Open Reduction And Internal Fixation of Tarsometatarsal (Lisfranc) Fracture Dislocations-Is Arthrodesis Necessary?

INTRODUCTION: Controversy remains regarding the optimal management of tarsometatarsal (Lisfranc) fracture dislocations. Open reduction and internal fixation (ORIF) and ORIF with primary arthrodesis (PA) have been described in the treatment of these injuries, although adverse sequelae remain problematic. Previous work has yielded small cohorts with heterogenous results. We aimed to describe the outcomes of Lisfranc fracture dislocations managed with ORIF and/or PA to identify risk factors for complications, such as nonunion and revision surgery. METHODS: A retrospective review of 206 consecutive tarsometatarsal fracture dislocations that underwent surgical repair between 2015 and 2021 was performed. Time to radiographic union was noted. Complications were recorded, including revision surgery, infection, symptomatic implant removal, posttraumatic arthritis, secondary arthrodesis, and nonunion. A comparative subgroup analysis of outcomes by treatment modality (ie, PA versus ORIF) and by injury severity (isolated injury versus concomitant lower extremity fracture) were performed. Logistic regression analysis was performed to assess factors associated with revision surgery. RESULTS: 104 patients met the inclusion criteria with a mean 13-month follow-up. Ninety-three (n = 93) patients underwent ORIF, and 11 patients underwent PA. Radiographic union was achieved in 94.2% of cases (98/104) at an average 106 days. Complications included superficial infection (3.8%), deep infection (7.7%), symptomatic implant removal (19.2%), posttraumatic arthritis (12.5%), secondary arthrodesis (4.8%), and nonunion (2.9%). No difference existed in the complication rates between those who underwent ORIF and those who underwent PA ( P = 0.50). Revision surgery rates were similar between patients who sustained isolated injuries and those with concomitant lower extremity fractures ( P = 0.31). Risk factors for revision surgery included open fractures (OR 4.01, P = 0.042) and previous psychiatric illness (OR 5.77, P = 0.016). DISCUSSION: The vast spectrum of injury in Lisfranc fracture dislocations makes uniform treatment challenging. In this large consecutive series, few failed to achieve union or required secondary arthrodesis. Open fractures and previous psychiatric illness portended worse clinical outcomes. ORIF without PA remains a viable treatment in these injuries. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Frame-shift mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells result in replication-stress sensitivity.

We recently documented that gain-of-function (GOF) mutant p53 (mtp53) R273H in triple negative breast cancer (TNBC) cells interacts with replicating DNA and PARP1. The missense R273H GOF mtp53 has a mutated central DNA binding domain that renders it unable to bind specifically to DNA, but maintains the capacity to interact tightly with chromatin. Both the C-terminal domain (CTD) and oligomerization domain (OD) of GOF mtp53 proteins are intact and it is unclear whether these regions of mtp53 are responsible for chromatin-based DNA replication activities. We generated MDA-MB-468 cells with CRISPR-Cas9 edited versions of the CTD and OD regions of mtp53 R273H. These included a frame-shift mtp53 R273Hfs387, which depleted mtp53 protein expression; mtp53 R273HΔ381-388, which had a small deletion within the CTD; and mtp53 R273HΔ347-393, which had both the OD and CTD regions truncated. The mtp53 R273HΔ347-393 existed exclusively as monomers and disrupted the chromatin interaction of mtp53 R273H. The CRISPR variants proliferated more slowly than the parental cells and mt53 R273Hfs387 showed the most extreme phenotype. We uncovered that after thymidine-induced G1/S synchronization, but not hydroxyurea or aphidicholin, R273Hfs387 cells displayed impairment of S-phase progression while both R273HΔ347-393 and R273HΔ381-388 displayed only moderate impairment. Moreover, reduced chromatin interaction of MCM2 and PCNA in mtp53 depleted R273Hfs387 cells post thymidine-synchronization revealed delayed kinetics of replisome assembly underscoring the slow S-phase progression. Taken together our findings show that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF that pertain to processes associated with DNA replication.