TNFR2 is critical for TNF-induced rheumatoid arthritis fibroblast-like synoviocyte inflammation.

OBJECTIVES: TNF-induced activation of fibroblast-like synoviocytes (FLS) is a critical determinant for synovial inflammation and joint destruction in RA. The detrimental role of TNF-receptor 1 (TNFR1) has thoroughly been characterized. The contributions of TNFR2, however, are largely unknown. This study was performed to delineate the role of TNFR2 in human FLS activation. METHODS: TNFR2 expression in synovial tissue samples was determined by immunohistochemistry. Expression of TNFR2 was silenced using RNAi or CRISPR/Cas9 technologies. Global transcriptional changes were determined by RNA-seq. QPCR, ELISA and immunoblotting were used to validate RNA-seq results and to uncover pathways operating downstream of TNFR2 in FLS. RESULTS: TNFR2 expression was increased in RA when compared with OA synovial tissues. In particular, RA-FLS demonstrated higher levels of TNFR2 when compared with OA-FLS. TNFR2 expression in RA-FLS correlated with RA disease activity, synovial T- and B-cell infiltration. TNF and IL1ß were identified as inflammatory mediators that upregulate TNFR2 in RA-FLS. Silencing of TNFR2 in RA-FLS markedly diminished the TNF-induced expression of inflammatory cytokines and chemokines, including CXCR3-binding chemokines and the B-cell activating factor TNFSF13B. Immunobiochemical analyses revealed that TNFR2-mediated expression of inflammatory mediators critically depends on STAT1. CONCLUSION: Our results define a critical role for TNFR2 in FLS-driven inflammation and unfold its participation in the unresolved course of synovial inflammation in RA.

Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research.

Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.

Pain management in hemophilia: expert recommendations.

INTRODUCTION: As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner. AIM: The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group. METHOD: The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts' clinical experience, the participants developed a set of recommendations presented in this paper. RESULTS: Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients' quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.

Inferior performance of established and novel serum inflammatory markers in diagnosing periprosthetic joint infections.

PURPOSE: Besides other diagnostic test methods, established serum inflammatory markers such as serum C-reactive protein or leukocyte count are widely used preoperatively to aid in diagnosing periprosthetic joint infections (PJI). Although low accuracies were reported, these parameters are easily accessible and routinely available. Novel biomarkers with promising results in diagnosing PJI (platelet count to mean platelet volume ratio) or other infectious conditions (percentage of neutrophils, neutrophils to lymphocytes ratio) were described. The purpose of this study was to investigate the diagnostic value of established and novel serum inflammatory biomarkers for the diagnosis of PJI so as to compare the results to find the serum inflammatory marker with the best performance. METHODS: In 177 patients with a previous total hip (n = 91) or knee (n = 86) arthroplasty and indicated revision surgery, the diagnostic value of the routinely available serum inflammatory markers C-reactive protein (CRP), white blood cell count (WBC), percentage of neutrophils (%N), neutrophils to lymphocytes ratio (NLR), fibrinogen and platelet count to mean platelet volume ratio (PC/mPV) were examined retrospectively via receiver operating characteristic curve analysis (AUC). The curves were compared using the z-test. RESULTS: Sensitivities of serum CRP, WBC, %N, NLR, fibrinogen and PC/mPV were calculated with 68%, 36%, 66%, 63%, 69% and 43%, respectively. Specificities were 87%, 89%, 67%, 73%, 89% and 81%, respectively. Serum CRP (0.78) and fibrinogen (0.79) showed significantly better AUCs compared with serum WBC (0.63), %N (0.67), NLR (0.68) and PC/mPV (0.62) (p < 0.0001). Patients with PJI caused by a low-virulent microorganism (median CRP: 17.6 mg/L) obtained lower CRP levels compared with infections caused by high-virulent microorganisms (median CRP: 49.2 mg/L; p = 0.044). The combination of CRP and fibrinogen showed a better sensitivity (77%) with similar specificity (83%) than one method alone but not at a significant level (CRP (p = 0.200); fibrinogen (p = 0.437)). CONCLUSION: Serum CRP and fibrinogen showed the best accuracies among these widely available serum inflammatory parameters. However, due to the insufficient performance, these biomarkers can only be recommended as suggestive criteria in diagnosing PJI. The preoperative workup should always be complemented by more specific tests such as synovial fluid analysis.

Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes : JAKinibs suppress the interferon response in RA-FLSs.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNß, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.

