Atypical femur fractures associated with bisphosphonate therapy: post-operative outcomes.

PURPOSE: Bisphosphonates are commonly used medication for the treatment of osteoporosis, and a well-established complication of this medication is bisphosphonate-associated atypical femur fractures (BAAFFs). The aim of this study was to assess the post-operative functional and radiographic outcomes of surgically treated BAAFFs. METHODS: An analysis of patients treated at a university-affiliated institution was performed. Patients who had undergone surgical fixation for a subtrochanteric or shaft of femur fracture which had been classified as atypical and treated with bisphosphonate therapy at the time of fracture were included. The outcome measures assessed included post-operative complications, length of stay, discharge destination, post-operative function, independence in activities of daily living (ADLs) and fracture union. RESULTS: Twenty patients were included in this study with a mean age of 75.2 years. The cohort was predominantly female. The average duration of bisphosphonate therapy was 7.35 years. Nine patients had contralateral bisphosphonate-related stress reactions at the time of their initial fracture and underwent prophylactic surgical intervention. The majority of patients received cephalomedullary nail fixation (95%) with more than half (65.0%) of the cohort experiencing one or more post-operative complications. The median length of stay was 6.5 days and 50% of the cohort required inpatient rehabilitation. At final review, independent mobilisation was recorded in only 10.0% of patients, and 70% of patients were dependent with their ADLs at their latest follow-up. Average follow-up was 8 months, and only six cases demonstrated union at the six-month review, with delayed union between 9 and 12 months being common. CONCLUSION: Patients with BAAFFs experience high rates of complications, record poor post-operative functional outcomes, and demonstrate a delayed time to union. Nearly half of our cohort had radiographic evidence of bilateral pathology.

Radiolucent line assessment in cemented stemmed total knee (RISK) arthroplasty: validation of a modernized classification system.

BACKGROUND: This study aims to implement and assess the inter- and intra-reliability of a modernized radiolucency assessment system; the Radiolucency In cemented Stemmed Knee (RISK) arthroplasty classification. Furthermore, we assessed the distribution of regions affected by radiolucency in patients undergoing stemmed cemented total knee arthroplasty. METHODS: Stemmed total knee arthroplasty cases over 7-year period at a single institution were retrospectively identified and reviewed. The RISK classification system identifies five zones in the femur and five zones in the tibia in both the anteroposterior (AP) and lateral planes. Post-operative and follow-up radiographs were scored for radiolucency by four blinded reviewers at two distinct time points four weeks apart. Reliability was assessed using the kappa statistic. A heat map was generated to demonstrate the reported regions of radiolucency. RESULTS: 29 cases (63 radiographs) of stemmed total knee arthroplasty were examined radiographically using the RISK classification system. Intra-reliability (0.83) and Inter-reliability (0.80) scores were both consistent with a strong level of agreement using the kappa scoring system. Radiolucency was more commonly associated with the tibial component (76.6%) compared to the femoral component (23.3%), and the tibial anterior-posterior (AP) region 1 (medial plateau) was the most affected (14.9%). CONCLUSION: The RISK classification system is a reliable assessment tool for evaluating radiolucency around stemmed total knee arthroplasty using defined zones on both AP and lateral radiographs. Zones of radiolucency identified in this study may be relevant to implant survival and corresponded well with zones of fixation, which may help inform future research.

Towards Clinical Translation of In Situ Cartilage Engineering Strategies: Optimizing the Critical Facets of a Cell-Laden Hydrogel Therapy.

BACKGROUND: Articular cartilage repair using implantable photocrosslinkable hydrogels laden with chondrogenic cells, represents a promising in situ cartilage engineering approach for surgical treatment. The development of a surgical procedure requires a minimal viable product optimized for the clinical scenario. In our previous work we demonstrated how gelatin based photocrosslinkable hydrogels in combination with infrapatellar derived stem cells allow the production of neocartilage in vitro. In this study, we aim to optimize the critical facets of the in situ cartilage engineering therapy: the cell source, the cell isolation methodology, the cell expansion protocol, the cell number, and the delivery approach. METHODS: We evaluated the impact of the critical facets of the cell-laden hydrogel therapy in vitro to define an optimized protocol that was then used in a rabbit model of cartilage repair. We performed cells counting and immunophenotype analyses, chondrogenic potential evaluation via immunostaining and gene expression, extrusion test analysis of the photocrosslinkable hydrogel, and clinical assessment of cartilage repair using macroscopic and microscopic scores. RESULTS: We identified the adipose derived stem cells as the most chondrogenic cells source within the knee joint. We then devised a minimally manipulated stem cell isolation procedure that allows a chondrogenic population to be obtained in only 85 minutes. We found that cell expansion prior to chondrogenesis can be reduced to 5 days after the isolation procedure. We characterized that at least 5 million of cells/ml is needed in the photocrosslinkable hydrogel to successfully trigger the production of neocartilage. The maximum repairable defect was calculated based on the correlation between the number of cells retrievable with the rapid isolation followed by 5-day non-passaged expansion phase, and the minimum chondrogenic concentration in photocrosslinkable hydrogel. We next optimized the delivery parameters of the cell-laden hydrogel therapy. Finally, using the optimized procedure for in situ tissue engineering, we scored superior cartilage repair when compared to the gold standard microfracture approach. CONCLUSION: This study demonstrates the possibility to repair a critical size articular cartilage defect by means of a surgical streamlined procedure with optimized conditions.

FLASH: Fluorescently LAbelled Sensitive Hydrogel to monitor bioscaffolds degradation during neocartilage generation.

Regenerative therapies based on photocrosslinkable hydrogels and stem cells are of growing interest in the field of cartilage repair. Cell-mediated degradation is critical for the successful clinical translation of implanted hydrogels. However, characterising cell-mediated degradation, while simultaneously monitoring the deposition of a distinct new matrix, remains a major challenge. In this study we generated a Fluorescently LAbelled Sensitive Hydrogel (FLASH) to correlate the degradation of a hydrogel bioscaffold with neocartilage formation. Gelatine Methacryloyl (GelMA) was covalently bound to the FITC fluorophore to generate FLASH and bioscaffolds were produced by casting different concentrations of FLASH GelMA, with and without human adipose-derived stem cells (hADSCs) undergoing chondrogenesis. The loss of fluorescence from FLASH bioscaffolds was correlated with changes in mechanical properties, expression of chondrogenic markers and accumulation of a cartilaginous extracellular matrix. The ability of the system to be used as a sensor to monitor bioscaffold degradability during chondrogenesis was evaluated in vitro, in a human ex vivo model of cartilage repair and in a full chondral defect in vivo rabbit model. This study represents a step towards the generation of a high throughput monitoring system to evaluate de novo cartilage formation in tissue engineering therapies.

Culture Time Needed to Scale up Infrapatellar Fat Pad Derived Stem Cells for Cartilage Regeneration: A Systematic Review.

Adipose tissue is a rich source of stem cells, which are reported to represent 2% of the stromal vascular fraction (SVF). The infrapatellar fat pad (IFP) is a unique source of tissue, from which human adipose-derived stem cells (hADSCs) have been shown to harbour high chondrogenic potential. This review aims to calculate, based on the literature, the culture time needed before an average knee articular cartilage defect can be treated using stem cells obtained from arthroscopically or openly harvested IFP. Firstly, a systematic literature review was performed to search for studies that included the number of stem cells isolated from the IFP. Subsequent analysis was conducted to identify the amount of IFP tissue harvestable, stem cell count and the overall yield based on the harvesting method. We then determined the minimum time required before treating an average-sized knee articular cartilage defect with IFP-derived hADSCs by using our newly devised equation. The amount of fat tissue, the SVF cell count and the stem cell yield are all lower in arthroscopically harvested IFP tissue compared to that collected using arthrotomy. As an extrapolation, we show that an average knee defect can be treated in 20 or 17 days using arthroscopically or openly harvested IFP-derived hADSCs, respectively. In summary, the systematic review conducted in this study reveals that there is a higher amount of fat tissue, SVF cell count and overall yield (cells/volume or cells/gram) associated with open (arthrotomy) compared to arthroscopic IFP harvest. In addition to these review findings, we demonstrate that our novel framework can give an indication about the culture time needed to scale up IFP-derived stem cells for the treatment of articular cartilage defects based on harvesting method.

Adjuvant radiation for positive margins in adult head and neck sarcomas is associated with improved survival: Analysis of the National Cancer Database.

