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PurposeThe R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases.MethodsFrom 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method.ResultsOf 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm.ConclusionIn ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Background: Mesenchymal chondrosarcoma (MCS) is an ultra‐rare sarcoma that follows a more aggressive course than conventional chondrosarcoma. This study evaluates prognostic factors, treatments (surgery, chemotherapy, and radiation), and outcomes in an Australian setting. Methods: We collected demographics, clinicopathological variables, treatment characteristics, and survival status from patients with MCS registered on the national ACCORD sarcoma database. Outcomes include overall survival (OS) and progression‐free survival (PFS). Results: We identified 22 patients with MCS between 2001–2022. Median age was 28 (range 10–59) years, 19 (86%) had localised disease at diagnosis of whom 16 had surgery (84%), 11 received radiation (58%), and 10 chemotherapy (53%). Ten (52%) developed recurrence and/or metastases on follow‐up and three patients with initial metastatic disease received surgery, radiation, and chemotherapy. At a median follow‐up of 50.9 (range 0.4–210) months nine patients had died. The median OS was 104.1 months (95% CI 25.8–182.3). There was improved OS for patients with localised disease who had surgical resection of the primary (p = 0.003) and those with ECOG 0–1 compared to 2–3 (p = 0.023) on univariate analysis. Conclusions: This study demonstrates contemporary Australian treatment patterns of MCS. The role of chemotherapy for localised disease remains uncertain. Understanding treatment patterns and outcomes help support treatment decisions and design of trials for novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

CIC‐rearranged sarcoma is a recently established, ultra‐rare, molecularly defined sarcoma subtype. We aimed to further characterise clinical features of CIC‐rearranged sarcomas and explore clinical management including systemic treatments and outcomes. Methods: A multi‐centre retrospective cohort study of patients diagnosed between 2014–2019. Results: Eighteen patients were identified. The median age was 27 years (range 13–56), 10 patients were male (56%), 11 patients (61%) had localised disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Of 11 patients with localised disease at diagnosis, median overall survival (OS) was 40.6 months and the 1‐, 2‐ and 5‐year OS estimates were 82%, 64% and 34% respectively. Nine patients (82%) underwent surgery (all had R0 resections), 8 (73%) patients received radiotherapy to the primary site (median dose 57Gy in 28 fractions), and 8 (73%) patients received chemotherapy (predominantly Ewing‐based regimens). Metastases developed in 55% with a median time to recurrence of 10.5 months. In patients with advanced disease at diagnosis, median OS was 12.6 months (95% CI 5.1–20.1), 1‐year OS was 57%. Median progression‐free survival was 5.8 months (95% CI 4.5–7.2). Durable systemic therapy responses occurred infrequently with a median duration of systemic treatment response of 2.1 months. One durable complete response of metastatic disease to VDC/IE chemotherapy was seen. Responses to pazopanib (n = 1) and pembrolizumab (n = 1) were not seen. Conclusion: In this series, CIC‐rearranged sarcomas affected young adults and had a high incidence of presenting with, or developing, metastatic disease. The prognosis overall was poor. In advanced disease, durable systemic therapy responses were infrequent. [ABSTRACT FROM AUTHOR]

Abstract Background Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours. Results The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft samples showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of > 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates. Conclusions The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to investigate clinically-relevant mechanisms of drug-induced gene regulation in ALL; the 8 hour timepoint provides the highest number of significantly differentially expressed genes; time-matched controls are redundant and excellent recovery scores can be obtained with 3 replicates.

ABSTRACT Background Methods Results Conclusion Gemcitabine and docetaxel (GD) is a common chemotherapy regimen for metastatic soft tissue sarcoma (STS). The GeDDiS trial compared GD with doxorubicin in the first‐line setting, using gemcitabine 675 mg/m2 over a prolonged rate of 90 min—reporting a 20% response rate and 5.4‐month median progression‐free survival (PFS). We aimed to examine the real‐world efficacy and toxicity of GD in our center, using a standardized dose of gemcitabine 900 mg/m2 over 30 min on Days 1 and 8 and intravenous docetaxel 75 mg/m2 over 60 min on Day 8 every 21 days.A retrospective analysis was conducted of patients with unresectable or metastatic STS receiving GD between July 2018 and October 2022. Data collected included patient and tumor characteristics, dose intensity, toxicity, response, PFS, and overall survival (OS).Thirty‐eight patients were included. Median follow‐up was 19 months (range 3–30). Line of treatment (n) was first line (10), second line (13), ≥ third line (15). The median number of cycles was 6. Response rate was 42%, including 5% with a complete response. At the time of data collection, 33 patients had disease progression and 24 patients had died. PFS (median, 6‐month rate) was 4.5 months and 44%. OS (median, 12‐month rate) was 15 months and 65%. Grade 3/4 toxicity included anemia (21%), neutropenia (5%), thrombocytopenia (5%), and febrile neutropenia (3%).These data demonstrate the activity of gemcitabine using a standardized dose and rate with docetaxel comparable to other published data and favorable toxicity in a real‐life patient population despite altered gemcitabine dosing and a heavily pretreated patient population. [ABSTRACT FROM AUTHOR]

Aim: Fluorescence in situ hybridization (FISH) is an important ancillary tool for the classification of bone/soft tissue (BST) tumors. The aim of this study was to evaluate the contribution of FISH to the final classification of common BST entities in the molecular pathology department of the Royal Prince Alfred Hospital (RPAH), which is one of the most important referral centers for the management of sarcomas in Australia. Methods: All routine diagnostic FISH tests performed on BST formalin‐fixed paraffin embedded (FFPE) tissue specimens at the RPAH in a 5‐year period (February, 2010–November, 2015) were reviewed. FISH analyses presented in this study include commercial break‐apart probes (SS18, FUS, DDIT3, FUS, USP6, PDGFB, TFE3 and ALK) and a single enumeration (MDM2) probe. Results: There were 434 interpretable FISH assays on BST samples including MDM2 (n=180), SS18 (n=97), FUS (n=64), DDIT3 (n=37), USP6 (n=30), PDGFB (n=13), TFE3 (n=8) and ALK (n=5). Discrepancies between the histopathological diagnosis and the FISH results were seen in 12% of the cases. In this subset of discordant cases, FISH contributed to the re‐classification of 7% of cases originally diagnosed as synovial sarcoma (SS18) and 6% of adipocytic neoplasms (MDM2) based on the presence or absence of the expected gene alteration. Conclusion: Our study confirms that paraffin FISH is a sensitive and specific ancillary tool in the diagnosis of BST neoplasms when used in the appropriate clinicopathological context. These findings highlight the need for further ancillary molecular tools in the diagnosis and characterization of challenging cases. [ABSTRACT FROM AUTHOR]