TNFα-dependent mTOR activity is required for tenotomy-induced ectopic ossification in mice.

INTRODUCTION: Ectopic ossifications often occur in skeletal muscles or tendons following local trauma or internal hemorrhage, and occasionally cause severe pain that limits activities of daily living. However, mechanisms underlying their development remain unknown. MATERIALS AND METHODS: The right Achilles tendon in 8-week-old female or male mice was dissected. Some mice were injected intraperitoneally either with phosphate-buffered saline, dimethyl sulfoxide, cimetidine, rapamycin, celecoxib or loxoprofen for 10 weeks. One week after surgery, immunohistochemical analysis was performed for mTOR, TNFα or F4/80. Ten weeks after surgery, ectopic ossification at the tenotomy site was detected by 3D micro-CT. RESULTS: Ectopic ossification was seen at dissection sites in all wild-type mice by dissection of the Achilles tendon. mTOR activation was detected at dissection sites, and development of ectopic ossification was significantly inhibited by administration of rapamycin, an mTOR inhibitor, to wild-type mice. Moreover, administration of the histamine 2 blocker cimetidine, which reportedly inhibits ectopic ossification in tendons, was not effective in inhibiting ectopic ossification in our models. TNFα-expressing F4/80-positive macrophages accumulate at dissection sites and that ectopic ossification of the Achilles tendon dissection was significantly inhibited in TNFα-deficient mice in vivo. Ectopic ossification is significantly inhibited by administration of either celecoxib or loxoprofen, both anti-inflammatory agents, in wild-type mice. mTOR activation by Achilles tendon tenotomy is inhibited in TNFα-deficient mice. CONCLUSION: The TNFα-mTOR axis could be targeted therapeutically to prevent trauma-induced ectopic ossification in tendons.

Preoperative evaluation of renal cell carcinoma patients with bone metastases on risks for blood loss, performance status and lethal event.

BACKGROUND: Surgical treatment for renal cell carcinoma metastases can be an effective modality for improving survival and patients' quality of life. However, it is often difficult to decide on the optimal surgical approach due to the lesion's high vascularity and uncertainty regarding postoperative performance status and survival. PATIENTS AND METHODS: Blood loss, postoperative performance status, overall survival, postoperative complication and related risk factors for surgical treatment were analysed in 61 renal cell carcinoma patients with bone metastases. RESULTS: Pelvic location and impending/pathological fracture in the metastatic lesion were both significant risk factors for increased blood loss. An unresectable primary lesion and poor preoperative performance status were independent risk factors for poor postoperative performance status. A shorter duration from the discovery of primary lesion to bone metastasis, the number of metastases, and unresectable primary lesion were independent risk factors for shorter survival. Postoperative complications were identified in 15 cases (24.6%). CONCLUSION: The preoperative prediction of intraoperative blood loss, performance status and survival in renal cell carcinoma patients with bone metastases may be possible based on the risk factors identified in this study.