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.

BackgroundSurgical site complications (SSCs) are the most common cause for readmission after total joint arthroplasty (TJA), increasing costs while predisposing to inferior long-term outcomes. Prophylactic use of closed-incision negative pressure therapy (ciNPT) may lower the risk of these complications, especially in high-risk populations, but appropriate-use guidelines are lacking for patients undergoing primary TJA. We sought to develop a risk-stratification algorithm to guide use of ciNPT dressings and test its use in normalizing the rate of superficial SSCs among high-risk groups.MethodsWe reviewed 323 consecutive primary TJAs, where 38% of those patients considered at elevated risk were risk-stratified to receive ciNPT dressings. An individual risk score was developed, assigning points based on patient-specific risk factors. We identified a historical control population of 643 patients who all received the same postoperative dressing to test the impact of this risk score.ResultsCompared with historical controls, we observed a modest but significant improvement in superficial SSCs after implementation of risk-stratification (12.0% vs 6.8%; P = .013). Among high-risk patients, there was a marked improvement in SSCs when treated prophylactically with ciNPT dressings as compared with historical controls (26.2% vs 7.3%; P < .001). Low-risk patients, who continued to be treated with standard postoperative dressings, demonstrated no significant improvement (8.6% vs 6.5%; P = .344).ConclusionsciNPT dressings are effective at reducing and normalizing risks of superficial SSCs among high-risk primary arthroplasty patients. The proposed risk-stratification algorithm may help identify those patients who benefit most from these dressings.

No abstract

Background: Younger patients are undergoing total knee arthroplasty (TKA) at increasing rates and may face multiple revisions during their lifetimes due to mechanical complications or infections. Questions/Purposes: We sought to compare the early complication rates and revision-free implant-survival rates across age groups of patients undergoing TKA, with particular focus on implant survival in younger patients. Methods: We conducted a retrospective analysis of data taken from a national insurance database on patients who underwent primary TKA from 2007 to 2015. Kaplan–Meier curve survival analysis and log rank test were performed to evaluate revision rates in 7 age groups (younger than 40, 40–49, 50–59, 60–69, 70–79, 80–89, and 90 or more years of age). Complication rates were compared to rates in the age 60 to 79 years age groups using multiple logistic regression, controlling for baseline demographics and comorbidities. Results: There were 114,698 patients included in the analysis. Patients in the younger than 40 years, 40 to 49 years, and 50 to 59 years age groups had increased rates of early mechanical complications; 90-day readmission rates were significantly higher in those age groups as well. Revision-free implant survival at 5 years was significantly worse in patients younger than 60 years of age, particularly those less than 40 years, who had a 77% revision-free implant-survival rate at 5 years. Conclusions: Younger patients had a higher risk of early revision after TKA, as well as an increased rate of mechanical complications and readmissions at 90 days. These outcomes suggest more study is needed to better understand these discrepancies and to better guide preoperative counseling for young patients considering TKA.

Objective Exportin 1/Chromosomal Region Maintenance Protein 1 (XPO1/CRM1) transports proteins bearing nuclear export signals from the cell nucleus to the cytoplasm. SINE are a family of small-molecules that selectively inhibit nuclear export through covalent binding to Cysteine 528 (Cys528) in the cargo binding pocket of XPO1. This leads to forced nuclear retention of cargo proteins that include major tumor suppressor proteins such as p53, FOXO, pRB and IkB. Preclinical and clinical studies have demonstrated selinexor activity in hematologic malignancies as well as in certain solid tumors, and it 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. Materials and Methods The efficacy of selinexor was tested in vitro and in vivo using 17 cell lines and 10 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Following exposure of cell lines to selinexor, effects on cell viability, cell cycle, and RNA and protein expression were determined. In sarcoma xenograft studies, selinexor was administered twice a week by oral gavage and changes in tumor size were recorded. Results Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). The ASPS cell lines were exceptionally resistant to selinexor with IC50 greater than 2 μM. Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. Cell lines from several sarcoma subtypes with defined molecular backgrounds, such as GIST with KIT mutations and dedifferentiated LPS with MDM2 and CDK4 amplification, were treated with selinexor to investigate its mechanism of action. Selinexor induced G1 arrest in GIST cells without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation status and induced G1-arrest irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA levels, indicating a post-transcriptional effect. Conclusions Selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models. Selinexor induced 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. Citation Format: Robert Nakayama, Yi-Xiang Zhang, Alex Anatone, Ewa Sicinska, George Demetri, Andrew Wagner. Preclinical activity of selinexor, an inhibitor of XPO1/CRM1, in sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1759. doi:10.1158/1538-7445.AM2015-1759

No abstract

The published article contained four sentences with incorrect reference citations. Here, those sentences and the reference list are corrected.