In glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors... Show moreIn glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors influencing cellular uptake of liposomes in glioma cells are poorly understood. Heparin and heparin analogues are commonly used in glioma patients to decrease the risk of thrombo-embolic events. Our results show that heparin inhibits pegylated liposome uptake by U87 glioma and GL261 cells in a dose dependent manner in vitro, and that heparin-mediated inhibition of uptake required presence of fetal bovine serum in the media. In a subcutaneous model of glioma, Cy5.5 labeled liposomes could be detected with in vivo imaging after direct intra-tumoral injection. Ex-vivo analysis with flow cytometry showed a decreased uptake of liposomes into tumor cells in mice treated systemically with heparin compared to those treated with vehicle only. Show less
Steen, W. van der; Sluijs, P.M. van der; Graaf, R.A. van de; Su, R.S.; Wolff, L.; Voorst, H. van; ... ; MR CLEAN-MED Investigators 2022
Objectives: We aimed to evaluate whether the overall harmful effect of periprocedural treatment with aspirin or heparin during endovascular stroke treatment is different in patients with a... Show moreObjectives: We aimed to evaluate whether the overall harmful effect of periprocedural treatment with aspirin or heparin during endovascular stroke treatment is different in patients with a successful reperfusion after the procedure. Materials and methods: We performed a post-hoc analysis of the MR CLEAN-MED trial, including adult patients with a large vessel occlusion in the anterior circulation eligible for endovascular treatment (EVT). In this trial, patients were randomized for periprocedural intravenous treatment with aspirin or no aspirin (1:1 ratio), and for moderatedose unfractionated heparin, low-dose unfractionated heparin or no unfractionated heparin (1:1:1 ratio). We tested for interaction between the post-EVT extended thrombolysis in cerebral infarction (eTICI) score and treatment with periprocedural medication with multivariable regression analyses. The primary outcome was the modified Rankin Scale score at 90 days. Secondary outcomes were final infarct volume, intracranial hemorrhage, and symptomatic intracranial hemorrhage. Results: Of 534 included patients, 93 (17%) had a post-EVT eTICI score of 0-2a, 115 (22%) a score of 2b, 73 (14%) a score of 2c, and 253 (47%) a score of 3. For both aspirin and heparin, we found no interaction between post-EVT eTICI score and treatment on the modified Rankin Scale score (p=0.76 and p=0.47, respectively). We found an interaction between post-EVT eTICI score and treatment with heparin on the final infarct volume (p=0.01). Of note, this interaction showed a biologically implausible distribution over the subgroups. Conclusions: The overall harmful effect of periprocedural aspirin and unfractionated heparin is not different in patients with a successful reperfusion after EVT. Show less
Background: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not... Show moreBackground: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not recover even after complete recanalization. To some extent, this may be attributable to incomplete microvascular reperfusion, which can possibly be improved by antiplatelet agents and heparin. It is unknown whether periprocedural antithrombotic medication in patients treated with EVT improves functional outcome. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone, or in combination, given to patients with an ischemic stroke caused by an intracranial large vessel occlusion in the anterior circulation during EVT.Methods: MR CLEAN-MED is a multicenter phase III trial with a prospective, 2 x 3 factorial randomized, open label, blinded end-point (PROBE) design, which aims to enroll 1500 patients. The trial is designed to evaluate the effect of intravenous ASA (300 mg), UFH (low or moderate dose), both or neither as adjunctive therapy to EVT. We enroll adult patients with a clinical diagnosis of stroke (NIHSS >= 2) and with a confirmed intracranial large vessel occlusion in the anterior circulation on CTA or MRA, when EVT within 6 h from symptom onset is indicated and possible. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days. Treatment effect on the mRS will be estimated with ordinal logistic regression analysis, with adjustment for main prognostic variables. Secondary outcomes include stroke severity measured with the NIHSS at 24 h and at 5-7 days, follow-up infarct volume, symptomatic intracranial hemorrhage (sICH), and mortality.Discussion: Clinical equipoise exists whether antithrombotic medication should be administered during EVT for a large vessel occlusion, as ASA and/or UFH may improve functional outcome, but might also lead to an increased risk of sICH. When one or both of the study treatments show the anticipated effect on outcome, we will be able to improve outcome of patients treated with EVT by 5%. This amounts to more than 50 patients annually in the Netherlands, more than 1800 in Europe, and more than 1300 in the USA. Show less
