Jozef Zustin

BACKGROUND: Resurfacing of the hip joint is experiencing a revival due to improvements in materials, design, and manufacturing techniques. Despite good midterm outcomes, the high early rate of failure and concerns about metal debris require a detailed morphological and wear analysis of retrieved resurfacing implants in order to understand failure mechanisms. METHODS: A worldwide collection of hip resurfacing revision devices was initiated, and 267 components were received. Devices were analyzed by patient demographics, radiographic positioning, and wear, as well as morphologically and histologically. Specimens were grouped into four different failure types. They were also stratified into rim-loaded or non-rim-loaded groups. Failures were also assessed by surgeon learning-curve effects. RESULTS: Time to failure was significantly different between the four revision-type groups: Specimens with fractures involving the implant rim were most common (46%) and failed earliest after surgery (mean of ninety-nine days), followed by fractures inside the femoral head (20%, 262 days) and loose cups (9%, 423 days). Revisions not due to fractures or cup loosening (25%) occurred at a mean of 722 days after surgery. Rim-loaded implants exhibited an average twenty-one to twenty-sevenfold higher wear rate than implants without rim-loading. Rim-loaded implants also showed a steeper mean cup inclination than their non-rim-loaded counterparts (59 degrees compared with 50 degrees ). Most failures occurred during the learning curve of the surgeon (the first fifty to 100 implantations). CONCLUSIONS: Failures on the femoral side usually occur within the first nine months after surgery and appear to be most directly related to the implantation technique or patient selection. Later failures are observed mainly due to acetabular problems, either due to dramatically increased wear or poor cup anchorage. Improper cup anteversion may be similar to or more important than cup inclination in producing excessive wear.

Progression of breast cancer to metastatic bone disease is linked to deregulated expression of the transcription factor Runx2. Therefore, our goal was to evaluate the potential for clinical use of Runx2-targeting miRNAs to reduce tumor growth and bone metastatic burden. Expression analysis of a panel of miRNAs regulating Runx2 revealed a reciprocal relationship between the abundance of Runx2 protein and two miRNAs, miR-135 and miR-203. These miRNAs are highly expressed in normal breast epithelial cells where Runx2 is not detected, and absent in metastatic breast cancer cells and tissue biopsies that express Runx2. Reconstituting metastatic MDA-MB-231-luc cells with miR-135 and miR-203 reduced the abundance of Runx2 and expression of the metastasis-promoting Runx2 target genes IL11, MMP-13, and PTHrP. In addition, tumor cell viability was decreased and migration suppressed in vitro. Orthotopic implantation of MDA-MB-231-luc cells delivered with miR-135 or miR-203, followed by an intratumoral administration of the synthetic miRNAs, reduced the tumor growth and spontaneous metastasis to bone. Furthermore, intratibial injection of these miRNA-delivered cells impaired tumor growth in the bone environment and inhibited bone resorption. Importantly, reconstitution of Runx2 in MDA-MB-231-luc cells delivered with miR-135 and miR-203 reversed the inhibitory effect of the miRNAs on tumor growth and metastasis. Thus, we have identified that aberrant expression of Runx2 in aggressive tumor cells is related to the loss of specific Runx2-targeting miRNAs and that a clinically relevant replacement strategy by delivery of synthetic miRNAs is a candidate for a therapeutic approach to prevent metastatic bone disease by this route.