A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis.

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.

Intramedullary Implant Choice and Cost in the Treatment of Pediatric Diaphyseal Forearm Fractures.

OBJECTIVES: To compare outcomes and costs between titanium elastic nails (TENs), stainless steel elastic nails (SENs), and Kirschner wires (K-wires) in the treatment of pediatric diaphyseal forearm fractures with intramedullary fixation. DESIGN: Retrospective cohort study. SETTING: Level 1 Pediatric Trauma Center. PATIENTS/PARTICIPANTS: A total of 100 patients (65 male and 35 female) younger than 18 years with diaphyseal forearm fractures treated with intramedullary fixation were included in the study. INTERVENTION: Patients received single or both bone intramedullary fixation with either TENs, SENs, or K-wires. MAIN OUTCOME MEASUREMENTS: Time to radiographic union, complication rate, surgical time, and average cost per implant. RESULTS: One hundred patients were included in the study. Thirty-one patients were treated with TENs, 30 with SENs, and 39 with K-wires. No significant difference in time to radiographic union, complication rate, or surgical time was found between the 3 types of fixation. Average time to union was 9.4 ± 5.4 weeks, and complication rate was 12.9% for TENs, 10.0% for SENs, and 12.8% for K-wires. There was a significant difference in cost per implant, with an average cost of $639, $172, and $24 for TENs, SENs, and K-wires, respectively (P < 0.001). CONCLUSIONS: This study demonstrates no difference between TENs, SENs, and K-wires in the treatment of pediatric diaphyseal forearm fractures with regards to outcome, time to union, surgical time, or complication rates. Given the significant cost difference between these implants, we recommend that surgeons consider modifying their implant selection to help mitigate cost. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.