Background
Since 2010, the Ovation Abdominal Stent Graft System has offered an innovative sealing option for abdominal aortic aneurysm (AAA) by including a sealing ring filled with polymer 13 mm from ...the renal arteries. In August 2020, the redesigned Ovation Alto, with a sealing ring 6 mm closer to the top of the fabric, received CE Mark approval.
Objective
This registry study aims to evaluate intraoperative, perioperative, and postoperative results in patients treated by the Alto stent graft (Endologix Inc.) for elective AAA repair in a multicentric consecutive experience.
Methods
All consecutive eligible patients submitted to endovascular aneurysm repair (EVAR) by Alto Endovascular AAA implantation will be included in this analysis. Patients will be submitted to EVAR procedures based on their own preferences, anatomical features, and operators experience. An estimated number of 300 patients submitted to EVAR with Alto stent graft should be enrolled. It is estimated that the inclusion period will be 24 months. The follow-up period is set to be 5 years. Full data sets and cross-sectional images of contrast-enhanced computed tomography scan performed before EVAR, at the first postoperative month, at 24 or 36 months, and at 5-year follow-up interval will be reported in the central database for a centralized core laboratory review of morphological changes. The primary endpoint of the study is to evaluate the technical and clinical success of EVAR with the Alto stent graft in short- (90-day), mid- (1-year), and long-term (5-year) follow-up periods. The following secondary endpoints will be also addressed: operative time; intraoperative radiation exposure; contrast medium usage; AAA sac shrinkage at 12-month and 5-year follow-up; any potential role of patients’ baseline characteristics, valuated on preoperative computed tomography angiographic study, and of device configuration (number of component) in the primary endpoint.
Results
The study is currently in the recruitment phase and the final patient is expected to be treated by the end of 2023 and then followed up for 5 years. A total of 300 patients will be recruited. Analyses will focus on primary and secondary endpoints. Updated results will be shared at 1- and 3-5-year follow-ups.
Conclusions
The results from this registry study could validate the safety and effectiveness of the new design of the Ovation Alto Stent Graft. The technical modifications to the endograft could allow for accommodation of a more comprehensive range of anatomies on-label.
Trial Registration
ClinicalTrials.gov NCT05234892; https://clinicaltrials.gov/ct2/show/NCT05234892
International Registered Report Identifier (IRRID)
PRR1-10.2196/36995
Background: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This ...retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only. Methods: This propensity score–matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients. Findings: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7–93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7–41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38–0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae. Interpretation: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug. Funding: Emilia-Romagna Region.
The aim of this paper was to report outcomes of endovascular aneurysm repair with percutaneous femoral access (pEVAR) using Prostar XL and Proglide closure systems (Abbot Vascular, Santa Clara, CA, ...USA), from the multicenter Italian Percutaneous EVAR (IPER) registry.
Consecutive patients affected by aortic pathology treated by EVAR with percutaneous access (pEVAR) between January 2010 and December 2014 at seven Italian centers were enrolled in this multicenter registry. All the operators had an experience of at least 50 percutaneous femoral access procedures. Data were prospectively collected into a dedicated online database including patient's demographics, anatomical features, intra- and postoperative outcomes. A retrospective analysis was carried out to report intraoperative and 30-day technical success and access-related complication rate. Uni- and multivariate analyses were performed to identify factors potentially associated with an increased risk of percutaneous pEVAR failure.
A total of 2381 accesses were collected in 1322 patients, 1249 (94.4%) male with a mean age of 73.5±8.3 years (range 45-97). The overall technical success rate was 96.8% (2305/2381). Major intraoperative access-related complications requiring conversion to surgical cut-down were observed in 3.2% of the cases (76/2381). One-month pEVAR failure-rate was 0.25% (6/2381). Presence of femoral artery calcifications resulted to be a significant predictor of technical failure (OR: 1.69; 95% CI: 1.03-2.77; P=0.036) at multivariate analysis. No significant association was observed with sex (P=0.28), obesity (P=0.64), CFA diameter (P=0.32), level of CFA bifurcation (P=0.94) and sheath size >18 F (P=0.24). The use of Proglide was associated with a lower failure rate compared to Prostar XL (2.5% vs. 3.3%) despite not statistically significant (P=0.33).