FOXO3 is involved in the tumor necrosis factor-driven inflammatory response in fibroblast-like synoviocytes.

Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha α (TNFα) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNFα (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNFα and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNFα.

Multiplex PCR Unyvero i60 ITI application improves detection of low-virulent microorganisms in periprosthetic joint infections.

PURPOSE: The aim of this study was to evaluate the pre-operative performance of an automated multiplex PCR (mPCR) system in patients with suspected periprosthetic joint infection (PJI). METHODS: Under sterile conditions, synovial fluid samples from patients with a suspected PJI were collected pre-operatively. One hundred eighty microliter of the aspirate was used for analysis in the mPCR. The remaining joint fluid was sent for microbiological analysis. PJI was diagnosed by using the Musculoskeletal Infection Society (MSIS) criteria. Total percentage agreement and Cohen's kappa coefficient were calculated to measure overall agreement. RESULTS: Overall, 90 patients with a suspected PJI were included. Using MSIS criteria, 38 (42%) patients were classified as septic. Total percent agreement between mPCR and synovial fluid culture was 86% with a Cohen's kappa of 0.68. The mPCR and synovial fluid culture showed sensitivities of 71% and 84%, respectively. Combined evaluation provided an even higher sensitivity of 92%. While Cutibacterium spp. were detected five times by mPCR, it could only be cultured once. A higher detection rate of CoNS by mPCR (n = 7) compared to conventional culture (n = 5) was also demonstrated. In comparison to synovial fluid culture, the mPCR missed Staphylococcus aureus five times. CONCLUSION: With a moderate agreement between synovial fluid mPCR and culture, the mPCR system could be a useful adjunct in diagnosing a PJI pre-operatively. Due to faster availability of results and a higher detection rate of low-virulent microorganisms, it can complement conventional culture.

One-stage exchange of septic shoulder arthroplasty following a standardized treatment algorithm.

BACKGROUND: Studies on 1-stage exchange in septic shoulder arthroplasty are limited and show a wide variation of treatment strategies. This retrospective study investigated infection-free survival and function of 1-stage exchange of septic shoulder arthroplasty following a standardized treatment algorithm. METHODS: The requirement for 1-stage exchange was an isolated microorganism from synovial fluid aspiration or synovial biopsy with an antibiotic susceptibility profile prior to revision surgery. If no microorganism was isolated or the underlying pathogen was a difficult-to-treat microorganism (not accessible for biofilm-active antibiotics, enterococci, and fungi), 2-stage exchange was performed. Function was assessed by the Constant score. RESULTS: Fourteen patients were included, with a mean follow-up period of 5.8 years. The most and second most commonly detected microorganisms were Cutibacterium acnes (formerly Propionibacterium acnes), and Staphylococcus epidermidis, respectively. At 1-stage exchange, patients received local and systemic antibiotics based on the susceptibility profile of the microorganism. Twelve patients with insufficient rotator cuffs received reverse shoulder arthroplasty, whereas 2 patients with intact rotator cuffs underwent anatomic total shoulder arthroplasty. The infection-free survival rate at 1 and 5 years was 100% and 93% (95% confidence interval [CI], 59%-99%), respectively, with 1 recurrence of infection 22 months after 1-stage exchange. Another patient with limited range of motion underwent revision 6 months postoperatively, leading to a revision-free survival rate of 93% (95% CI, 59%-99%) and 86% (95% CI, 54%-96%) at 1 and 5 years, respectively. The mean Constant score was 65 (range, 44-95). CONCLUSION: One-stage exchange with prior detection of the underlying microorganism provides satisfactory infection-free survival and function.

mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation.

Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-κB-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA).

C-reactive protein: An independent predictor for dedifferentiated chondrosarcoma.

Dedifferentiated chondrosarcoma is a rare primary bone malignancy with a very poor prognosis. The aim of the study was to identify pretreatment serum markers as prognostic factors for the overall survival (OS) of patients with dedifferentiated chondrosarcoma. We retrospectively reviewed 33 patients with histologically confirmed dedifferentiated chondrosarcoma treated at our department from 1977 to 2015. Kaplan-Meier estimation, uni- and multivariable Cox proportional hazard model were performed to evaluate the association between serum markers such as the C-reactive protein and OS. In univariable analysis, CRP was strongly associated with OS (HR 1.35; 95%CI 1.13-1.61; p = 0.001). This association prevailed after adjustment for AJCC tumor stage (HR 1.31; 95%CI 1.02-1.57; p = 0.031) in multivariable analysis. In conclusion, our data gave evidence that baseline CRP is an independent predictor for OS in patients with dedifferentiated chondrosarcoma. CRP could be exploited for the clinical prediction of this disease in the future. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:2797-2801, 2018.

