National trends in the treatment of femur fractures in the preschool population: Age and geography play a role.

BACKGROUND: Spica casting and elastic stable intramedullary nailing (ESIN) are options for diaphyseal femur fractures in preschool-age children (ages 3-6 years). Clinical practice guidelines (CPG) are only of moderate or limited strength, which may lead to variation in practice. The purpose of this study is to analyze the epidemiology of children undergoing these procedures in the United States. METHODS: The Pediatric Health Information System, a national database consisting of 49 children's hospitals, was queried for patients between the ages of 3 and 6 years undergoing spica casting or ESIN for a diaphyseal femur fracture between 2011 and 2017. Non-diaphyseal fractures, subjects with associated syndromes or neuromuscular disorders, and pathologic fractures were excluded. Census guidelines were used to categorize hospitals geographically into regions and divisions. Univariate analysis was followed by purposeful entry multivariate regression to adjust for confounders. RESULTS: Analysis included 4059 subjects. Spica casting was performed in 2878 children (71%) and ESIN in 1181 (29%). The median age of those undergoing spica casting was 3.0 years [interquartile range (IQR) 1 year] compared to 5.0 years for ESIN (IQR 2 years; p<0.01). When adjusting for covariates in a multivariate model, each year of increasing age resulted in 4.4 times higher odds that ESIN would be performed (95% CI 4.0-4.8, p<0.01). Compared to the Northeast, a child in the Midwest had 3.6 times higher odds of undergoing ESIN rather than spica casting (95% CI 2.6-5.1, p<0.01). Age at time of ESIN was lowest in the Midwest and highest in the Northeast (4.8±1.0 versus 5.3±0.9 years; p<0.01). There was no variation in the ratio of spica casting to ESIN performed in this age group between 2011 and 2017, including after release of the 2015 CPG. CONCLUSIONS: In the United States, there is substantial variation in the chosen treatment for diaphyseal femur fractures in preschool-age children. ESIN is more likely to be chosen for older children. It is also most likely to be performed in the Midwest and least likely in the Northeast. These findings may have implications in terms of cost and resource utilization and suggest the need for more clinical data to guide surgical indications.

Spica Casting Results in More Unplanned Reoperations than Elastic Intramedullary Nailing: A National Analysis of Femur Fractures in the Preschool Population.

BACKGROUND: Spica casting and elastic stable intramedullary nailing (ESIN) are treatment options for femur fractures in preschool-age children. Clinical practice guidelines are only of moderate or limited strength, which may lead to variation in practice. The purpose of this study was to compare the revision surgery rate in young children undergoing these procedures. METHODS: The Pediatric Health Information System, a database of 49 children hospitals, was queried for patients aged 3 to 6 years undergoing spica casting or ESIN for a diaphyseal femur fracture. ESIN removal was not considered an unplanned revision surgery because the indication for removal could not be determined in the database. Univariate analysis was followed by multivariate regression. RESULTS: Analysis included 4,059 subjects with a mean age of 3.9 ± 1.1 years. Unplanned revision surgery was done in 227/2,878 children (8%) with a spica cast and 35/1,181 (3%) of those with ESIN (P < 0.01). Approximately 2% of children in each cohort underwent ESIN or open reduction and internal fixation as a revision procedure (P = 0.35). In multivariate analysis, spica casting resulted in 4.4 times higher odds of unplanned revision surgery than ESIN (95% confidence interval [CI], 2.9-6.7; P < 0.01). In the spica cast cohort, each year of increasing age resulted in 1.3 times higher odds of revision surgery (95% CI, 1.1-1.6; P < 0.01). Children who were aged 5 or 6 years at the time of spica casting had 1.9 times higher odds of requiring a subsequent procedure compared with 3- and 4-year-olds (95% CI, 1.3-2.7; P < 0.01). CONCLUSIONS: In this large, nationally representative cohort, spica casting resulted in higher odds of requiring an unplanned revision surgery than ESIN, when nail removal was not included as an unplanned procedure. Spica casting in 5- and 6-year-olds yielded higher odds of revision surgery. Regardless of whether spica casting or ESIN is chosen as the initial treatment, 2% of patients will subsequently undergo ESIN or open reduction and internal fixation as a revision procedure.

Pediatric Medial Epicondyle Fractures Are We There Yet?

Several controversies surround the evaluation and treatment of medial epicondyle fractures of the humerus in children. As is well established, the medial epicondyle is the point of attachment for the medial collateral ligament and flexor and pronator musculature, thereby conferring a potentially important role in elbow stability and wrist strength. Traditional x-ray evaluation has been shown to be inaccurate in measuring fracture displacement. While novel radiographic views or advanced imaging modalities may improve this accuracy, the role of displacement in guiding treatment decisions remains unclear. Previous literature on medial epicondyle fractures-all of which is level III or IV evidence-suggests that outcomes may be similar between operative and non-operative treatment. However, most studies are hamstrung by inadequate power, potential for bias, or evaluation of antiquated surgical techniques. In the face of these uncertainties, a shared decision should be made with the patient and family after thorough consideration of treatment goals and discussion of the benefits and disadvantages of both surgical and non-surgical care. Prospective studies are underway and hope to provide clarity on the many debates surrounding this injury.

Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. METHODS: Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. RESULTS: Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. CONCLUSION: MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.