The results of the IPER registry confirm the high technical success rate of percutaneous EVAR when performed by experienced operators, even in presence of demanding anatomies. Femoral calcification represents the only predictor of percutaneous access failure.
The anti-tumoral effect of lenalidomide is increased in vivo by hypoxia-inducible factor (HIF)-1α inhibition in myeloma cells We investigated the effect of stable suppression of hypoxia inducible ...factor (HIF)-1α in myeloma cells on sensitivity to lenalidomide (LEN) in vivo. We found that the in vivo anti-tumoral effect of LEN is enhanced by HIF-1α suppression in myeloma cells. It has been reported that HIF-1α is over-expressed by myeloma cells 1-4 and that HIF-1α suppression significantly blocks myeloma-induced angiogenesis, and reduces both tumoral burden and bone destruction in vivo in multiple myeloma (MM) mouse models. 3 The potential effects of HIF-1α modulation on drug sensitivity in MM cells are not known and are currently under investigation. The immunomodulatory drugs (IMiDs®), including LEN, are a class of drugs derived from thalidomide 4 able to exert anti-myeloma effects by the selective Cereblon-dependent destruction of IKZF proteins, 5,6 either through a direct action on MM cell proliferation and survival, 7 or through indirect immunomodulatory and anti-angiogenic effects. 7 Previous data indicated that HIF-1α inhibition did not increase the anti-proliferative in vitro effect of bortezomib on MM cells; 2,3 this drug induces a strong downregula-tion of HIF-1α in MM cells. 2 We recently reported that HIF-1α knockdown in the human myeloma cell line (HMCL) JJN3 potentiated the in vitro effect of LEN treatment (48-72 h) on cell proliferation through a significant upregulation of p27 without changing cell viability. 3 It has been consistently reported that LEN only slightly down-regulated HIF-1α expression in MM cells. 2 Such evidence has provided the rationale to investigate the effect of stable suppression of HIF-1α in myeloma cells on LEN sensitivity in vivo. Therefore, in the present study, we first inhibited HIF-1α in three HMCLs (JJN3, OPM2 and H929) using an anti-HIF1α lentiviral shRNA pool, as previously described. 3 H929 showed a very high mortality rate after anti-HIF1α lentiviral infection (data not shown) and were not used for the subsequent in vivo experiments. We assessed the effect of LEN in combination with HIF-1α inhibition in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) subcutaneous in vivo mouse model. 3 Different groups of animals (5 animals in each group) of two sets of independent experiments were injected with JJN3 pLKO.1 (empty vector) or JJN3 anti-HIF1α. When tumors became palpable (approx. 7-10 days after injection) mice were treated with LEN 5 mg/kg (Selleckchem, Houston, TX, USA) or vehicle (DMSO) using the intraperitoneal route. The same mouse model, grouping strategy and treatment conditions were used for OPM2 pLKO.1 or OPM2 anti-HIF1α. After three weeks, we evaluated tumor volume and weight, as previously described, 3 and immunohisto-chemistry was used to evaluate the microvascular density (MVD) and checked by CD34 immunostaining (Santa Cruz, Dallas, TX, USA). 3 In addition, in the first set of mice experiments, the expression of p27 (Abcam, Cambridge, UK) was evaluated by immunohistochem-istry. The expression of S-phase kinase-associated protein 2 (SKP2), a p27 inhibitor, expression of the HIF-1α target key mediator of glycolysis and tumoral growth, Hexokinase II (HK2), and levels of pERK 1/2, and total Caspase-3 (Casp-3) were evaluated in the ex vivo plasma-cytoma lysates by western blot using the following anti-bodies: SKP2, Casp-3 (Santa Cruz, Dallas, TX, USA), HK2, pERK 1/2, (Cell Signaling, Danvers, MA, USA). b-actin was used as internal control (Millipore,