Is Total Femur Replacement a Reliable Treatment Option for Patients With Metastatic Carcinoma of the Femur?

BACKGROUND: The majority of metastatic bone lesions to the femoral bone can be treated without surgery or with minimally invasive intramedullary nailing. In rare patients with extensive metastatic disease to the femur, total femur replacement may be the only surgical alternative to amputation; however, little is known about this approach. QUESTIONS/PURPOSES: In a highly selected small group of patients with metastatic carcinoma of the femur, we asked: (1) What was the patient survivorship after this treatment? (2) What was the implant survivorship free from all-cause revision and amputation, and what complications were associated with this treatment? (3) What functional outcomes were achieved by patients after total femur replacement for this indication? METHODS: Eleven patients (three men, eight women) with a mean age of 64 years (range, 41-78 years) received total femur replacements between 1986 and 2016; none were lost to followup. The most common primary disease was breast cancer. In general, during this period, our indications for this procedure were extensive metastatic disease precluding internal fixation or isolated proximal or distal femur replacement, and an anticipated lifespan exceeding 6 months. Our contraindication for this procedure during this time was expected lifespan less than 6 months. Patient survival was assessed by Kaplan-Meier analysis; implant survival free from revision surgery and amputation were assessed by competing risk analysis. Function was determined preoperatively and 6 to 12 weeks postoperatively with the Musculoskeletal Tumor Society (MSTS) score normalized to a 100-point scale, with higher scores representing better function from a longitudinally maintained institutional database. RESULTS: Eleven patients died at a median of 5 months (range, 1-31 months) after surgery. One-year revision-free and limb survival were 82% (95% CI, 51%-98%) and 91% (95% CI, 61%-99%), respectively. Reasons for reoperation were hip dislocation, infection and local recurrence in one patient each. The latter two complications resulted in amputation in two patients. The median MSTS score was 32 (range, 13-57). CONCLUSIONS: Despite attempts to select patients who might have anticipated greater life expectancy, eight of 11 patients died by 6 months after surgery, and an additional two patients had undergone an amputation at 8 and at 17 months postoperatively. Most patients undergoing total femur replacement in this series did not recover from the procedure by the time they died, despite our best attempts to perform the procedure in patients whom we thought would live at least 6 months. Based on this, we believe that most patients with extensive metastatic disease to the femur should be offered palliative care, rather than major reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic study.

[Therapy of Periprosthetic Shoulder Infection]. / Therapeutische Optionen beim periprothetischen Infekt des Schultergelenks.

There are several therapeutic options for the treatment of periprosthetic joint infections of shoulder arthroplasties. In acute infections, the implant can remain in place with open debridement, septic lavage with antibacterial solutions such as octinedine or polyhexanide solution and exchange of all mobile components. In late infections, the therapeutic options after removal of the infected implant are: permanent spacer, resection arthroplasty, one stage revision and two stage revision with or without a temporary spacer. The functional results are best for one stage revisions, with similar prosthetic survival to two stage revisions. For one stage revisions, the microorganism has to be identified prior to revision surgery, in order to use targeted antibiotics locally in the cement, and systemically.

Targeted inhibition of Janus kinases abates interfon gamma-induced invasive behaviour of fibroblast-like synoviocytes.

Objectives: The aim was to explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodelling in RA and to determine whether IFNγ signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods: To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions. Results: Histological analyses of micromasses revealed unique effects of IFNγ on FLS shape and tissue organization. This was consistent with accelerated migration upon IFNγ stimulation. Given that cell shape and cell motility are under the control of the focal adhesion kinase (FAK), we next analysed its activity. Indeed, IFNγ stimulation induced the phosphorylation of FAK-Y925, a phosphosite implicated in FAK-mediated cell migration. Small interfering RNA knockdown of JAK2, but not JAK1, substantially abrogated FAK activation by IFNγ. Correspondingly, IFNγ-induced FAK activation and invasion of FLS was abrogated by the JAK inhibitor, baricitinib. Conclusion: Our study contributes insight into the synovial response to IFNγ and reveals JAK2 as a potential therapeutic target for FLS-mediated joint destruction in arthritis, especially in RA.

