Association of systemic antibody response against polyethylene terephthalate with inflammatory serum cytokine profile following implantation of differently coated vascular prostheses in a rat animal model.

Experimental studies demonstrated antibodies against matrix and coating of polyester-based vascular prostheses. Thus, this study examined associations of these antibodies with serum cytokines (IL-2, IL-4, and IL-10) and local inflammatory reactions. Rats (n = 8/group) intramuscularly received prosthesis segments [PET-C, PET-G, and PET-A groups: polyethylene terephthalate (PET)-based prostheses coated with bovine collagen and gelatin or human serum albumin, respectively; uncoated polytetrafluoroethylene-based (PTFE) prosthesis], with sham-operated controls. Blood was drawn pre-operatively and weekly until day 22. Polymer-specific or coating-specific antibodies and cytokines were detected by enzyme immunoassays, inflammatory reactions were immunohistochemically evaluated on day 23. Polymer-specific antibodies were detected in all PET-groups using uncoated PET as antigenic target, but not for PTFE or controls, coating-specific antibodies only for PET-A. IL-10 was increased in all PET-groups and correlated with polymer-specific antibodies for PET-G and PET-A. IL-2 was increased for PET-A, but overall correlated with PET-specific antibodies. IL-4 remained unchanged in all groups. Intense local inflammatory reactions (ED1+ /ED2+ macrophages and T lymphocytes) were found within all PET-groups, but only minor for PTFE or controls. In conclusion, PET-specific antibodies were associated with increased IL-10 and along with concurrent coating-specific antibodies also with increased IL-2, indicating a specific T cell response. Thus, matrix and/or coating of polymeric vascular prostheses elicit distinct systemic immune reactions, probably influencing local inflammatory reactions.

Brivanib, a novel dual VEGF-R2/bFGF-R inhibitor.

The process of neo-vascularisation from pre-existing blood vessels (angiogenesis) plays a critical role in both tumour growth and dissemination in multiple cancer types. Tumour angiogenesis is an attractive target for cancer treatment, and the VEGF/VEGF-R and FGF/FGF-R systems have been identified as key factors for neo-angiogenesis. Several active compounds have been developed so far and some of them are already widely used in clinical protocols. However, currently, only very few drugs have been shown to act synergistically with VEGF. Brivanib (BMS-582664) is a novel, orally available and selective receptor tyrosine kinase inhibitor that targets the key angiogenesis receptors VEGF-R2 and FGF-R1 and -2. The drug is currently under clinical evaluation and published data as well as data on biomarker studies with brivanib are reviewed and discussed.

[SRC kinases in tumor therapy]. / Src-Kinasen in der Tumortherapie.

The proto-oncogene src encodes a nonreceptor tyrosine kinase whose expression and activity are correlated with advanced malignancy and poor prognosis in a variety of human cancers. Nine additional enzymes with homology to src have been identified and collectively are referred to as src family kinases (SFKs). SFKs represent the largest family of nonreceptor tyrosine kinases and interact directly with receptor tyrosine kinases, G-protein-coupled receptors, steroid receptors, signal transducers and activators of transcription, and molecules involved in cell adhesion and migration. These interactions lead to a diverse array of biological functions including proliferation, cell growth, differentiation, cell shape, motility, migration, angiogenesis, and survival. Studies investigating mutational activation of src in human cancers suggest that this may be a rare event and that wild-type src is weakly oncogenic. Thus, the role of src in the development and progression of human cancer remains unclear; however, it has been suggested that SFK activity may be linked to cancer progression and metastatic disease by facilitating the action of other signaling proteins. SFKs may therefore represent a promising therapeutic target. As a consequence, src-targeting therapies are a recent development. Although numerous agents have been discovered, few have reached clinical development. Amongst them, dasatinib, bosutinib and saracatinib are already in phase II testing and data from these trials suggest that these agents are well tolerated, however, they possessed little clinical activity as monotherapy. Future clinical development will therefore include trials of combination therapy.

Time course of fibronectin in the peri-implant tissue and neointima formation after functional implantation of polyester-based vascular prostheses with different porosity in pigs.