Observational clinical studies have demonstrated that only 30–40 % of patients with arterial hypertension achieve the recommended blood pressure goals (below 140/90 mmHg). In contrast, interventional ...trials consistently showed that it is possible to achieve effective blood pressure targets in about 70 % of treated hypertensive patients with different cardiovascular risk profiles, especially through the use of rational, effective and well tolerated combination therapies. In order to bridge the gap between current and desired blood pressure control and to achieve more effective prevention of cardiovascular diseases, the Italian Society of Hypertension (SIIA) has developed an interventional strategy aimed at reaching nearly 70 % of treated controlled hypertensive patients by 2015. This ambitious goal can be realistically achieved by a more rational use of modern tools and supports, and also through the use of combination therapy in hypertension in daily clinical practice, especially if this approach can be simplified into a single pill (fixed combination therapy), which is a therapeutic option now also available in Italy. Since about 70–80 % of treated hypertensive patients require a combination therapy based on at least two classes of drugs in order to achieve the recommended blood pressure goals, it is of key importance to implement this strategy in routine clinical practice. Amongst the various combination therapies currently available for hypertension treatment and control, the use of those strategies based on drugs that antagonize the renin-angiotensin system, such as angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) and ACE inhibitors, in combination with diuretics and/or calcium channel blockers, has been shown to significantly reduce the risk of major cardiovascular events and to improve patient compliance to treatment, resulting in a greater antihypertensive efficacy and better tolerability compared with monotherapy. The present document of the Italian Society of Arterial Hypertension (SIIA) aims to gather the main indications for the implementation of combination therapy in the treatment of hypertension, in order to improve blood pressure control in Italy.
Galectin-1 (Gal-1) is a lectin, involved in several processes related to cancer, including immunosuppression, angiogenesis, hypoxia, and metastases. However, the expression profiles of Gal-1 and its ...pathophysiological role in multiple myeloma (MM) cell growth, in the relationship between MM cells and the bone marrow (BM) microenvironment and in the MM-induced angiogenesis are unknown and were investigated in this study.
Firstly we evaluatedGal-1 expression by CD138+ cells of a dataset of 133 MM patients at diagnosis (GSE16122) and 23 human myeloma cell lines (HMCLs) (GSE6205) or on a proprietary? dataset of primary mesenchymal stromal cells (MSCs) and osteoblasts (OBs) of 16 MM and 4 MGUS. CD138+ cells and HMCLs were positive for LGALS1 with no statistically significant differences. LGALS1 mRNA expression was positively correlated with 154 genes and negatively with 109 genes including ERG1 and SPARC. MSCs cells showed a higher expression of LGALS1 compared to the OBs and MM-OBs showed a higher expression of LGALS1 mRNA than that obtained from healthy subjects. Gene expression profiling (GEP) data were then validated by Real-Time PCR and western blot in freshly purified primary CD138+ and BM MSCs samples as well as in 6 HMCLs and in both human MSC (HS-5 and hMSC-Tert) and osteoblastic cell lines (HOBIT and HOB-01). Moreover, immunohistochemistry analyses on bone biopsies obtained from 12 MM, 9 smoldering MM, 9 MGUS and 3 plasma cell leukemia samples revealed an high level of Gal-1 protein expression by MM cells, OBs and vessels in all the patients tested. Secondly, we evaluated whether Gal-1 expression was regulated by hypoxia and by Hypoxia Inducible Factor-1a (HIF-1a) checking the effect of hypoxic treatment (1% of O2) and HIF-1α inhibition by shRNA lentivirus. We found that Gal-1 was upregulated in HMCLs upon hypoxic treatment and consistently the re-oxygenation process significantly restored the expression level of Gal-1. Interestingly the stable knock-down of HIF-1a significantly down-regulated Gal-1 expression in HMCLs both in normoxic and hypoxic conditions.