The influence of antibiotic-loaded cement spacers on the risk of reinfection after septic two-stage hip revision surgery.

PURPOSE: The aim of this study was the evaluation of possible outcome differences of patients undergoing two-stage hip exchange with antibiotic-loaded spacers, compared to patients without an interim spacer implantation. METHODS: We evaluated 46 patients undergoing two-stage hip revision surgery. Twenty-five patients received an interim ALS. Additional to a Kaplan-Meier survival analysis, a competing risk analysis was performed to estimate the cumulative incidence function for re-revisions due to infection accounting for death as a competing event. RESULTS: Nine patients (seven non-ALS vs. two ALS) had to undergo re-revision surgery due to reinfection of the hip joint. The non-ALS group showed a risk of re-revision of 19% (95% CI 5-38%) at 12 and 24 months and 30% (95% CI 12-51%) at 36 months. The group with ALS implantation displayed a 0% risk of re-revision surgery in the first 36 months. The Gray test revealed a significant difference in the cumulative incidence between both observed groups (p = 0.026). CONCLUSION: Our findings suggest that ALS implantation significantly reduces the risk of reinfection after two-stage hip revision surgery.

[Diagnosis of Periprosthetic Joint Infection of Shoulder Arthroplasties]. / Diagnostik der periprothetischen Gelenkinfektion bei Schulterendoprothesen.

Periprosthetic joint infection of shoulder arthroplasties is one of the most frequent reasons for pain and revision surgery of shoulder arthroplasties. Propionibacterium acnes is one of the commonest microorganisms causing periprosthetic joint infection in shoulder arthroplasties. It is difficult to detect this slow growing microorganism. This paper gives an overview of the different diagnostic methods. A combination of unspecific and specific tests (detection of microorganism and sensitivity to antibiotics) is helpful in identifying a periprosthetic shoulder infection. Aspiration of the joint can combine different unspecific and specific tests. In patients with punctio sicca and suspected periprosthetic joint infection, we recommend biopsy of periprosthetic tissue.

Periprosthetic Joint Infection of Shoulder Arthroplasties: Diagnostic and Treatment Options.

Periprosthetic joint infection (PJI) is one of the most frequent reasons for painful shoulder arthroplasties and revision surgery of shoulder arthroplasties. Cutibacterium acnes (Propionibacterium acnes) is one of the microorganisms that most often causes the infection. However, this slow growing microorganism is difficult to detect. This paper presents an overview of different diagnostic test to detect a periprosthetic shoulder infection. This includes nonspecific diagnostic tests and specific tests (with identifying the responsible microorganism). The aspiration can combine different specific and nonspecific tests. In dry aspiration and suspected joint infection, we recommend a biopsy. Several therapeutic options exist for the treatment of PJI of shoulder arthroplasties. In acute infections, the options include leaving the implant in place with open debridement, septic irrigation with antibacterial fluids like octenidine or polyhexanide solution, and exchange of all removable components. In late infections (more than four weeks after implantation) the therapeutic options are a permanent spacer, single-stage revision, and two-stage revision with a temporary spacer. The functional results are best after single-stage revisions with a success rate similar to two-stage revisions. For single-stage revisions, the microorganism should be known preoperatively so that specific antibiotics can be mixed into the cement for implantation of the new prosthesis and specific systemic antibiotic therapy can be applied to support the surgery.

EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance.

BACKGROUND: Enhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR might also be hyperactivated in human sarcomas. Aim of this study was to investigate the influence of EGFR inhibition on cell viability and its interaction with chemotherapy response in osteosarcoma cell lines. METHODS: We have investigated a panel of human osteosarcoma cell lines regarding EGFR expression and downstream signalling. To test its potential applicability as therapeutic target, inhibition of EGFR by gefitinib was combined with osteosarcoma chemotherapeutics and cell viability, migration, and cell death assays were performed. RESULTS: Osteosarcoma cells expressed distinctly differing levels of functional EGFR reaching in some cases high amounts. Functionality of EGFR in osteosarcoma cells was proven by EGF-mediated activation of both MAPK and PI3K/AKT pathway (determined by phosphorylation of ERK1/2, AKT, S6, and GSK3ß). The EGFR-specific inhibitor gefitinib blocked EGF-mediated downstream signal activation. At standard in vitro culture conditions, clinically achievable gefitinib doses demonstrated only limited cytotoxic activity, however, significantly reduced long-term colony formation and cell migration. In contrast, under serum-starvation conditions active gefitinib doses were distinctly reduced while EGF promoted starvation survival. Importantly, gefitinib significantly supported the anti-osteosarcoma activities of doxorubicin and methotrexate regarding cell survival and migratory potential. CONCLUSION: Our data suggest that EGFR is not a major driver for osteosarcoma cell growth but contributes to starvation- and chemotherapy-induced stress survival. Consequently, combination approaches including EGFR inhibitors should be evaluated for treatment of high-grade osteosarcoma patients.

