Device migration after endoluminal abdominal aortic aneurysm repair: Analysis of 113 cases with a minimum follow-up period of 2 years

AbstractPurpose: Device migration (DM) has been shown to cause late failure after endoluminal abdominal aortic aneurysm (AAA) repair. To establish the incidence rate and the predictive factors of distal migration of the proximal portion of the endograft, computed tomographic (CT) scans performed at different time intervals during follow-up examination of 113 patients were reviewed. Patients and Methods: Between April 1997 and March 1999, 148 patients underwent endoluminal AAA repair with a modular endograft with infrarenal fixation (Medtronic-AVE AneuRx, Santa Rosa, Calif) at our unit. CT scans performed at 1, 6, and 12 months after surgery and yearly thereafter were prospectively stored in a computer imaging database. Patient demographics, risk factors, operative details, and follow-up events were prospectively collected. No patients were lost to follow-up examination. Twelve patients died within 2 years of surgery, four patients underwent immediate conversion to open repair, and adequate CT measurements were not feasible in 19 cases, which left 113 patients available for a minimum 2-year assessment and 418 CT scan results reviewed. Two vascular surgeons, blinded to patient identity and history with tested interobserver agreement (κ = 0.64), separately reviewed axial reconstructions of CT scans. DM was defined as changes of 10 mm or more in the distance between the lower renal artery and the first visible portion of the endograft at follow-up examination. Ten possible independent predictors of DM were analyzed with multivariate Cox proportional hazards regression model. Results: One AAA rupture, which was successfully treated, occurred at a mean follow-up period of 28 months (range, 24 to 46 months). Seventeen patients (15%) showed DM. Eight patients (47%) with DM underwent reintervention: a proximal cuff was positioned in six patients and late conversion to open repair was performed in two patients. Of the 10 variables analyzed with Cox proportional hazards regression model, AAA neck enlargement of more than 10% after endoluminal repair (hazard ratio, 7.3; confidence interval, 1.8 to 29.2; P =.004) and preoperative AAA diameter of 55 mm or more (hazard ratio, 4.5; confidence interval, 1.2 to 16.7; P =.02) were positive independent predictors of DM. The probability of DM at 36 months was 27% according to life table analysis. Conclusion: DM occurred in a significant portion of our patients, yet aggressive follow-up examination and a high reintervention rate prevented aneurysm-related death. According to our data, dilatation of the infrarenal aortic neck is an important factor that contributes to the distal migration of stent grafts, and patients with large aneurysms are at high risk for DM. (J Vasc Surg 2002;35:229-35.

PO-038 PDGFRβ as a new biomarker for metastatic triple-negative breast cancer: development of a theranostic anti-PDGFRβ aptamer for imaging and suppression of metastases

Introduction Triple-negative breast cancers (TNBCs) are a heterogeneous group of aggressive tumours lacking oestrogen and progesterone receptors and HER2 receptor, thus excluding the possibility of using targeted therapy against these proteins. Mesenchymal-like (ML) subtype, characterised by a stem-like, undifferentiated phenotype, is more invasive and metastatic than other TNBC subtypes and has a strong tendency to form vasculogenic mimicry (VM). Recently, platelet derived growth factor receptor β (PDGFRβ) has been shown to play a role in VM of TNBC. Regrettably, therapies targeting PDGFRβ with tyrosine kinase inhibitors are not effective in treating TNBCs, thus developing new strategies to target PDGFRβ in TNBC patients is crucial to improve their chances of survival. Here, we describe the characterisation of the Gint4.T anti-PDGFRβ nuclease-resistant RNA aptamer as high efficacious theranostic tool for imaging and suppression of ML TNBC metastases. Material and methods Immunohistochemical analyses on a human TNBC tissue microarray was performed to correlate PDGFRβ expression with clinical and molecular features of different subtypes. Functional assays were conducted on PDGFRβ-positive ML BT-549 and MDA-MB-231 cells to investigate the effect of Gint4.T in interfering with cell growth in 3D conditions, migration, invasion and VM formation. Gint4.T was conjugated with near-infrared (NIR) fluorescent VivoTag-S680 and its binding specificity to receptor was confirmed both in vitro (confocal microscopy and flow cytometry analyses of TNBC cells) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). MDA-MB-231 cells were i.v. injected in nude mice and Gint4.T-NIR was used to detect lung metastases in mice untreated or i.v. injected with Gint4.T or a scrambled aptamer. Results and discussions The expression of PDGFRβ was observed in human TNBC samples characterised by higher metastatic behaviour. Treatment of TNBC cell lines with Gint4.T aptamer blocked their invasive growth and vasculogenic properties in 3D culture conditions, and strongly reduced cell migration/invasion in vitro and metastases formation in vivo. The Gint4.T-NIR was able to specifically bind to TNBC xenografts and detect lung metastases in vivo. Therefore, the aptamer revealed a high efficacious theranostic tool for imaging and suppression of TNBC metastases. Conclusion These studies indicate PDGFRβ as a new biomarker for ML and metastatic TNBC subtype and propose a novel targeting agent for the diagnosis and treatment of metastatic TNBCs

