Diffuse-type tenosynovial giant cell tumor (D-TGCT) is a mono-articular, soft-tissue tumor. Although it can behave locally aggressively, D-TGCT is a non-malignant disease. This is the first study describing the natural course of D-TGCT and evaluating active surveillance as possible treatment strategy. This retrospective, multicenter study included therapy naïve patients with D-TGCT from eight sarcoma centers worldwide between 2000 and 2019. Patients initially managed by active surveillance following their first consultation were eligible. Data regarding the radiological and clinical course and subsequent treatments were collected. Sixty-one patients with primary D-TGCT were initially managed by active surveillance. Fifty-nine patients had an MRI performed around first consultation: D-TGCT was located intra-articular in most patients (n = 56; 95 %) and extra-articular in 14 cases (24 %). At baseline, osteoarthritis was observed in 13 patients (22 %) on MRI. Most of the patients' reported symptoms: pain (n = 43; 70 %), swelling (n = 33; 54 %). Eight patients (13 %) were asymptomatic. Follow-up data were available for 58 patients; the median follow-up was 28 months. Twenty-one patients (36 %) had radiological progression after 21 months (median). Eight of 45 patients (18 %) without osteoarthritis at baseline developed osteoarthritis during follow-up. Thirty-seven patients (64 %) did not clinically deteriorate during follow-up. Finally, eighteen patients (31 %) required a subsequent treatment. Active surveillance can be considered adequate for selected therapy naïve D-TGCT patients. Although follow-up data was limited, almost two-thirds of the patients remained progression-free, and 69 % did not need treatment during the follow-up period. However, one-fifth of patients developed secondary osteoarthritis. Prospective studies on active surveillance are warranted.

Background: Infection after tumor resection and endoprosthetic reconstruction is a potentially limb-threatening complication. The duration of surgery has been shown to be a risk factor for infection, but the ability of an extended duration of postoperative prophylactic antibiotics to potentially minimize that risk has not been specifically studied. The objective of this study was to determine whether extended postoperative antibiotic therapy protects against surgical site infection (SSI) in the setting of prolonged surgical duration in patients undergoing endoprosthetic reconstruction after tumor resection. Methods: This study was a planned secondary analysis of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial data set. Patients in the PARITY trial were randomized to receive 24 hours or 5 days of postoperative prophylactic antibiotics. The current study assessed the risk of SSI in those cohorts on the basis of surgical duration. A multivariable regression model was used to examine the adjusted effects of the duration of surgery on SSI, after controlling for other significant risk factors and potential confounders. Results: All 604 patients who had been included in the final data analysis in the PARITY trial were also included in this secondary analysis. Those who sustained an SSI had a greater mean duration of surgery (6.2 hours) compared with those who did not sustain an SSI (4.9 hours, p < 0.0001). There was no specific time point at which the risk of infection significantly increased. Extended postoperative prophylactic antibiotic therapy did not appear to mitigate the risk of SSI even in patients with prolonged surgical duration. Conclusions: Increased surgical duration was an independent risk factor for SSI in orthopaedic patients undergoing endoprosthetic reconstruction after tumor resection. However, surgical duration is multifactorial and is influenced by several variables. For example, there may be protective features of flap coverage that increase surgical duration while paradoxically decreasing the risk of SSI. Extended postoperative antibiotic therapy did not mitigate the risk of infection in this cohort, and other risk mitigation strategies will need to be considered in future studies. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Purpose: High-grade complex karyotype sarcomas are a heterogeneous group of tumors with a uniformly poor prognosis. Within complex karyotype sarcomas, there are innumerable genetic changes but identifying those that are clinically relevant has been challenging. Experimental Design: To address this, we utilized a pooled genetic screening approach, informed by The Cancer Genome Atlas (TCGA) data, to identify key drivers and modifiers of sarcoma development that were validated in vivo. Results: YAP1 and wild-type KRAS were validated as drivers and transformed human mesenchymal stem cells into two distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma and myxofibrosarcoma, respectively. A subset of tumors driven by CDK4 and PIK3CA reflected leiomyosarcoma and osteosarcoma demonstrating the plasticity of this approach and the potential to investigate sarcoma subtype heterogeneity. All generated tumors histologically reflected human sarcomas and had increased aneuploidy as compared to simple karyotype sarcomas. Comparing differential gene expression of TCGA samples to model data identified increased oxidative phosphorylation signaling in YAP1 tumors. Treatment of a panel of soft tissue sarcomas with a combination of YAP1 and oxidative phosphorylation inhibitors led to significantly decreased viability. Conclusions: Transcriptional co-analysis of TCGA patient samples to YAP1 and KRAS model tumors supports that these sarcoma subtypes lie along a spectrum of disease and adds guidance for further transcriptome-based refinement of sarcoma subtyping. This approach can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes, and to identify and validate new therapeutic vulnerabilities for this aggressive and heterogeneous disease.