Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.

Introduction: Surgical site infections (SSIs) are common complications after surgeries involving musculoskeletal tumors, but we know little about SSI risk factors unique to orthopaedic oncology. A greater understanding of these factors will help risk-stratify patients and guide surgical decision-making. Methods: A retrospective review at a single-institution identified 757 procedures done on 624 over 6 years. The patients had a preoperative diagnosis of a malignant or potentially malignant neoplasm of the bone or soft tissues. Patient-specific and procedure-specific variables and diagnosis of SSI were recorded for each case. Data were analyzed through univariate analysis and multiple logistic regression. Results: On univariate analysis, significant patient-specific risk factors for SSI included malignancy (P < 0.001), smoking history (P = 0.041), and American Society of Anesthesiologists Score (P = 0.002). Significant procedure-specific risk factors for SSI on univariate analysis included surgery time (P < 0.001), estimated blood loss (P < 0.001), blood transfusion volume (P < 0.001), neoadjuvant chemotherapy (P < 0.001), neoadjuvant radiation therapy (P < 0.001), inpatient surgery (P < 0.001), and number of previous surgeries within the study period (P < 0.001). The two factors that independently predicted risk of SSI when controlling for all other variables in a multiple logistic regression were whether the surgery was done on an inpatient basis (P = 0.005) and the number of previous surgeries done on the same site (P = 0.001). Conclusions: We found a number of risk factors that correlate markedly with SSI after orthopaedic oncology surgery. The surgeon can use these risk factors to aid in surgical decision-making.