Gladdy, Rebecca A.

Abstract CIC-rearranged sarcoma (CRS) is a rare disease driven by a specific fusion protein involving the CIC gene. The occurrence in the brain is 3% in all CRS patients, and these tumors frequently metastasize to the brain. The most common rearrangement is with the double homeobox 4 (DUX4) transcription factor (CIC-DUX4), and others, such as CIC-NUTM1 fusions, have been identified in a subset of pediatric primitive neuroectodermal tumors. However, the molecular mechanisms by which CIC-fusions drive CRS remain unknown. Preliminary data show that CIC-DUX4/NUTM1 fusions activate JAK and its downstream effector STAT1/3. We hypothesize that JAK/STAT1/3 signaling cooperates with CIC-fusions to drive CIC-sarcomas by inducing ETV1/4/5 expression. Patient-derived CRS cell lines showed elevated levels of JAK1/STAT1/3 activation compared to fusion-negative sarcoma lines. Inhibition of JAK1 using Ruxolitinib and Solicitinib reduced STAT1/3 phosphorylation, downregulated ETV1/4/5 expression at both mRNA and protein levels, and diminished ETV5 promoter activity, cell proliferation, and tumorigenicity. Although the mechanism by which CIC-fusions activate oncogenic targets is still under investigation, histone acetylation appears to play a central role. STAT1/3 interacts with p300/CBP to enhance transcription, and STAT1 is necessary for p300 acetyltransferase activity. Ruxolitinib significantly reduced histone acetylation at ETV1/4/5 promoters in hMSC cells expressing CIC-DUX4/NUTM1, as well as in CRS cell lines. Unlike the p300 inhibitor C646, which causes global hypoacetylation, Ruxolitinib’s effects were promoter-specific, indicating its potential as a more targeted and less toxic therapeutic option. Importantly, we found that STAT1/3 binds to ETV1/4/5 promoters only in the presence of CIC-fusions. Luciferase assays confirmed that STAT1/3 alone cannot activate ETV5 transcription without CIC-fusions, revealing a novel cooperative mechanism. In vivo, Ruxolitinib treatment of CRS xenografts led to significant reductions in tumor volume, STAT1/3 activation, and ETV1/4/5 expression. These findings support JAK1/STAT1/3 inhibition as a promising therapeutic strategy for CRS and warrant further preclinical investigation.

As leiomyosarcoma patients are challenged by the development of metastatic disease, effective systemic therapies are the cornerstone of outcome. However, the overall activity of the currently available conventional systemic treatments and the prognosis of patients with advanced or metastatic disease are still poor, making the treatment of this patient group challenging. Therefore, in a joint effort together with patient networks and organizations, namely Sarcoma Patients EuroNet (SPAEN), the international network of sarcoma patients organizations, and the National LeioMyoSarcoma Foundation (NLMSF) in the United States, we aim to summarize state-of-the-art treatments for leiomyosarcoma patients in order to identify knowledge gaps and current unmet needs, thereby guiding the community to design innovative clinical trials and basic research and close these research gaps. This position paper arose from a leiomyosarcoma research meeting in October 2020 hosted by the NLMSF and SPAEN.

AbstractBackgroundPrimary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function.ObjectivesTo determine the overall survival (OS) and recurrence‐free survival (RFS) for patients undergoing primary resection for mesenteric STS.MethodsThe Trans‐Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019.ResultsFifty‐six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher‐grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery.ConclusionPrimary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

Background In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR). Methods Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence. Results Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re‐resection (61.9%). The 5‐year OS rate varied significantly based on the pattern of failure ( P < .001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [ P < .001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [ P < .001]). The 5‐year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection. Conclusions Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease‐free survivors were identified after surgery for second LR in patients selected for this intervention.