Aim

We present the greatest study of patients with proximal fibula resection. Moreover we describe a new classification system for tumour resection of the proximal fibula independent of the tumour dignity.

Early and late infections are the most uneventfull complications after tumor resection and implantation of a maegaendoprosthesis. Therefore, silver-coating was introduced by our department years ago with successful reduction in infection rates. After promising results in animal and Phase exclusion of side effects in our Phase I trial, we would like to share our knowledge about latest research, especially the actual results of the Phase II study. We included the results off all implanted silver-coated Megaendoprosthesis since introduction in our department. Implantation had to be more than 12 months ago to guarantee a acceptable minimum follow up for calculation of the infection rate. Actually our infection rate lies at 3,1% (N=131) in the prevention group (no previous infection in medical history) and at 19% (N=36) in our “Highest-Risk” and previous infection group. Still no side-effects could be noticed. In one case we examined retrieved samples of three silver-coated Megaendoprosthesis. Macroscopically a leopard shaped figures could be noticed on the silver-coated surface in shiny and dark areas after being implanted in an infected region. Electron microscopy pictures show still intact surface and remaining silver with dark staining. Biofilm formation coulod not be noticed, though some few dead single bacteria could be found without any signs of proliferation or matrix production after adhesion. Signs of biofilm couldn’t be seen anywhere. Despite the discoloration silver is still intact in these areas without any loss of antibacterial properties. Blisterings or even flaking off the silver coating cannot be noticed. The thickness of the silver was not thinned in a significant way leading to a breakdown after a few years.

Up to these days we have no experience in covering the whole prosthesis including the stem in human beings. Concerning osteointegration of silver-coated stems, our animal trial could not prove their effectiveness in comparison to titanium. Pull-out tests showed high significant discrepancies in osteointegration between titanium and silver coated stems in a dog model after a period of 12 months after implantation.

Summarizing we recommend silver as a safe adjuvant therapy in patients undergoing endoprosthetic reconstruction after tumor resection. Intramedullary use of silver can be done only in experimental cases and needs further changes in the technical design of the coating.

The use of megaprostheses is accompanied with periprosthetic infection in up to 15% of cases. Among metals with antimicrobial activity, silver has raised the interest of investigators because of its good antimicrobial activity. The aim of this study was to determine the infection rate of silver-coated megaprostheses in comparision to uncoated titanium prostheses.

We prospectively identified 40 patients who were treated with a silver-coated proximal femur (n=17) or proximal tibia (n=23) replacement (Mutars^®, Implantcast, Germany). Patients with a silver-coated tumor endoprosthesis were compared with 74 (proximal femur replacement n=33, proximal tibia n=41) retrospectively assessed patients with a titanium endoprosthesis regarding the number of infections.

In the titanium group a proximal femur replacement was associated with the highest infection rate (18.2%; time of infection in mean 15 months postoperatively). In the silver-group infection could be reduced to 5.9% (time of infection 12 months postoperatively). In patients with a proximal tibia replacement the infection rate could be reduced from 17.1% (time of infection in mean 28 months postoperatively) to 4.3% (time of infection 4 months postoperatively) in the silver group.

Regarding the final, successful treatment of infection it can be stated that in the silver group the patients could be treated either by intravenous antibiotics only or by a one-stage exchange of the prosthetic body. In the titanium group seven patients (53%) were treated by a two-stage reimplantation of the prosthesis, in 4 patients (31%) an amputation and in one patient rotationplasty was performed.

We conclude that silver-coated megaendoprostheses can reduce the risk of infection on a short-term followup. Importantly, minor revisions in the case of infection in patients with a silver-coated prostheses were more often successful. Further studies with more patients and a longer followup are necessary in order to evaluate the possible benefit of silver exactly.

Infections are the most uneventfull complications after tumor resection and implantation of a maegaendopros-thesis.Silver-coating of megaendoprosthesis has become a regular procedure in our department since last year in tumor cases. Especially in revision cases with high risk of infection they play a major role in preventing adhesion of bacteria. The successful reduction in infection rates show the effectiveness of the coating but still leave the question “how much coating do we need?” and “how much coating can be tolerated.

Latest research concentrated on the coating of the stems, since they can still be the source of the infection if everything else is coated by silver already.

Summarised so far, our experience in a rabbit model, a phase I Trial in humans and prelimnary results in Phase II Trials in humans showed no toxic side effects.

Driven so far it seems to be sensible to extent the silver coating. So far, the coating is limited to all areas without joint movement or bone contact. An Animal trial was performed anylising the osteointegrative properties of an silver-coated stem versus an regular Titanium stem in 17 dogs. After 12 months of regular X-Ray Analysis a Pull-out test and a concentration analysis has been done.

Results showed high significantly (p< 0.001) an osteointegration in 8 out of 8 titanium stems with an average pull-out force of 3764 Newton (Range 1755– 5967 Newton). Silver-coated stems showed no signs of Osteointegration in all 9 out of 9 femurs. The average pull-out force was 21 Newton (Range 0– 186 Newton). A cemented control could resist a pull out force of 350 Newton. Analysis of the silver concentration directly in the first millimeter of the bone-implant interface and the second millimeter showed highly elevated silver levels.

The silver concentration in the bone-implant interface at Titanium stems ranged from 0.3 to 3502 parts per Billion (ng/g) compared to silver-coated stems ranging from 303 to 2.418.800 ppb parts per Billion (ng/g).

Discussion: Sharing the histologic picture and reactions of the osteoblasts to the silver-coating there are several possible reasons for failed osteointegration. We want o discuss wether these has to be considered as a toxic response or just an adverse reaction.

In summary, surgeons have to decide in the future how much silver they need in each individual case concerning intramedullary infection prophylaxis. The balance between loosening or infection should be based on long term expectations, taking into account that even after successful resection of a tumor an ongoning infection can lead to loosening of a limb or even life. Apart from intramedullary use, we recommend silver as a safe adjuvant therapy in all suited patients undergoing endoprosthetic reconstruction after tumor resection.

Chondrosarcoma are rare malignant tumors. About the biological characteristics of chondrosarcoma is little-known [2]. Endothelin and its receptors are involved in regulating angiogenesis and metastatic dissemination [1]. The aim of this study is first to identify if chondrosarcoma are expressing endothelin-1 (ET-1) and the endothelin-receptors and thereupon to identify potential molecular markers for new target therapies. Another aim is to determine if endothelin is a prognostic factor in chondrosarcoma.

32 cases were investigated clinically and histopathologically. The expression of vascular endothelial growth factor (VEGF), Endothelin-1, Endothelin-Receptor-A (ETR-A) and Endothelin-Receptor-B (ETR-B) were determined. All data were analyzed by Fisher’s exact test (p< 0,05). All tumors show an expression of either ET-1, ETR-A or ETR-B. Chondrosarcomas with grade (G) I are mostly expressing less than 10-% ET-1 in cells, Chondrosarcomas G II are expressing in most cases between 10–50% and nearly all Chondrosarcoms G III more than 50%. In addition ET-1-expression is correlating with the histological grading. The patients also show a significant high metastatic dissemination probability at the time when tumor samples present more than 10%-storing ET-1-cells. The intensity of ET-1-expression is correlating with VEGF, which is the most important angiogenetic factor in tumors.

Chondrosarcomas are expressing ET-1, ETR-A and ETR-B. ET-1 seems to play a role in the angiogenesis of chondrosarcoma. Increased expression of ET-1 is accompanied with a high probability of metastatic dissemination. Endothelin receptor antagonists, which are used for example in prostate and breast cancer, can represent a potential therapy for chondrosarcoma [1]. Experiments on animals and clinical studies are required.