Background and Purpose Recently pentoxifylline, a non‐selective phosphodiesterase inhibitor and adenosine receptor antagonist, has attracted much interest for the treatment of the increased vascular resistance and endothelial dysfunction in pre‐eclampsia. We therefore investigated the placental transfer, vascular effects and anti‐inflammatory actions of pentoxifylline in healthy and pre‐eclamptic human placentas. Experimental Approach The placental transfer and metabolism of pentoxifylline were studied using ex vivo placenta perfusion experiments. In wire myography experiments with chorionic plate arteries, pentoxifyllines vasodilator properties were investigated, focusing on the cGMP and cAMP pathways and adenosine receptors. Its effects on inflammatory factors were also studied in placental explants. Key Results Pentoxifylline transferred from the maternal to foetal circulation, reaching identical concentrations. The placenta metabolized pentoxifylline into its active metabolite lisofylline (M1), which was released into both circulations. In healthy placentas, pentoxifylline potentiated cAMP‐ and cGMP‐induced vasodilation, as well as causing vasodilation by adenosine A1 antagonism and via NO synthase and PKG. Pentoxifylline also reduced inflammatory factors secretion. In pre‐eclamptic placentas, we observed that its vasodilator capacity was preserved, however not via NO‐PKG but likely through adenosine signalling. Pentoxifylline neither potentiated vasodilation through cAMP and cGMP, nor suppressed the release of inflammatory factors from these placentas. Conclusion and Implications Pentoxifylline is transferred across and metabolized by the placenta. Its beneficial effects on the NO pathway and inflammation are not retained in pre‐eclampsia, limiting its application in this disease, although it could be useful for other placenta‐related disorders. Future studies might focus on selective A1 receptor antagonists as a new treatment for pre‐eclampsia.
Background In patients with glioblastoma, radiological recurrence of enhancing tissue after chemoradiotherapy can originate from progressive disease (PD) or from pseudoprogression/treatment-associated changes. There are no widely approved consensus criteria for treatment-associated changes. In the randomised EORTC-CENTRIC study (NCT00689221), patients with MGMT promoter-methylated glioblastoma were treated with chemoradiotherapy or chemoradiotherapy with cilengitide, an integrin inhibitor. We assessed the rate of treatment-associated changes in these groups according to the modified response assessment in neuro-oncology (RANO) criteria of 2017. Methods CENTRIC patients from both study arms with ≥3 follow-up MRIs were included. Preliminary PD (PPD) was defined as a ≥25% increase of the sum of perpendicular diameter (SPD) of a new or increasing lesion compared to baseline or nadir on the T1-MRI with gadolinium. Subsequent PD was defined as a second ≥25% increase of the SPD, at least 4 weeks later, or as a new lesion outside the radiation field. Treatment-associated changes were defined as stabilisation on ≥2 follow-up MRIs after PPD, each one 4 weeks later, or partial/complete regression on ≥1 follow-up MRI 4 weeks later. Results In total, 4,051 MRIs from 584 patients were available. This interim analysis included data on 462 patients with similar proportions in the cilengitide and control arm (50.9% and 49.1%). Due to missing MRIs or values, 128 were excluded. Of the remaining 334 patients, 157 (47%) patients showed RANO measurable disease at baseline or nadir (median SPD, 0mm2; interquartile range (IQR) 552.1 (0-552.1). After chemoradiotherapy with or without cilengitide, PPD occurred in 214 patients (64.1%) after a median time of 6.08 months after finishing radiation (IQR 11.4 (2.4-13.8), and 3.65 months after baseline or nadir (IQR 6.4 (2.1-8.5). After follow-up of these 214 patients, treatment-associated changes were diagnosed in 62 (18.6%) and PD was diagnosed in 48 (14.4%). The remaining 104 (31.1%) patients had no further follow-up MRI after PPD, mostly because a clinical decision to call PD was made. In the cilengitide group of 178 patients, 37 (20.8%) patients developed treatment-associated changes, and 23 (12.9%) patients developed PD, whereas in the control group of 156 patients, 25 (16%) patients developed treatment-associated changes, and 25 (16%) patients PD. Conclusion With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in newly diagnosed MGMT promoter-methylated glioblastoma. This rate did not change with addition of cilengitide. RANO-recommended radiological follow-up was not always awaited, which reflects clinical practice. Full data will be presented.
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