BACKGROUND: Adult head and neck (H&N) sarcomas are a rare malignancy with limited data delineating the role of postoperative radiotherapy (PORT), particularly for a positive surgical margin. There are no randomized trials supporting the use of PORT, therefore treatment trends vary between institutions. A positive margin predicts recurrence and poor survival outcomes. This study uses the National Cancer Database (NCDB) to investigate whether PORT improves overall survival (OS) in adult H&N sarcomas with a positive margin and how utilization has changed. METHODS: Patients (n = 1142) in the NCDB from 2004-2013 with adult H&N sarcomas who underwent resection and had a positive margin. RESULTS: Factors significantly associated with increased utilization of PORT were: having insurance, salivary gland primary site, high-risk histology, poor differentiation, and a macroscopic positive margin. Treatment with PORT was associated with improved 5-year OS for all patients with a positive margin (57% vs 48%; P = .002), both microscopic (57% vs 49%; P = .010) and macroscopic (57% vs 41%; P = .036). Improved OS was significant after controlling for other known covariates on multivariate analysis (HR: 0.76; [0.64-0.90]; P = .002). Treatment at a community-based facility was an independent predictor for reduced OS (HR: 1.37; [1.15-1.64]; P < .001). The percentage utilization (53%) of PORT for these patients did not change significantly over time. CONCLUSION: PORT provides a significant survival benefit for adult H&N sarcoma patients with either a microscopic or macroscopic positive margin; however, PORT is underutilized. Treatment at academic/research cancer programs was associated with increased utilization of PORT and improved survival outcomes.

Cartilage Tissue Engineering Using Stem Cells and Bioprinting Technology-Barriers to Clinical Translation.

There is no long-term treatment strategy for young and active patients with cartilage defects. Early and effective joint preserving treatments in these patients are crucial in preventing the development of osteoarthritis. Tissue engineering over the past few decades has presented hope in overcoming the issues involved with current treatment strategies. Novel advances in 3D bioprinting technology have promoted more focus on efficient delivery of engineered tissue constructs. There have been promising in-vitro studies and several animal studies looking at 3D bioprinting of engineered cartilage tissue. However, to date there are still no human clinical trials using 3D printed engineered cartilage tissue. This review begins with discussion surrounding the difficulties with articular cartilage repair and the limitations of current clinical management options which have led to research in cartilage tissue engineering. Next, the major barriers in each of the 4 components of cartilage tissue engineering; cells, scaffolds, chemical, and physical stimulation will be reviewed. Strategies that may overcome these barriers will be discussed. Finally, we will discuss the barriers surrounding intraoperative delivery of engineered tissue constructs and possible solutions.

Adipose-Derived Mesenchymal Stem Cells in the Use of Cartilage Tissue Engineering: The Need for a Rapid Isolation Procedure.

Mesenchymal stem cells (MSCs) have shown much promise with respect to their use in cartilage tissue engineering. MSCs can be obtained from many different tissue sources. Among these, adipose tissue can provide an abundant source of adipose-derived mesenchymal stem cells (ADMSCs). The infrapatellar fat pad (IFP) is a promising source of ADMSCs with respect to producing a cartilage lineage. Cell isolation protocols to date are time-consuming and follow conservative approaches that rely on a long incubation period of 24-48 hours. The different types of ADMSC isolation techniques used for cartilage repair will be reviewed and compared with the view of developing a rapid one-step isolation protocol that can be applied in the context of a surgical procedure.

Adjuvant radiation for T1-2N1 oral cavity cancer survival outcomes and utilization treatment trends: Analysis of the SEER database.

OBJECTIVE: Evaluate current practice patterns in the use of adjuvant radiation for T1-2N1 OCSCC patients and investigate its efficacy in the population-based setting. MATERIALS AND METHODS: This study extracted patients who were treated surgically for T1N1 and T2N1 OCSCC without adverse nodal features from the SEER database from 2004 to 2013. Patients with distant metastatic disease, unknown surgery or radiation status, or prior malignancies were excluded. Patients were divided into those who underwent surgical resection with and without adjuvant radiation. Disease-specific survival (DSS) and overall survival (OS) were the primary outcomes measured. RESULTS: 746 patients met inclusion criteria and 70% received adjuvant radiation therapy. Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (65% versus 51%; p < 0.001) and OS (54% versus 44%; p = 0.007) for T1N1 tumors. Likewise, improved 5-year DSS (58% versus 38%; p = 0.009) and OS (48% versus 28%; p = 0.004) was shown in T2N1 tumors. Patients with T2N1 tumors wer significantly more likely to receive adjuvant radiation (75% versus 63%; p < 0.001). Those with insurance and high risk primary subsites: buccal, retromolar trigone, and hard palate were more likely to receive adjuvant radiation. The percent utilization of adjuvant radiation remained constant through the study period for T2N1 tumors (72-74%) but significantly decreased for T1N1 (71-55%) (p = 0.047). CONCLUSION: Adjuvant radiation therapy is independently associated with a significant survival benefit for patients with both T1N1 and T2N1 OCSCC. However, this study demonstrates that patients with T1N1 cancer are less likely to receive adjuvant radiation and utilization is decreasing.