Total Femur Replacement After Tumor Resection: Limb Salvage Usually Achieved But Complications and Failures are Common.

BACKGROUND: Primary bone or soft tissue tumors of the femur sometimes present with severe and extensive bone destruction, leaving few limb-salvage options other than total femur replacement. However, there are few data available regarding total femur replacement and, in particular, regarding implant failures. QUESTIONS/PURPOSES: We asked: (1) What are the revision-free and overall implant survival rates of conventional total femur replacements in patients treated for sarcoma of the femur or soft tissues? (2) What are the revision-free and overall implant survival rates of expandable total femur replacements in skeletally immature patients? (3) Using the comprehensive International Society of Limb Salvage failure-mode classification, what types of complications occur with conventional and expandable total femur replacements? PATIENTS AND METHODS: Our retrospective, single-center cohort study was based on data prospectively collected for 50 patients who received a total femur replacement after tumor resection for indications other than carcinoma or metastatic disease. Of the 50 patients, six (12%) were lost to followup before 6 months. Ten of the remaining 44 patients received expandable implants. The mean followup was 57 months (range, 1-280 months) and 172 months (range, 43-289 months) for patients who underwent conventional and expandable total femur replacements, respectively. For implant survival, competing risk analyses were used. RESULTS: At 5 years, revision-free implant survival of conventional total femur replacements was 48% (95% CI, 0.37-0.73), and overall implant survival was 97% (95% CI, 0.004-0.20). Five-year revision-free implant survival of expandable total femur replacements was 30% (95% CI, 0.47-1.00) and overall implant survival was 100%. With conventional total femur replacements soft tissue failures occurred in 13 of 34 patients, structural failures in three, infection in six, and local tumor progression in one. No patient had aseptic loosening with conventional total femur replacements, but hip disarticulation occurred in two patients owing to extensive wound-healing problems and infection. With expandable total femur replacements soft tissue failure, aseptic loosening, and infection occurred in one patient each of 10, and structural failures in three of 10 (two periprosthetic fractures, one loosening of an enhanced tendon anchor). No hip disarticulations were performed. Additionally expandable total femur replacement-related failures included hip instability in eight of 10 patients, contractures attributable to massive scar tissue in six, and defect of the implant's expansion mechanism in four patients. CONCLUSIONS: Although the indications for total femoral resection are rare, we think that total femur replacement is a reasonable treatment option for reconstruction of massive femoral bone defects after tumor resection in adults and skeletally immature patients, and results in limb salvage in most patients. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Body image and self-esteem in lower-limb amputees.

BACKGROUND: Limb amputation is often an inevitable procedure in the advanced condition of various diseases and poses a dramatic impact on a patient's life. The aim of the present study is to analyze the impact of lower-limb amputations on aesthetic factors such as body image and self-esteem as well as quality of life (QoL). METHODS: 298 patients (149 uni- or bilateral lower-limb amputees and 149 controls) were included in this cross-sectional study in three centers. Demographic data was collected and patients received a 118-item questionnaire including the Multidimensional Body-Self Relations Questionnaire (MBSRQ), the Rosenberg Self-esteem (RSE) scale and the SF-36 Health Survey (QoL). ANOVA and student's t-test were used for statistical analysis. RESULTS: Unilateral lower-limb amputees showed a significant lower MBSRQ score of 3.07±0.54 compared with 3.41±0.34 in controls (p<0.001) and a lower score in the RSE compared to controls (21.63±4.72 vs. 21.46±5.86). However, differences were not statistically significant (p = 0.36). Patients with phantom pain sensation had a significantly reduced RSE (p = 0.01). The SF-36 health survey was significantly lower in patients with lower-limb amputation compared to controls (42.17±14.47 vs. 64.05±12.39) (p<0.001). CONCLUSION: This study showed that lower-limb amputations significantly influence patients' body image and QoL. Self-esteem seems to be an independent aspect, which is not affected by lower-limb amputation. However, self-esteem is influenced significantly by phantom pain sensation.