Rapamycin-coated expanded polytetrafluoroethylene bypass grafts exhibit decreased anastomotic neointimal hyperplasia in a porcine model

ObjectiveWe tested the hypothesis that rapamycin coated onto, and eluted from, expanded polytetrafluoroethylene (ePTFE) grafts would diminish neointimal hyperplasia in a porcine model.MethodsRapamycin (also called sirolimus) was coated onto the luminal surface of 6-mm-internal-diameter thin-walled ePTFE grafts by using an adhesive polymer that allows timed release of the drug. An adhesive polymer that allows timed release of rapamycin from ePTFE was developed with commercially available chemicals and applied on 6-mm ePTFE grafts. Graft integrity was characterized by scanning electron microscopy, and rapamycin levels were quantified by using high-performance liquid chromatography. Twenty-two mongrel pigs were randomized into three groups: untreated ePTFE (n = 6), adhesive-only coated ePTFE (n = 6), or adhesive- and rapamycin-coated ePTFE (n = 10). End-to-side unilateral aortoiliac bypasses were performed by using 6-mm-internal-diameter ePTFE grafts and standardized anastomotic lengths. Unilateral end-to-side aortoiliac ePTFE grafts (6-mm internal diameter) were inserted by using polypropylene sutures, 6-0 proximally and 7-0 distally; all anastomoses were 12 mm long. All animals received aspirin (325 mg orally) daily. All animals were given oral aspirin (325 mg) daily beginning on the day before surgery. At 28 days, the animals were killed, and the grafts were explanted in continuity with the adjacent aortic cuff and the outflow iliac artery. Variables compared between groups included graft patency, distal anastomotic length and cross-sectional narrowing, and intimal thickness at the arterial-graft junction indexed to the adjacent graft thickness. Microscopic analysis was performed with hematoxylin and eosin and Masson trichrome stains on paraffin sections. A pathologist blinded to experimental groups graded sections for collagen deposition, neointima formation, inflammatory cellular infiltrates, medial necrosis, and aneurysmal degeneration.ResultsAll animals survived until they were killed without clinical evidence of limb ischemia or graft infection. Preplanned t tests in the context of one-way analysis of variance showed no difference in outcome measures between the untreated ePTFE and adhesive-only coated ePTFE groups; therefore, they were combined in further comparisons with the adhesive- and rapamycin-coated ePTFE group. The Rapamycine eluting expanded polytetrafluoroethylene group had longer anastomoses (85.6% vs 60.6% of the initial anastomotic length maintained; P < .0001) and less cross-sectional narrowing in the outflow graft (16.2% vs 28.5%; P = .0007) when compared with the other two groups by using two-tailed Student t tests. There was no evidence of medial necrosis or aneurysmal degeneration. All patent grafts had complete endothelialization on hematoxylin and eosin sections. Rapamycin was detectable and quantifiable in the arterial wall at 28 days after implantation.ConclusionsRapamycin can be coated onto and eluted from ePTFE by using a nonionic polymer and a simple coating technique. At 4 weeks after implantation, the rapamycin-eluting ePTFE grafts demonstrate gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with non–drug-eluting ePTFE. Four weeks after implantation in a porcine model, rapamycin-eluting ePTFE grafts demonstrated gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with untreated and adhesive-only coated ePTFE grafts.Clinical RelevanceRapamycin-eluting ePTFE grafts decrease neointimal hyperplasia in a porcine model. Further studies are needed to evaluate whether patency will be improved. Rapamycin-eluting ePTFE grafts may allow the use of prosthetic grafts in situations in which autologous vein is unavailable and in which neointimal hyperplasia is pronounced, such as in small-diameter (<6-mm) vessels typical of infrapopliteal interventions

Staging for prostate cancer

BACKGROUND. The American Joint Committee on Cancer (AJCC) staging system for prostate cancer is based primarily based on clinical tumor (T) classification. In this article, the authors summarize arguments for incorporating additional pretreatment parameters and creating a new staging system for prostate cancer. METHODS. Men with localized prostate cancer who received treatment with external beam radiation alone were analyzed using the 1997 AJCC staging system compared with a system that included pretreatment prostate-specific antigen (pPSA) level and Gleason score (GS). Multivariate analyses using a Cox proportional-hazards model were carried out to evaluate T classification, GS, and pPSA as predictors of overall survival (OS), disease-specific survival (DSS), and freedom from PSA failure (FFPF). RESULTS. Based on pretreatment characteristics in a series of contemporary patients, only 0.6% of patients were classified with AJCC stage I disease, 16.0% were classified with AJCC stage III disease, and 83.4% were classified with AJCC stage II disease. Multivariate analyses indicated the independent statistical significance of T classification, GS, and pPSA in predicting OS, DSS, and FFPF (model chi-square value, P < .0001 for each). Using these 3 predictors, subsets of patients who had similar outcomes were combined to provide examples of the insensitivity of the AJCC system for predicting outcomes. Incorporating pPSA and GS allowed the identification of differences in OS, DSS, and FFPF for subsets of patients with AJCC stage II disease ( P < .0001, P = .005, and P < .0001, respectively). CONCLUSIONS. The current AJCC staging system does not divide contemporary patients with prostate cancer into prognostic subgroups and does not identify patients who have comparable biochemical control and survival. The AJCC staging system for prostate cancer should be changed to incorporate pPSA, GS, and risk stratification. Cancer 2007. © 2006 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55927/1/22403_ftp.pd

Role of Pelvic Lymph Node Dissection in Prostate Cancer Treatment

Pelvic lymph node dissection (PLND) is the most accurate and reliable staging procedure for detecting lymph node invasion (LNI) in prostate cancer. Recently, [11C]-choline positron emission tomography imaging and magnetic resonance imaging with lymphotropic superpara-magnetic nanoparticles have shown potential for detecting LNI but are still under investigation. The risk of LNI in low-risk groups could be underestimated by use of the current nomograms, which rely on data collected from patients who underwent only limited PLND. Extended PLND (ePLND) shows higher lymph node yield, which leads to the removal of more positive nodes and fewer missed positive nodes. It may be possible to refrain from performing PLND on low-risk patients with a prostate-specific antigen value <10 ng/ml and a biopsy Gleason score ≤6, but the risk of biopsy-related understaging should be kept in mind. Theoretically, meticulous ePLND may also impact prostate cancer survival by clearing low-volume diseases and occult micrometastasis even in pN0. The therapeutic role of PLND in prostate cancer patients is still an open question, especially in individuals with low-risk disease. Patients with intermediate- to high-risk disease are more likely to benefit from ePLND

Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer

In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 μg l−1 at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients