Aim

In patients with bone sarcoma, placing mega prostheses in the proximal tibia is associated with high rates of infection. In studies with small numbers of patients and short follow-up periods, silver-coated mega prostheses have been reported to lead to reduced infection rates. To the best of our knowledge, this study is the largest one that has compared the infection rates with titanium versus silver-coated mega prostheses in patients treated for sarcomas in the proximal tibia.

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.

Megaendoprotheses are widely used in the reconstruction of large bone defects in orthopaedic tumour surgery. The major complications (up to 36%) are periprosthetic infections. Persisting periprosthetic infections lead to secondary amputation up to 37% of the cases. One underestimated reason for persisting infections are subpopulations of S. aureus called “small colony variants” (SCVs). Aim of this study was to evaluate that silver ions might prevent or cure a periprosthetic infection caused by SCVs.

For testing the antimicrobial activity of silver-coated titanium we used a technique introduced by Bechert et al. Therefore an adhesion and proliferation assay was performed with clinical isolates of S. aureus SCV (A22616/3). We tested the adhesion and proliferation properties of S aureus SCV on stainless steel (steel), Cobalt-Chrome-Molybdenum-alloy (CoCrMo), Titan-Aluminium-Vanadium-alloy (TiAlVa) and silver-coated Titan-Aluminium-Vanadium-alloy (scTiAlVa).

Adhesion of S. aureus SCV is significantly reduced on scTiAlVa vs. steel (p> 0001). We could also demonstrate that the proliferation rate of scTiAlVa vs. all tested materials is significant (p> 0001) lower.

We concluded that silver-coating has an effective antimicrobial activity against S. aureus SCVs. Thus silver-coated megaendoprostheses are a good prophylaxis against persisting infections caused by S. aureus SCVs.

Although the recurrence rate of giant cell tumors of bone (GCTB) is relatively high exact data on treatment options for the recurrent cases is lacking. The possible surgical procedures range from repeated intralesional curettage to wide resection.

214 patients with histologically certified GCTB have been treated at the authors department from 1980 to 2007. 67 patients with at least one local recurrence were included in this study. The mean follow-up was 77.3 months. The data was evaluated according the re-recurrence rate with regard to the surgical procedure for the recurrence.

The mean time until the first local recurrence was 22.0 months; the mean number of recurrences per patient was 1.4. The recurrence occurred in 69.7 % (46 out of 66 patients) within the first two years. If after intralesional procedures (curettage or intralesional resection) no adjunct was used the re-recurrence rate was 58.8 % (10 out of 17 patients) and decreased to 21.7 % (5 out of 23 patients) if a combination of all adjuncts (PMMA + burring) was used. The likelihood of re-recurrence was reduced by the factor 5.508 which was clearly significant (p = 0.016). In case of wide resection no re-recurrence occurred. Seven patients (10.5 %) developed pulmonary metastases. Fourteen patients (20.9 %) finally received an endoprosthesis; 12 due to tumor recurrence, 2 due to secondary arthritis.

Recurrent GCTB can be treated by further curettage with additional burring and cementing with an acceptable re-recurrence rate of 21.7 %. The rate of patients finally needing an endoprosthesis is 20.9 %. Due to the high rate of pulmonary metastases recurrent GCTB may be considered as a severe disease.

Several studies report a diminished BMD as a consequence of childhood cancer treatment. The aim of this study was to investigate the effects of an exercise intervention on BMD during treatment, since limited mobility is characteristic for cancer therapy and is a major determinant for bone loss.

We analysed DXA scans (Lunar Prodigy, GE Healthcare) of 53 patients (range 8 to 21 years at time of diagnosis) perioperatively (n=49), six (n=38) and twelve months (n=18) after surgery. Scans were performed for the established sites of the lumbar spine and both femora, as well as experimentally for both calcanei. Areal BMD was corrected to obtain volumetric BMD using the model of Kröger.

For both groups, areal and calculated volumetric BMD values were similar at the lumbar spine at time of surgery, as were the differences between affected and not affected femur and calcaneus. The six and twelve months postoperative measurements revealed higher volumetric and areal BMD at the lumbar spine for the intervention group, although significant differences were only found for volumetric BMD values six months postoperatively.

Furthermore, a comparison of both groups showed that the loss in bone density of the affected lower extremity was less pronounced for the intervention group: differences between affected and not affected femur were 9% to 73% higher in the femur and 20% to 29% higher in the calcaneus for the control group.

Previous reports dealing with diminished BMD in pediatric cancer patients were confirmed in this study. However, differences found in BMD between both groups indicate that an exercise intervention during treatment, consisting primarily of strength and endurance training, may inhibit bone loss in pediatric sarcoma patients. Furthermore, the calcaneal site may be an alternative when the determination of femur BMD is not feasible.

A revision of a first generation KMFTR prosthesis due to stem breakage is a problem oncologic surgeons are regularly faced with. We designed an adapter which allows us to connect new MUTARS components to the original KMFTR devices. Thus it is possible to bypass an exchange of the whole prosthesis.

We used this adapter in 10 patients. Time of revision was in average 16.6 years after primary implantation of the KMFTR prostheses. Reasons for revision were femoral stem breakage (n = 5), breakage of the tibial component (n = 3) and periprosthetic fracture (n = 2, one femoral, one tibial).

The femoral stem (3 cases) and the tibial stem (2 cases) as well as the tibial plateau and body (2 cases) could be replaced by MUTARS parts and conjoined with the remaining KMFTR devices. Three cases were converted to MUTARS total femur.

Postoperative complications were one aseptic loosening and one cone-dislocation. Pre-incidence function was restored in all cases. The average Musculoskeletal-Tumour-Society-Score was 82.9% of normal function.

The results show that the new adapter facilitates to restore pre-incidental extremity function by performing a relatively modest revision.

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.

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.

Because of the lack of a suitable in vivo model for giant cell tumors of bone little is known about their biological behavior and mechanisms of metastasis. No existing cell line contains all tumor components, so that testing of anti tumor agents is hardly possible. We therefore modified the chick chorio-allantoic membrane (CAM) assay for giant cell tumor of bone (GCTB).

Out of tumor tissue obtained during surgery of 5 patients a solution was produced. The solute was grafted onto the CAM at day 10 of embryonic development. The growth process was monitored by daily observation and photo documentation using in vivo microscopy. After 5 to 6 days of tumor growth the samples were fixed in formalin and further analyzed using standard histology (hematoxylin and eosin stains).

The tissue solute of all 5 patients formed solid tumors when grafted to the CAM. In vivo microscopy and standard histology revealed a rich vascularisation of the tumors. The tumors were composed of the typical components of GCTB including multinuclear giant cells.

A reliable protocol for grafting of human giant cell tumors onto the chick chorio-allantoic membrane was established. This model is the first in vivo model for giant cell tumors of bone. Further characterization of the growing tissue is necessary in further experiments.

Pediatric patients with lower extremity sarcoma often experience long lasting restrictions concerning physical activity and walking due to the required off-loading of the limb and other consequences of surgeries. Activity promotion during treatment in addition to physiotherapy could improve patients’ activity levels and walking capabilities.

In the present study we investigated the ambulatory activity of 31 pediatric patients (13.7 ± 3.1 years, 1.63 ± 0.15 m, 51.9 ± 15 kg, 19.3 ± 3.7 kg/m2) with Osteosarcoma or Ewing sarcoma at the lower limb using the StepWatch™ Activity monitor (SAM; Orthocare Innovations, USA). Sixteen patients regularly underwent supervised exercise interventions during inpatient stays, 15 did not receive any additional intervention. Step activities were measured for seven consecutive days during home stays at five different points in time, to determine a possible transfer of activity to everyday life.

Patients without intervention assembled considerably less steps than those in the intervention group. Before surgery they reached 25.4% of the intervention group (total n=16), six weeks after surgery 40% (total n= 8), after three months 46% (total n=10), after six months 72% (total n=13) and after one year 90%. However differences only reached significance at the first measurement.

Data presented must be considered as preliminary. Not all patients could be measured at all appointments due to impaired walking ability. Nevertheless activity promoting interventions during inpatient stays seem to have a positive influence on patients’ daily walking activity. Though the differences between the groups are not significant they are considerable. Especially during treatment – as reflected by the first three measurements- patients could benefit from additional interventions exceeding typical therapy regimes. Interventions should be individualized to the patients’ capabilities. Conclusions concerning tumor location or surgical procedures are not yet possible. Future research should furthermore concentrate on the effects of activity promotion on other fields of well-being.