Thereafter, we explored the effect of persistent Gal-1 inhibition in MM cells and BM microenvironment cells on cell proliferation, survival and the transcriptional and pro-angiogenic profiles. An anti-Gal-1 Lentivirus shRNA was used for Gal-1 stable knock-down in HMCLs (JJN3-anti-Gal-1 and OPM-2-anti-Gal-1) and MSC cell lines (HS-5 and HMSC-Tert) and the Scramble lentiviral vector (JJN3-Scramble and OPM-2-Scramble) was used as the empty control vector. The stable inhibition of Gal-1 did not affect the proliferation rate and viability of both HMCLs and MSC cell lines. On the other hand Gal-1 inhibition by shRNA lentivirus significantly modified the transcriptional profiles of HMCLs and HS-5, evaluated by U133 Plus2.0 Arrays (Affymetrix®) either in normoxic or hypoxic or re-oxygenation conditions. Among the genes significantly modulated by Gal-1 inhibition in HMCLs, we found that pro-angiogenic (eg. CCL2, MMP9) and adhesion molecules (eg. MCAM and STEAP1) were down-regulated by Gal-1 suppression in both normoxic and hypoxic conditions as well as some putative anti-tumoral genes, including EGR1, SPARC and TGFBI, and anti-angiogenic ones, including SEMA3A, were up-regulated by Gal-1 inhibition. In line with these observations, we found that Gal-1 suppression by shRNA significantly decreased the pro-angiogenic proprieties of HMCLs by an in vitro angiogenesis assay.
Finally, we found that mice, injected subcutaneously with JJN3-anti-Gal-1 and OPM-2-anti-Gal-1, showed a reduction in the weight and volume of the tumor burden compared to mice inoculated with the JJN3-Scramble and OPM-2-Scramble. Moreover, a significant reduction in the number of CD34 positive vessels X field was observed. In an intratibial mouse model, JJN3-anti-Gal-1, JJN3-Scramble and JJN3 wild type were injected: in the anti-Gal-1 group tumors grew in reduced number and size compared to the Scramble group, moreover JJN3 anti-Gal-1 mice developed fewer and smaller lytic lesions on x-ray compared to the controls.
Overall our data indicate that Gal-1 is highly expressed by MM cells and those of the BM microenvironment and that its expression is regulated by hypoxia. Gal-1 shows a role in MM-induced angiogenesis and its inhibition in MM cells significantly reduced tumor growth in vivo, suggesting that Gal-1 is a potential new therapeutic target in MM.
Giuliani:Celgene Italy: Research Funding.
Essential hypertension arises from the combined effect of genetic and environmental factors. A pharmacogenomics approach could help to identify additional molecular mechanisms involved in its ...pathogenesis.
The aim of SOPHIA study was to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan, with a whole-genome approach.
We performed a genome-wide association study on blood pressure response in 372 hypertensives treated with losartan and we looked for replication in two independent samples.
We identified a peak of association in CAMK1D gene (rs10752271, effect size -5.5 ± 0.94 mmHg, p = 1.2 × 10(-8)). CAMK1D encodes a protein that belongs to the regulatory pathway involved in aldosterone synthesis. We tested the specificity of rs10752271 for losartan in hypertensives treated with hydrochlorothiazide and we validated it in silico in the GENRES cohort.
Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension.
Glioblastoma multiforme (GBM) is characterized by extensive angiogenesis that is mostly orchestrated by the hypoxia inducible factor HIF-1. Deregulation of HIF-1 is believed to contribute to cancer ...initiation and progression. However, instances have been described in which loss of HIF-1 leads to more aggressive tumors. Here we investigated the consequences of downregulating HIF-1 function in the human GBM cell line TB10, both on cell proliferation in vitro and on tumor growth in vivo. RNA interference targeting the O2-regulated HIF-1alpha subunit efficiently reduced HIF-1alpha expression and transcriptional induction of HIF-1-responsive genes without affecting cell growth. Thus, singularly grown wild-type and HIF-1alpha-inhibited GBM cell populations did not significantly differ in proliferation rate. However, when the two populations were co-cultured, wild-type cells overgrew the HIF-1alpha-inhibited cells. Subcutaneous grafting in nude mice of wild-type and HIF-1alpha-inhibited GBM cells lead to comparable tumor formation and growth. Interestingly, cografting of wt and HIF-1alpha- inhibited GBM cells in nude mice resulted in more aggressive tumors, both in terms of tumor appearance and tumor growth. This suggests that cellular populations that differ in their ability to mount a response to hypoxia may compete in vitro but cooperate in vivo resulting in increased tumor aggressiveness.
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