL3 were associated with an increased risk of VTE. CCL3 might serve as a potential biomarker to predict VTE risk in patients with glioma.

IntroductionThe role of the adaptive immune system in the pathophysiology of cancer-associated venous thromboembolism (VTE) has not been investigated in detail. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule responsible for immune evasion in several cancer entities, as expression on tumour cells silences the T cell-mediated immune response. Given the interrelation between inflammation, haemostasis and cancer, we aimed to investigate the association of players of the adaptive immunity (eg, lymphocytes, tumour PD-L1) with risk of VTE in patients with glioma, one of the most prothrombotic cancer types.MethodsIn this prospective observational single-centre cohort study, patients with newly diagnosed glioma or regrowth after resection were included. Primary endpoint was objectively confirmed VTE. At study inclusion, a blood draw was performed. Tumour PD-L1 expression was assessed via immunohistochemistry.ResultsIn total, 193 patients were included. PD-L1 expression in ≥1% of tumour cells was observed in 20/193 (10.4%) glioma. In multivariable cox-regression analysis, on adjustment for age, sex and WHO grade IV, systemic lymphocyte counts were significantly associated with risk of VTE (HR per 1 G/L increase (95% CI): 1.15 (1.03 to 1.29), p=0.013). In contrast, no significant difference in risk of VTE was found regarding the PD-L1 status: the cumulative 24 months probability of VTE was 17.0% in patients with no PD-L1 and 11.8% in those with PD-L1 expressing tumours (p=0.663).ConclusionIn summary, PD-L1 expression was not associated with risk of VTE. Interestingly, peripheral lymphocytes, which are key players in adaptive immunity, were linked to an increased risk of glioma-associated VTE.

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2052 Background: Immune modulating therapies have been a long withstanding treatment approach in glioma. However, gliomas are characterized by a particular absence of tumor infiltrating lymphocytes in the local tumor microenvironment. We aimed to gain insight on the distinct patterns of inflammation associated with survival prognosis in glioma. Methods: Patients were recruited at time of glioma diagnosis or progression in the prospective observational Vienna Cancer and Thrombosis Study (CATS). A single blood draw was performed at study inclusion. PD-L1 expression in the tumor tissue was investigated via immunohistochemistry. Optimal cut-off according to ROC curve was used to assess cut off values for survival analysis. Results: 193 patients with glioma (75.6% glioblastoma (WHO grade IV), 19.7% anaplastic glioma (WHO grade III), and 4.7% diffuse glioma (WHO grade II)) were included. 40/193 (20.7%) glioma had an IDH1 mutation. Membranous PDL1 expression in the tumor tissue was observed in 20/193 (10.4%) patients. 1/20 patient presented with PD-L1 expression and IDH1 mutation ( p = 0.082). PD-L1 significantly correlated with increased monocyte count (median: 0.657 vs. 0.450 [G/L], p = 0.008), higher C-reactive protein (CRP) (0.43 vs. 0.1 [mg/dL], p = 0.005) and higher fibrinogen (379 vs. 303 [mg/dL], p = 0.001). Presence of IDH1 mutation significantly correlated with increased platelet count (303 vs. 232 [G/L], p = 0.001) and lower Neutrophil/Lymphocyte (N/L) ratio (3.34 vs. 5.13, p = 0.016). Higher lymphocyte count ( > 1.484 [G/L], log-rank: p = 0.011), higher platelet count ( > 245.5 [G/L], p = 0.0001), as well as decreased N/L ratio ( < 5.13, p = 0.001) were significantly associated with increased survival prognosis. Conclusions: PD-L1 expression in tumor tissue was associated with markers of systemic inflammation in glioma patients. Systemic inflammation markers furthermore predicted improved survival. Immune modulating therapy approaches might be a promising approach in subgroups of glioma associated with increased baseline interaction of immune system and glioma.

Background: Venous thromboembolism occurs frequently in patients with primary brain tumors. Aims: Given the strong interplay between inflammation and haemostasis, the aim of the current study was to investigate the association of serum cytokine levels and risk of VTE development in patients with glioma. Methods: Within the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective and observational cohort study of patients with active cancer, we conducted an exploratory analysis. Patients were recruited at the time of cancer diagnosis or progression of disease after remission and followed for two years. Primary endpoint was