TNBC Challenge: Oligonucleotide Aptamers for New Imaging and Therapy Modalities

Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and no alternative targetable molecules have been identified so far. The high biological and clinical heterogeneity adds a further challenge to TNBC management and requires the identification of new biomarkers to improve detection by imaging, thus allowing the specific treatment of each individual TNBC subtype. The Systematic Evolution of Ligands by EXponential enrichment (SELEX) technique holds great promise to the search for novel targetable biomarkers, and aptamer-based molecular approaches have the potential to overcome obstacles of current imaging and therapy modalities. In this review, we highlight recent advances in oligonucleotide aptamers used as imaging and/or therapeutic agents in TNBC, discussing the potential options to discover, image and hit new actionable targets in TNBC

Optimization of Short RNA Aptamers for TNBC Cell Targeting

Triple-negative breast cancer (TNBC) is an aggressive cancer with limited targeted therapies. RNA aptamers, suitably chemically modified, work for therapeutic purposes in the same way as antibodies. We recently generated 2′Fluoro-pyrimidines RNA-aptamers that act as effective recognition elements for functional surface signatures of TNBC cells. Here, we optimized three of them by shortening and proved the truncated aptamers as optimal candidates to enable active targeting to TNBC. By using prediction of secondary structure to guide truncation, we identified structural regions that account for the binding motifs of the full-length aptamers. Their chemical synthesis led to short aptamers with superb nuclease resistance, which specifically bind to TNBC target cells and rapidly internalize into acidic compartments. They interfere with the growth of TNBC cells as mammospheres, thus confirming their potential as anti-tumor agents. We propose sTN145, sTN58 and sTN29 aptamers as valuable tools for selective TNBC targeting and promising candidates for effective treatments, including therapeutic agents and targeted delivery nanovectors

Aptamer-Functionalized Nanoparticles Mediate PD-L1 siRNA Delivery for Effective Gene Silencing in Triple-Negative Breast Cancer Cells

Small interfering RNA (siRNA) therapies require effective delivery vehicles capable of carrying the siRNA cargo into target cells. To achieve tumor-targeting, a drug delivery system would have to incorporate ligands that specifically bind to receptors expressed on cancer cells to function as portals via receptor-mediated endocytosis. Cell-targeting and internalizing aptamers are the most suitable ligands for functionalization of drug-loaded nanocarriers. Here, we designed a novel aptamer-based platform for the active delivery of siRNA targeting programmed cell death-ligand 1 (PD-L1) to triple-negative breast cancer (TNBC) cells. The generated nanovectors consist of PLGA-based polymeric nanoparticles, which were loaded with PD-L1 siRNA and conjugated on their surface with a new RNA aptamer, specific for TNBC and resistant to nucleases. In vitro results demonstrated that these aptamer-conjugated nanoparticles promote siRNA uptake specifically into TNBC MDA-MB-231 and BT-549 target cells, along with its endosomal release, without recognizing non-TNBC BT-474 breast cancer cells. Their efficiency resulted in an almost complete suppression of PD-L1 expression as early as 90 min of cell treatment. This research provides a rational strategy for optimizing siRNA delivery systems for TNBC treatments

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC