CO2-EVAR: An innovative approach to Automated Carbon Dioxide Angiography during Endovascular Abdominal Aortic Aneurysm repair

Objectives CO2-EVAR was proposed for treatment of AAA especially in patients with CKD. Issues regarding standardization, such as visualization of lowest renal artery (LoRA) and quality image in angiographies performed from pigtail or introducer-sheath, are still unsolved. Aim of the study was to analyze different steps of CO2-EVAR to create an operative protocol to standardize the procedure. Methods Patients undergoing CO2-EVAR were prospectively enrolled in 5 European centers (2018-2021). CO2-EVAR was performed using an automated injector. LoRA visualization and image quality (1-4) were analyzed and compared at different procedure steps: preoperative CO2-angiography from Pigtail/Introducer-sheath (1st Step), angiographies from Pigtail at 0%,50%,100% main body (MB) deployment (2nd Step), contralateral hypogastric artery (CHA) visualization with CO2 injection from femoral Introducer-sheath (3rd Step) and completion angiogram from Pigtail/Introducer-sheath (4th Step). Intra-/postoperative adverse events were evaluated. Results Sixty-five patients undergoing CO2-EVAR were enrolled, 55/65(84.5%) male, median age 75(11.5) years. Median ICM was 20(54)cc; 19/65(29.2%) procedures were performed with 0-iodine. 1st Step: median image quality was significantly higher with CO2 injected from femoral introducer [Pigtail2(3)vs.3(3)Introducer,p=.008]. 2nd Step: LoRA was more frequently detected at 50% (93%vs.73.2%, p=.002) and 100% (94.1%vs.78.4%, p=.01) of MB deployment compared with first angiography from Pigtail; image quality was significantly higher at 50% [3(3)vs.2(3),p=<.001] and 100% [4(3) vs.2(3),p=.001] of MB deployment. CHA was detected in 93% cases (3rd Step). Mean image quality was significantly higher when final angiogram (4th Step) was performed from introducer (Pigtail2.6±1.1vs.3.1±0.9Introducer,p=<.001). Rates of intra-/postoperative adverse events (pain,vomit,diarrhea) were 7.7% and 12.5%. Conclusions Preimplant CO2-angiography should be performed from Introducer-sheath. MB steric bulk during its deployment should be used to improve image quality and LoRA visualization with CO2. CHA can be satisfactorily visualized with CO2. Completion CO2-angiogram should be performed from femoral Introducer-sheath. This operative protocol allows to perform CO2-EVAR with minimal ICM and low rate of mild complications.

The impact of polymorphisms in P-gp, DNA repair and folic acid metabolism genes in newly diagnosed multiple myeloma patients treated with thalidomide plus dexamethasone, with or without bortezomib

The principle aim of this study was to investigate biological predictors of response and resistance to multiple myeloma treatment. Two hypothesis had been proposed as responsible of responsiveness: SNPs in DNA repair and Folate pathway, and P-gp dependent efflux. As a first objective, panel of SNPs in DNA repair and Folate pathway genes, were analyzed. It was a retrospective study in a group of 454, previously untreated, MM patients enrolled in a randomized phase III open-label study. Results show that some SNPs in Folate pathway are correlated with response to MM treatment. MTR genotype was associated with favorable response in the overall population of MM patients. However, this relation, disappear after adjustment for treatment response. When poor responder includes very good partial response, partial response and stable/progressive disease MTFHR rs1801131 genotype was associated with poor response to therapy. This relation - unlike in MTR – was still significant after adjustment for treatment response. Identification of this genetic variant in MM patients could be used as an independent prognostic factor for therapeutic outcome in the clinical practice. In the second objective, basic disposition characteristics of bortezomib was investigated. We demonstrated that bortezomib is a P-gp substrate in a bi-directional transport study. We obtain apparent permeability rate values that together with solubility values can have a crucial implication in better understanding of bortezomib pharmacokinetics with respect to the importance of membrane transporters. Subsequently, in view of the importance of P-gp for bortezomib responsiveness a panel of SNPs in ABCB1 gene - coding for P-gp - were analyzed. In particular we analyzed five SNPs, none of them however correlated with treatment responsiveness. However, we found a significant association between ABCB1 variants and cytogenetic abnormalities. In particular, deletion of chromosome 17 and t(4;14) translocation were present in patients harboring rs60023214 and rs2038502 variants respectively.

Development of strategies for vascular damage repair in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and rare disease with so far unclear pathogenesis, limited treatment options and poor prognosis. Unbalance of proliferation and migration in pulmonary arterial smooth muscle cells (PASMCs) is an important hallmark of PAH. In this research Sodium butyrate (BU) has been evaluated in vitro and in vivo models of PAH. This histone deacetylase inhibitor (HDACi) counteracted platelet-derived growth factor (PDGF)-induced ki67 expression in PASMCs, and arrested cell cycle mainly at G0/G1 phases. Furthermore, BU reduced the transcription of PDGFRbeta, and that of Ednra and Ednrb, two major receptors in PAH progression. Wound healing and pulmonary artery ring assays indicated that BU inhibited PDGF-induced PASMC migration. BU strongly inhibited PDGF-induced Akt phosphorylation, an effect reversed by the phosphatase inhibitor calyculinA. In vivo, BU showed efficacy in monocrotaline-induced PAH in rats. Indeed, the HDACi reduced both thickness of distal pulmonary arteries and right ventricular hypertrophy. Besides these studies, Serial Analysis of Gene Expression (SAGE) has be used to obtain complete transcriptional profiles of peripheral blood mononuclear cells (PBMCs) isolated from PAH and Healthy subjects. SAGE allows quantitative analysis of thousands transcripts, relying on the principle that a short oligonucleotide (tag) can uniquely identify mRNA transcripts. Tag frequency reflects transcript abundance. We enrolled patients naïve for a specific PAH therapy (4 IPAH non-responder, 3 IPAH responder, 6 HeritablePAH), and 8 healthy subjects. Comparative analysis revealed that significant differential expression was only restricted to a hundred of down- or up-regulated genes. Interestingly, these genes can be clustered into functional networks, sharing a number of crucial features in cellular homeostasis and signaling. SAGE can provide affordable analysis of genes amenable for molecular dissection of PAH using PBMCs as a sentinel, surrogate tissue. Altogether, these findings may disclose novel perspectives in the use of HDACi in PAH and potential biomarkers.