Scarf osteotomy for correction of painful hallux valgus is an effective technique, giving a predictable correction of the deformity. However, some patients remain less than fully satisfied, despite normalisation of the usual radiographic parameters. This study examines whether lateral soft tissue release can cause late splaying of the forefoot. A series of 32 feet in 29 consecutive patients in a single centre, operated on by a single surgeon, over a 12 month period were studied. After pre-operative weight-bearing x-rays and consenting, a standardised ‘Barouk-technique’ Scarf procedure was undertaken with on-table assessment for lateral soft tissue release and phalangeal varisation. Post-operatively, patients were kept heel weight-bearing without cast for 6 weeks, with use of a fabric splint after removal of bandages at 2 weeks. HVA and IMA were measured pre-operatively, at 6 weeks, and at 6-12 month follow-up. Distance from the mid-points of the 1st to the 5th metatarsal heads and distance from lateral sesamoid to 2nd metatarsal shaft were also recorded by blinded observers. AOFAS Foot Scores were collected prospectively. Student's t-test for single-tailed paired data was applied and p-values calculated. There were 22 female and 10 male feet; in patients aged 27 to 74 (mean 58). Average HVA improved from 34° to 17° and was maintained at 16°. IMA improved from 14° to 7°, but then increased significantly to 10°. Overall inter-metatarsal width reduced from 76mm to 65mm but then significantly increased to 71mm. Sesamoid distance was also reduced and later increased, but not significantly. Mean foot scores improved from 52 to 85 at late follow-up. Complication rate was low. Late widening occurred more in those feet with bigger original HVA, which were likely to have had more extensive soft tissue release (deep inter-metatarsal ligament). We recommend cautious release; and pre-operatively counselling specifically regarding eventual overall foot-width.
Mutations of the p53 gene are uncommon in synovial sarcoma, a high-grade tumor genetically characterized by the chromosomal translocation t:(X;18), that results in the fusion of SS18 with SSX gene. We recently reported that SS18-SSX1 negatively regulates the stability of p53 by promoting its ubiquitination and degradation in a manner dependent on the ubiquitin ligase activity of HDM2. The negative effect of SS18-SSX1 expression on p53 was mediated by its ability to promote HDM2 stabilization through inhibition of HDM2 autoubiquitination. The final outcome translates into a deficient transactivation of p53-regulated genes: HDM2, PUMA, and NOXA that are important to preserve genomic integrity in response to cellular stress. Our data uncovers a novel mechanism whereby, in synovial sarcoma cells with wild type p53, the SS18-SSX oncoprotein can negatively regulate p53 tumor-suppressive function by increasing the stability of its negative regulator HDM2. We further hypothesise that chemical compounds that target the p53-HDM2 regulatory axis may rescue p53 function in synovial sarcoma. With this in mind we investigated the potential of the HDM2 antagonists, nutlin-3 and of the recently discovered tenovin 1, to rescue p53 activity in synovial sarcoma cells lines. Nutlin-3 effectively stabilized p53 half-life and trans-activating function, resulting in cell growth arrest and apoptosis. We further observed that chemotherapeutic agents like doxorubicin also stabilized p53 in response to DNA damage but did not restore p53 transcriptional activity due to rapid complexing of p53 to HDM2. On the contrary, nutlin-,3 stabilized p53 and inhibited p53-HDM2 interaction, thereby rescuing p53 tumor suppression function. Our results suggest that the inhibition of the p53-HDM2 interaction by small molecules is a highly potential therapeutic strategy for soft tissue sarcomas with wild type p53.
