Mid-term outcome following radial head arthroplasty in acute trauma: risk factors for poor outcome.

BACKGROUND: The aims of this study were to evaluate the outcomes of a single type of radial head implant in a large cohort of patients at mid-term follow-up and to determine the associated risk factors for inferior functional outcomes. METHODS: We performed a retrospective follow-up assessment of 65 patients (33 women and 32 men; mean age, 53.3 years [range, 22-81 years]) who underwent radial head arthroplasty (RHA) for acute trauma between 2012 and 2018, after a minimum follow-up period of 3 years. The Mayo Elbow Performance Score, Oxford Elbow Score, Disabilities of the Arm, Shoulder and Hand score, and Mayo Modified Wrist Score were evaluated, and all available radiographs were analyzed. All complications and revision procedures were assessed. Bivariate and multivariate regression analyses were performed to identify potential risk factors for a poor outcome following RHA. RESULTS: After an average follow-up period of 4.1 years (range, 3-9.4 years), the mean Mayo Elbow Performance Score was 77.2 (standard deviation [SD], 18.9); mean Oxford Elbow Score, 32.0 (SD, 10.6); mean Mayo Modified Wrist Score, 74.6 (SD, 13.7); and mean Disabilities of the Arm, Shoulder and Hand score, 29.0 (SD, 21.2). Average range of motion measured 10° (SD, 15°) in extension, 125° (SD, 14°) in flexion, 81° (SD, 14°) in pronation, and 63° (SD, 24°) in supination. The overall complication and reoperation rates were 38.5% and 30.8%, respectively, with severe elbow stiffness being the most common reason for revision. Patient age >50 years, the use of an external fixator, the presence of accompanying medial collateral ligament injuries, and the development of higher-grade osteoarthritis were associated with a poor outcome. CONCLUSION: Satisfactory medium-term outcomes can be achieved using a monopolar, long-stemmed RHA in patients with acute trauma. However, complication and revision rates are high, frequently leading to inferior outcome scores. Additionally, a higher patient age, the use of an external fixator, the presence of accompanying medial collateral ligament injuries, and the occurrence of higher-grade osteoarthritis were associated with a poor outcome; these factors should raise awareness by the treating trauma surgeon.

Tissue sampling is non-inferior in comparison to sonication in orthopedic revision surgery.

BACKGROUND: The aim of this study was to assess the role of sonication fluid cultures in detecting musculoskeletal infections in orthopedic revision surgery in patients suspected of having peri-prosthetic joint infection (PJI), fracture-related infections (FRI), or postoperative spinal implant infections (PSII). METHODS: Between 2016 and 2019, 149 cases with a data set including sonication fluid cultures and tissue specimen and histological analysis were included. Accuracy of each diagnostic tool as well as the influence of antibiotic therapy was analyzed. Pathogens identified in the sonication cultures and in the associated tissue samples were compared based on the matching of the antibiograms. Therapeutic benefits were then assessed. RESULTS: Of 149 cases, 43.6% (n = 65) were identified as PJI, 2.7% (n = 4) as FRI, 12.8% (n = 19) as PSII, 6.7% (n = 10) as aseptic non-union, and 34.2% (n = 51) as aseptic implant loosening. The sensitivity and specificity of tissue and synovial specimens showed no significant difference with respect to sonication fluid cultures (sensitivity/specificity: tissue: 68.2%/96.7%; sonication fluid cultures: 60.2%/98.4%). The administration of antibiotics over 14 days prior to microbiological sampling (n = 40) resulted in a lower sensitivity of 42.9% each. Histological analysis showed a sensitivity 86.3% and specificity of 97.4%. In 83.9% (n = 125) of the cases, the results of sonication fluid cultures and tissue specimens were identical. Different microorganisms were found in only four cases. In 17 cases, tissue samples (n = 5) or sonication (n = 12) were false-negatives. CONCLUSION: Sonication fluid culture showed no additional benefit compared to conventional microbiological diagnostics of tissue and synovial fluid cultures. Preoperative administration of antibiotics had a clearly negative effect on microbiologic test accuracy. In over 83.9% of the cases, sonication fluid and tissue cultures showed identical results. In the other cases, sonication fluid culture did not further contribute to the therapy decision, whereas other factors, such as fistulas, cell counts, or histological analysis, were decisive in determining therapy.

The iron load of lipocalin-2 (LCN-2) defines its pro-tumour function in clear-cell renal cell carcinoma.

BACKGROUND: We aimed at clarifying the role of lipocalin-2 (LCN-2) in clear-cell renal cell carcinoma (ccRCC). Since LCN-2 was recently identified as a novel iron transporter, we explored its iron load as a decisive factor in conferring its biological function. METHODS: LCN-2 expression was analysed at the mRNA and protein level by using immunohistochemistry, RNAscope® and qRT-PCR in patients diagnosed with clear-cell renal cell carcinoma compared with adjacent healthy tissue. We measured LCN-2-bound iron by atomic absorption spectrometry from patient-derived samples and applied functional assays by using ccRCC cell lines, primary cells, and 3D tumour spheroids to verify the role of the LCN-2 iron load in tumour progression. RESULTS: LCN-2 was associated with poor patient survival and LCN-2 mRNA clustered in high- and low-expressing ccRCC patients. LCN-2 protein was found overexpressed in tumour compared with adjacent healthy tissue, whereby LCN-2 was iron loaded. In vitro, the iron load determines the biological function of LCN-2. Iron-loaded LCN-2 showed pro-tumour functions, whereas iron-free LCN-2 produced adverse effects. CONCLUSIONS: We provide new insights into the pro-tumour function of LCN-2. LCN-2 donates iron to cells to promote migration and matrix adhesion. Since the iron load of LCN-2 determines its pro-tumour characteristics, targeting either its iron load or its receptor interaction might represent new therapeutic options.

Complex elbow fracture-dislocations- what factors are associated with a poor post-operative outcome?

PURPOSE: Despite standardized treatment algorithms, patients with complex elbow fracture-dislocation frequently suffer from poor post-operative elbow function leading to reduced quality of life. Up to now, there is no valuable data regarding risk factors that lead to poor post-operative outcome after surgical reconstruction of complex elbow fracture-dislocations. METHODS: From 06/2010 to 12/2020 134 patients (51.3 ± 15.1 years, 44% women) undergoing surgical treatment of complex elbow fracture-dislocations could be included in this study. Follow-up period was 4.4 years (SD 2.5). All patients were clinically evaluated for elbow movement, elbow stability and common elbow scores (MEPS, OES, DASH-Score). Potential risk factors for poor post-operative outcome were identified using bi- and multivariate analyses. RESULTS: Overall good post-operative outcome has been achieved, mean MEPS was 88.8 ± 17.6. Post-operative complications occurred in 31.3% of the cases, while 25.4% required surgical revision. Patients with transolecranon dislocation fractures showed the significantly worst functional outcomes (p = 0.01). In addition, it has been shown that a patient's age of more than 70 years (OR = 10, p = 0.003) and a BMI of more than 35 kg/m2 (OR = 7.6, p = 0.004) are independent risk factors for a poor post-operative outcome. In contrast, gender and time to surgery showed no significant influence on post-operative outcome. CONCLUSION: In most cases, good post-operative functional results can be achieved using standardized treatment protocols. However, complication and revision rates remain high. Patients older than 70 years of age or with a BMI over 35 kg/m2 are at risk for an inferior outcome and require close follow-up monitoring.

Above-knee amputation shows higher complication and mortality rates in line with lower functional outcome compared to knee arthrodesis in severe periprosthetic joint infection.

