Is failure of tuberosity suture repair in hemi-arthroplasty for fracture mechanical?

BACKGROUND: Tuberosity suture repair in hemiarthroplasty for fracture carries risk of malunion giving poor results. Is failure mechanical or biochemical? We investigated the mechanical aspect with repetitive loading in cadaveric repairs. MATERIALS AND METHODS: Tests were carried out in line with U.K. Human Tissue Authority regulations. A 4-part fracture was created in 8 cadaver shoulders by osteotomizing the tuberosities. A standard hemiarthroplasty implant was cemented in at correct height and retroversion, and standardized repairs applied. Initial firmness of repair was confirmed by attempting to manually displace the tuberosities with a forceps in multiple planes. All pre-stress tests showed 0 mm movement. Repairs were then subjected to cyclical tension on the cuff musculature and simultaneous gleno-humeral motion for 8000 cycles. The tuberosities were reprobed with a forceps to record any movement. RESULTS: Defining repair failure as the ability to manually displace a tuberosity more than 3 mm, every specimen failed: 100% failure (exact 95% confidence interval 65.2-100% due to sample size). Movements of at least 1 cm were commonly observed. The sutures were loose but had never snapped. Sutures were noted to dig into the tendon and cut partially through bone. Collapse of cancellous bony volume led to looseness and migration of the sutures. CONCLUSION: Suture repair of tuberosities has mechanical weaknesses; failure may be a mechanical phenomenon.

Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models.

Metastatic prostate cancer is essentially incurable and is a leading cause of cancer-related morbidity and mortality in men, yet the underlying molecular mechanisms are poorly understood. Plexins are transmembrane receptors for semaphorins with divergent roles in many forms of cancer. We show here that prostate epithelial cell-specific expression of a mutant form of Plexin-B1 (P1597L) which was identified in metastatic deposits in patients with prostate cancer, significantly increases metastasis, in particular metastasis to distant sites, in two transgenic mouse models of prostate cancer (PbCre+Ptenfl /flKrasG12V and PbCre+Ptenfl /flp53fl/ fl ). In contrast, prostate epithelial cell-specific expression of wild-type (WT) Plexin-B1 in PbCre+Ptenfl /flKrasG12V mice significantly decreases metastasis, showing that a single clinically relevant Pro1597Leu amino-acid change converts Plexin-B1 from a metastasis-suppressor to a metastasis-promoter. Furthermore, PLXNB1P1597L significantly increased invasion of tumor cells into the prostate stroma, while PLXNB1WT reduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in Ptenfl /flKrasG12VPLXNB1P1597L mice suppressed metastasis, implicating the Rho/ROCK pathway in this phenotypic switch. Germline deletion of Plexin-B1, to model anti-Plexin-B1 therapy, significantly decreased invasion and metastasis in both models. Our results demonstrate that Plexin-B1 plays a complex yet significant role in metastasis in mouse models of prostate cancer and is a potential therapeutic target to block the lethal spread of the disease. Significance: Few therapeutic targets have been identified specifically for preventing locally invasive/oligometastatic prostate cancer from becoming more widely disseminated. Our findings suggest Plexin-B1 signaling, particularly from the clinically relevant P1597L mutant, is such a target.