Intima hyperplasia, resulting from extracellular matrix (ECM) secretion, can lead to vascular prosthesis occlusion and is a major problem in vascular surgery. Fibronectin might contribute to ongoing ECM secretion. However, the exact role of fibronectin and its influence on neointima formation remains unclear. This study was aimed at investigating the time course of the fibronectin area fraction and neointima formation following the functional implantation of three different polyester vascular prostheses into pigs. The infrarenal aorta from 15 animals (n = 5/group) was replaced by prosthesis segments with low, medium and high primary porosity. After 7, 14, 21, 28 and 116 days, the prostheses were morphometrically examined. Overall, the fibronectin area fraction was inversely correlated with the neointima thickness, demonstrating high fibronectin levels in the early phase (days 7 and 14) and low levels in the later phase with almost complete neointima formation (days 21-116). Throughout the study, fibronectin levels were highest at the proximal anastomosis region. The low porosity prosthesis had the highest fibronectin area fraction and a delayed neointima formation in the middle phase (days 21 and 28) but the highest neointima lining on day 116. The results indicate a relationship between fibronectin and neointima formation with the prosthesis porosity, demonstrating the importance of the textile design for tissue reactions following implantation.

Local tissue reaction and differentiation of the prosthesis-specific antibody response following functional implantation of vascular grafts in pigs.

The study was aimed at investigating the local tissue reactions through a histological examination of beta-1-integrin expression and neointima formation, and humoral immune responses by detection of prosthesis-specific antibodies, after functional implantation of vascular prostheses. In three groups of pigs, the infrarenal aorta was replaced with segments of collagen-impregnated Dacron-prostheses: M-prosthesis--medium primary porosity, double velour layer, crimping; C-prosthesis--low primary porosity, no velour, crimping; T-prosthesis--high primary porosity, no velour, no crimping. For each prosthesis type, one series with four animals was used for examining the tissue reactions, and a second series with eight animals was used to study the antibody response, both until 116 days postoperative. In the first three weeks, the M-prosthesis caused the highest tissue reactions and the highest antipolyester antibodies, but the lowest anticollagen antibodies, whereas the T-prosthesis caused the highest anticollagen antibodies, but the least tissue response and antipolyester antibodies in the early phase. On day 116, the C-prosthesis caused the highest tissue reactions and highest polyester-specific antibodies. These results indicate a possible association between local inflammatory reactions and humoral immune responses, influenced by properties of vascular grafts.

Immune response against polyester implants is influenced by the coating substances.

The aim of this study was to evaluate the influence of the coating of polymer implants upon the individual humoral immune response to the polymer matrix. Intramuscular implantation and explantation of samples from three different polyester vascular prostheses coated with collagen, gelatin, or human serum albumin was performed in LEW.1A rats and subsequently compared to sham operated control animals. Antibodies in serum samples were detected by means of enzyme immunoassays employing particles of pure polyester and the respective prosthesis, or solid phase bound coating substances as targets. In contrast to the controls, all animals with implants demonstrated a high antipolyester antibody response with a broad individual variability graduated according to the prosthesis coatings: gelatin > albumin > collagen. This was further significantly increased after the second implantation/first explantation and declined following the last explantation. Only animals with albumin-coated implants revealed specific antibodies to the coating as well as the strongest overall immunological reaction against the prosthesis already on day 8. Specificity of polymer antibodies was demonstrated by competitive inhibition of median antibody binding. Our results showed a specific immune reaction as a result of the applied polymer, which varied due to the surface-coating and individual factors.

Digital image analysis for morphometric evaluation of tissue response after implanting alloplastic vascular prostheses.

The aim of this study was to examine the suitability of digital image analysis, using the KS400 software system, for the morphometric evaluation of the tissue response after prosthesis implantation in an animal model. Twenty-four female pigs aged 10 weeks were implanted with infrarenal Dacron(R) prostheses for 14, 21, 28, and 116 days. Following the explantation and investigation of the neointima region, the expression of beta-1-integrin, the proliferation rate by means of Ki-67 positive cells, and the intima thickness were evaluated as exemplary parameters of the tissue response after implantation. Frozen tissue sections were immunohistochemically stained and subsequently examined using computer-aided image analysis. A maximum expression of 32.9% was observed for beta-1-integrin 14 days after implantation, gradually declining over time to 9.8% after 116 days. The proliferation rate was found to be 19% on day 14, increasing to 39% on day 21 with a subsequent gradual decline to 5% after 116 days. The intima thickness increased from 189.9 microm on day 14 to 1228.0 microm on day 116. In conclusion, digital image analysis was found to be an efficient and reproducible method for the morphometric evaluation of a peri-prosthetic tissue response.

Vascular graft infections: in vitro and in vivo investigations of a new vascular graft with long-term protection.

We investigated a polyester vascular prosthesis (PET) coated with elemental silver (SC). Measurement of silver release over a period of 52 weeks by means of inductively coupled plasma atomic emission spectrometry of PET with (PET-G) and without (PET-N) gelatine impregnation revealed a silver release on the first day of 1.2 +/- 0.2 microg (PET-N) and 1.2 +/- 0.1 microg (PET-G) (calculated for 1 g of prosthesis); from the 90th day onward, it was between 0.22 +/- 0.14 microg (PET-N) and 0.18 +/- 0.12 microg (PET-G) per day. The prostheses were incubated with Staphylococcus aureus (S.a.), Staphylococcus epidermidis (S.e.), or Escherichia coli (E.c.) to investigate in vitro antibacterial efficacy. After 6 h of incubation, no colony-forming units were to be seen for any of the bacterial suspensions for PET with SC (p < 0.001). To investigate in vivo antibacterial efficacy, PET-G rings with and without SC contaminated with S.a., S.e., or E.c. were implanted in 18 albino rabbits and examined 7 days after agar culture for 48 h. The silver coating was associated with a significant reduction in bacterial growth (S.a., p = 0.001; S.e., p < 0.005; E.c., p < 0.001). The silver-coated prosthesis, with and without gelatine impregnation, had a significantly antibacterial effect with continuous release of silver.

Characteristics of titanium-coated polyester prostheses in the animal model.

Commercially available polyester vascular prostheses (n = 6) in the control group (CG) and titanium-coated vascular prostheses (TP; n = 7) were interposed within the infrarenal aorta of pigs. The respective healing characteristics and patency rates were compared after 3 months. For evaluation purposes, macroscopic, histological, and immunohistochemical criteria were applied. The macroscopic evaluation revealed complete healing of the TP in comparison with the CG. Extraluminal inspection revealed prominent firm cicatricial tissue in the prosthesis bed of the TP group. All TP were occluded. In the CG, occlusion of the prostheses occurred in n = 1 (16 %). On average, neointimal hyperplasia (NIH) in the proximal part of the anastomosis was not significantly different to the CG. The extraluminal proliferation index (Ki67) was reduced in the TP group (p = 0.002). The immunohistochemical analysis of intraluminal changes revealed no significant differences between CG and TP. All of the titanium-coated polyester vascular prostheses were found to be occluded. The additional coating of polyester prostheses with titanium would not appear to be of any particular benefit.

Impact of age on the short-term postoperative outcome of patients undergoing surgery for colorectal carcinoma.

BACKGROUND: Patient age has a decisive impact on the short-term postoperative results in surgery for carcinoma. PATIENTS AND METHODS: This prospective multicenter study involved 75 German hospitals and 3756 patients undergoing treatment in 1999: 1447 aged under 65 years, 1847 aged 65-79 years, and 458 aged over 80 years. RESULTS: In the oldest patient group, there was a significantly higher proportion of extensive, localized tumors (UICC stage II: 25.9%, 28.4%, and 36.1%, respectively) and significant differences were found among the three groups in operation rates (98.8%, 98.6%, and 96.5%), resection rate (94.2%, 93.2%, and 83.9%), general postoperative complications (21.5%, 28.6%, and 41.2%), morbidity (36.5%, 42.6%, and 50.0%) and mortality (2.7%, 6.6%, and 11.8%). CONCLUSION: In the elderly, locally advanced tumors, but not metastasizing tumors, are to be expected. The increase in postoperative morbidity and mortality rates with increasing age was due to the increase in general postoperative complications. Surgery for colorectal carcinoma in patients of advanced age is not associated with any increase in intraoperative or specific postoperative complications.