Aims: In cases of severe periprosthetic joint infection (PJI) of the knee, salvage procedures such as knee arthrodesis (KA) or above-knee amputation (AKA) must be considered. As both treatments result in limitations in quality of life (QoL), we aimed to compare outcomes and factors influencing complication rates, mortality, and mobility. Methods: Patients with PJI of the knee and subsequent KA or AKA between June 2011 and May 2021 were included. Demographic data, comorbidities, and patient history were analyzed. Functional outcomes and QoL were prospectively assessed in both groups with additional treatment-specific scores after AKA. Outcomes, complications, and mortality were evaluated. Results: A total of 98 patients were included, 52 treated with arthrodesis and 47 with AKA. The mean number of revision surgeries between primary arthroplasty and arthrodesis or AKA was 7.85 (SD 5.39). Mean follow-up was 77.7 months (SD 30.9), with a minimum follow-up of two years. Complications requiring further revision surgery occurred in 11.5% of patients after arthrodesis and in 37.0% of AKA patients. Positive intraoperative tissue cultures obtained during AKA was significantly associated with the risk of further surgical revision. Two-year mortality rate of arthrodesis was significantly lower compared to AKA (3.8% vs 28.3%), with age as an independent risk factor in the AKA group. Functional outcomes and QoL were better after arthrodesis compared to AKA. Neuropathic pain was reported by 19 patients after AKA, and only 45.7% of patients were fitted or were intended to be fitted with a prosthesis. One-year infection-free survival after arthrodesis was 88.5%, compared to 78.5% after AKA. Conclusion: Above-knee amputation in PJI results in high complication and mortality rates and poorer functional outcome compared to arthrodesis. Mortality rates after AKA depend on patient age and mobility, with most patients not able to be fitted with a prosthesis. Therefore, arthrodesis should be preferred whenever possible if salvage procedures are indicated.

Local Administration of Antibiotics in Orthopedics and Traumatology. / Lokale Antibiotikatherapie in der Orthopädie und Unfallchirurgie.

2022 marks the 50th anniversary of the development of the antibiotic loaded PMMA chain. The loading of bone cements with antibiotics was a major advance in the treatment of musculoskeletal infections and is still a proven standard today. The research and use of novel antibiotic carriers continues to be an important part of research in the context of musculoskeletal infections. The article provides an overview of the various local antibiotics available and their specifics. In addition, current adapted treatment concepts are discussed.

A Novel Tool for Collaborative and Blinded Orthopedic Image Analysis.

Image analysis plays a central role in orthopedics and research but comes with many challenges, including anonymization, bias, and achieving efficient analyses using multiple independent observers. Appropriate software is still lacking. Tyche is a free online tool that displays images in a random order without showing any metadata. Additionally, when using Tyche, observers can store results in the same window, and the final results are immediately visible to the project manager. In this study, we compared results from Tyche with those from a validated tool. One hundred pelvic radiographs were analyzed separately by five orthopedic surgeons using both Tyche and the validated software. Common orthopedic measurement modalities and scores were determined. The methods were compared using intra-class correlations and Fleiss' kappa coefficients as well as Bland-Altman plots. Significant correlations ranging from r = 0.17 (Kallgren and Lawrence Score) to r = 0.99 (area measurements) were calculated for inter- and intraobserver agreements between the two tools for all measurements. The Bland-Altman plots indicated the non-inferiority of either tool. The images were analyzed significantly faster when Tyche was used. We conclude that Tyche is a valid tool for use in orthopedic image analysis. Tyche could be utilized for determining inter- and intraobserver agreements, in multicenter studies and for score validations.

Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin.

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2-/- PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2-/- compared to wildtype tumors stored more iron. In contrast, Lcn-2-/- tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2-/- tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

Iron-Bound Lipocalin-2 Protects Renal Cell Carcinoma from Ferroptosis.

While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. Applying RNA sequencing analysis in renal CAKI1 tumor cells to explore highly upregulated molecular signatures in response to hLcn-2, we identified a cluster of genes (SLC7A11, GCLM, GLS), which are implicated in regulating ferroptosis. Indeed, hLcn-2-stimulated cells are protected from erastin-induced ferroptosis. We also noticed a rapid increase in reactive oxygen species (ROS) with subsequent activation of the antioxidant Nrf2 pathway. However, knocking down Nrf2 by siRNA was not sufficient to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. In contrast, preventing oxidative stress through N-acetyl-l-cysteine (NAC) supplementation was still able to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. Besides an oxidative stress response, we noticed activation of the integrated stress response (ISR), shown by enhanced phosphorylation of eIF-2α and induction of ATF4 after hLcn-2 addition. ATF4 knockdown as well as inhibition of the ISR sensitized hLcn-2-treated renal tumor cells to ferroptosis, thus linking the ISR to pro-tumor characteristics of hLcn-2. Our study provides mechanistic details to better understand tumor pro-survival pathways initiated by iron-loaded Lcn-2.

The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth.

Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth.