A novel fusion variant LSM14A::NR4A3 in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue neoplasm of uncertain lineage characterized by the pathognomonic rearrangement of the NR4A3 gene, which in most cases is fused with EWSR1. Other NR4A3 fusion partners have been described, namely TAF15, FUS, TCF12, and TGF. Some studies suggest that EMCs with non-EWSR1 variant fusion are associated with high-grade morphology and worst clinical behavior compared to EWSR1::NR4A3 tumors, supporting the potential significance of particular fusion variant in EMC. We report a case of a 34-year-old male who presented with calf EMC and subsequently developed a slowly progressive metastatic disease 3 years after diagnosis. Whole-transcriptome analysis with total RNA sequencing enabled identification of a novel fusion transcript LSM14A::NR4A3, expanding the molecular spectrum of EMC.

Surgical management of soft tissue tumors of the abdominal wall: A retrospective study in a high-volume sarcoma center.

BACKGROUND: The aim of the study is to evaluate functional and oncological outcomes of patients undergoing abdominal wall soft tissue tumors (AWSTT) surgery. METHODS: All consecutive patients that underwent surgery for malignant and intermediate AWSTT from 1999 to 2019 were retrospectively analyzed. RESULTS: Ninety-two patients were identified, 20 (22%) operated on for a desmoid tumor and 72 (78%) for a soft tissue sarcoma (STS). Fifty-two patients (57%) had in toto resection of the abdominal wall (from the skin to the peritoneum) and 9 (10%) required simultaneous visceral resection. The closure was direct in 28 patients (30%) and requiring a mesh, a flap or a combination of the two in respectively 42, 16, and 6 patients (47%, 17%, 6%). The postoperative complications rate was 26%. Thirteen patients (14%) developed an incisional hernia after a median delay of 27 months. After a median follow-up of 40 months, out of the 72 patients operated on for STS, 7 (10%) developed local recurrence and 11 (15%) distant recurrence. The median recurrence-free and overall survivals were 61 and 116, months respectively. CONCLUSIONS: Management of AWSTT requires extensive surgery but allows good local control with an acceptable rate of incisional hernia.

Alveolar soft-part sarcoma: can MRI help discriminating from other soft-tissue tumors? A study of the French sarcoma group.

OBJECTIVES: To investigate the imaging features of alveolar soft-part sarcomas (ASPS) on pre-treatment MRI in order to identify relevant criteria to distinguish ASPS from other soft-tissue tumors. METHODS: A series of 25 patients (mean age, 18.5 years old) with histologically proven ASPS from five French comprehensive cancer centers was compared to a control cohort of 292 patients with various histologically proven benign and malignant soft-tissue tumors representative of the 10-year long activity of one center. All had a baseline MRI with contrast-agent administration. Two radiologists independently reviewed the MRIs. Features assessing location, size, signal, architecture, periphery, and vascularization were reported. Their association with the histological diagnosis of ASPS was evaluated with chi-square or Fisher's test. Their prevalence, sensitivity, specificity, odds ratio, and reproducibility were calculated. RESULTS: Eight MRI features were significantly associated with ASPS: deep location (p < 0.001), high signal intensities on T1-weighted imaging (p < 0.001), central area of necrosis (p = 0.001), absence of fibrotic component (p = 0.003), infiltrative growth pattern (p = 0.003), absence of tail sign (p = 0.001), presence of intra- and peritumoral flow-voids (p < 0.001), and number of flow-voids ≥ 5 (p < 0.001). Twenty out of the 25 (80%) ASPS showed at least 7 of these 8 features compared to only four out of 292 (1.4%) tumors of the control cohort (1 benign vascular tumor, 1 solitary fibrous tumor, 2 high-grade soft-tissue sarcomas). The five ASPS with less than 7 out of 8 features measured less than 40 mm. CONCLUSION: The striking histological uniformity of ASPS translates into imaging. However, ASPS may be misdiagnosed as benign tumors or pseudo-tumors, notably intramuscular benign vascular tumors or vascular malformations. KEY POINTS: • ASPS are rare aggressive mesenchymal tumors displaying recurrent MRI features highly reminiscent of the diagnosis. • Deep-seated tumors presenting with mainly high signal intensity on T1-weighted imaging, an absence of fibrotic component, ill-defined margins without aponeurotic extension, and more than five central and peripheral flow-voids are very likely to be ASPS. • ASPS may be misdiagnosed as intramuscular benign vascular tumor or vascular malformation, which occur in the same age group.

Management of locoregional recurrence after radical resection of a primary nonmetastatic retroperitoneal soft tissue sarcoma: The Gustave Roussy experience.

BACKGROUND: Despite surgery, many patients experience locoregional recurrence (LR), the optimum treatment of which is still debated. METHODS: All 297 consecutive patients operated for a nonmetastatic primary retroperitoneal soft tissue sarcoma (RPS) between 1994 and 2017 were retrospectively analyzed to report our experience in treating LR. RESULTS: After a median follow-up of 97 months, 55 patients (19%) developed LR. The first site of recurrence was locoregional in 100% with associated peritoneal metastases in 45% and distant metastases in 5%. After LR treatment, the 1-, 3-, and 5-year overall survival (OS) rates were 71%, 46%, and 33%. Low tumor grade, disease-free interval above 24 months, exclusive LR, and well-differentiated liposarcoma were predictive of better OS. The treatment strategy (best supportive care, chemotherapy radiotherapy, and/or surgery) was not statistically significant. Fourteen patients underwent initial surveillance (strategic delay) for low-grade LR and eventually required treatment in 86% after a median delay of 20 months during which no patient developed distant metastases. CONCLUSIONS: The management of LR in RPS is complex. An initial surveillance may not alter survival in asymptomatic low-grade and slow-growing LR. An LR decision scheme is proposed.

Single-agent gemcitabine in patients with advanced, pre-treated angiosarcoma: A multicenter, retrospective study.

Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single-agent in a larger series of patients with advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single-agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI-CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1-6.5), and median OS was 9.9 months (95%CI: 6.6-13.4). Single-agent gemcitabine has clinically meaningful activity in advanced, heavily pre-treated angiosarcoma.

An artificial intelligence model predicts the survival of solid tumour patients from imaging and clinical data.

BACKGROUND: The need for developing new biomarkers is increasing with the emergence of many targeted therapies. Artificial Intelligence (AI) algorithms have shown great promise in the medical imaging field to build predictive models. We developed a prognostic model for solid tumour patients using AI on multimodal data. PATIENTS AND METHODS: Our retrospective study included examinations of patients with seven different cancer types performed between 2003 and 2017 in 17 different hospitals. Radiologists annotated all metastases on baseline computed tomography (CT) and ultrasound (US) images. Imaging features were extracted using AI models and used along with the patients' and treatments' metadata. A Cox regression was fitted to predict prognosis. Performance was assessed on a left-out test set with 1000 bootstraps. RESULTS: The model was built on 436 patients and tested on 196 patients (mean age 59, IQR: 51-6, 411 men out of 616 patients). On the whole, 1147 US images were annotated with lesions delineation, and 632 thorax-abdomen-pelvis CTs (total of 301,975 slices) were fully annotated with a total of 9516 lesions. The developed model reaches an average concordance index of 0.71 (0.67-0.76, 95% CI). Using the median predicted risk as a threshold value, the model is able to significantly (log-rank test P value < 0.001) isolate high-risk patients from low-risk patients (respective median OS of 11 and 31 months) with a hazard ratio of 3.5 (2.4-5.2, 95% CI). CONCLUSION: AI was able to extract prognostic features from imaging data, and along with clinical data, allows an accurate stratification of patients' prognoses.

No Geographical Inequalities in Survival for Sarcoma Patients in France: A Reference Networks' Outcome?

The national reference network NETSARC+ provides remote access to specialized diagnosis and the Multidisciplinary Tumour Board (MTB) to improve the management and survival of sarcoma patients in France. The IGéAS research program aims to assess the potential of this innovative organization to address geographical inequalities in cancer management. Using the IGéAS cohort built from the nationwide NETSARC+ database, the individual, clinical, and geographical determinants of the 3-year overall survival of sarcoma patients in France were analyzed. The survival analysis was focused on patients diagnosed in 2013 (n = 2281) to ensure sufficient hindsight to collect patient follow-up. Our study included patients with bone (16.8%), soft-tissue (69%), and visceral (14.2%) sarcomas, with a median age of 61.8 years. The overall survival was not associated with geographical variables after adjustment for individual and clinical factors. The lower survival in precarious population districts [HR 1.23, 95% CI 1.02 to 1.48] in comparison to wealthy metropolitan areas (HR = 1) found in univariable analysis was due to the worst clinical presentation at diagnosis of patients. The place of residence had no impact on sarcoma patients' survival, in the context of the national organization driven by the reference network. Following previous findings, this suggests the ability of this organization to go through geographical barriers usually impeding the optimal management of cancer patients.

Prospective evaluation of intensity-modulated radiotherapy toxicity in extremity soft tissue sarcomas patients: A role for irradiated healthy soft tissue volume?

AIM: To prospectively assess toxicities of curative-intent intensity-modulated conformal radiotherapy (IMRT) in patients with extremity soft tissue sarcomas (ESTS). METHODS: Data from 59 consecutive patients with ESTS between 2014 and 2019 were both retrospectively and prospectively analysed. Toxicity data were collected both by confidential mailed survey (39% completed) and medical charts, and graded according to CTCAE v5.0. Normal tissues dosimetric data (healthy soft tissue segment, joint and bone) were included. The healthy soft tissue segment was created by adding 5 cm on either side of the PTV on CT axial slices, the PTV and bone (and articulation if present) were then removed from the generated volume. RESULTS: IMRT was delivered post-operatively for nearly half of patients (n = 24, 41%), preoperatively for 18 (31%) and exclusively for 17 (28%; salvage: 13% or immediately inoperable: 15%). The median total dose delivered to the planned target volume (PTV) was 50.4 Gy (36-68 Gy) and 13 patients (22%) received a boost. With a median follow-up of 27 months (6-94 months), a total of 87 late effects were identified in 44/59 (75%) patients: 89% G1-2, and 11% G3-4. The main G1-2 toxicities were: functional limitation (36%), oedema (29%), gait disorders (20%), neurological disorders (20%) and chronic pain (32%). G3-4 toxicities were pain (n = 2), arterial stricture (n = 1) and a chronic wound requiring skin graft (n = 2). No bone fracture was observed. Quality of life was rated as good or very good in 70% patients who completed the survey. Larger (>3500 cm3) healthy soft tissue segment volume was associated with decreased late toxicities (p = 0.02). No other predictive factor of toxicity was identified. The 2-year rates of local control, overall survival and recurrence-free survival were 90%, 90% and 64%, respectively. CONCLUSION: Healthy soft tissue segment volume influenced toxicity. Long-term prospective monitoring in a homogeneous population remains critical to assess the impact of IMRT induced chronic toxicity in ESTS patients. This should ideally lead to a validated normal tissue dose constraint (e.g.: healthy soft tissue segment volume > 3500 cm3) to recommend for practitioners to help reduce the late toxicity risk.

[Preoperative versus postoperative radiotherapy in soft tissue sarcomas: State of the art and perspectives]. / Radiothérapie préopératoire versus postopératoire dans les sarcomes des tissus mous : état des lieux et perspectives.

Radiation therapy is a standard treatment for limbs soft tissue sarcomas. Preoperative versus postoperative radiotherapy has been a controversial topic for years. With preoperative irradiation, the treatment volume is more limited, the delivered dose possibly lower and the tumor volume easier to delimit. Only one randomized trial compared these two irradiation sequences. The results in terms of local control and survival were equivalent but the risk of acute postoperative complications was higher if irradiation was administered before surgery. However, in the latest update of this trial, patients who received adjuvant irradiation exhibited more severe late toxicity than those treated preoperatively. In addition, with modern irradiation techniques such as conformal with image-guided intensity modulated radiotherapy and flap coverage techniques, the incidence of complications after preoperative irradiation were lower than historically published rates. Locally advanced proximal sarcomas and the failure of other neoadjuvant treatments are nowadays classical indications for preoperative irradiation. As with other neoadjuvant treatments, induction radiotherapy must be personalized according to the histological subtype, the tumor site and the benefit/risk ratio, which is best appreciated by a multidisciplinary surgical and oncological team in a specialized center in the management of soft-tissue sarcomas.

Postoperative Outcome of Surgery with Pancreatic Resection for Retroperitoneal Soft Tissue Sarcoma: Results of a Retrospective Bicentric Analysis on 50 Consecutive Patients.

BACKGROUNDS: Multivisceral resection is the standard treatment for retroperitoneal sarcoma (RPS) during which pancreas resection may be necessary. METHODS: All consecutive patients operated for RPS with pancreatectomy in 2 expert centers between 1993 and 2018 were retrospectively analyzed. RESULTS: Fifty patients (median age: 57 years, IQR: [46-65]) with a primary (n = 33) or recurrent (n = 17) RPS underwent surgery requiring pancreas resection (distal pancreatectomy (DP) (n = 43), pancreaticoduodenectomy (PD) (n = 5), central pancreatectomy (n = 1), and atypical resection (n = 1)). Severe postoperative morbidity (Clavien-Dindo III-IV) was observed in 14 patients (28%), and 7 of them (14%) required reoperation for anastomotic bowel leakage (n = 5), gastric volvulus (n = 1), or hemorrhage (n = 1). Pancreas-related complications occurred in 25 patients (50%): 10 postoperative pancreatic fistulas (POPF) (grade A (n = 12), grade B (n = 6), grade C (n = 1)), 13 delayed gastric emptying (grade A (n = 8), grade B (n = 4), grade C (n = 1)), 1 hemorrhage (grade C). Postoperative mortality was 4% (n = 2), all following PD, caused by a massive intraoperative air embolism and by a multiple organ failure after anastomotic leakage. Pathological analysis confirmed pancreatic involvement in 17 (34%) specimens. Microscopically complete resection (R0) was achieved in 22 (44%) patients. After a follow-up of 60 months, 36 patients (75%) were still alive, among whom 27 without recurrence (56%). CONCLUSION: Pancreatic resection during RPS surgery is associated with significant postoperative morbidity and mortality. PD should be avoided whenever possible while other procedures seemed achievable without excessive morbidity and with long-term survival.

Efficacy and safety of oral metronomic etoposide in adult patients with metastatic osteosarcoma.

Therapeutic options in patients with metastatic osteosarcoma are limited and effective systemic treatments are needed in this setting. The aim of this case series was to assess the efficacy and toxicity of oral metronomic etoposide in adult patients with progressive metastatic osteosarcoma. We retrospectively reviewed the electronic records of patients treated with oral metronomic etoposide (25 mg thrice daily, 3 weeks out of 4) from December 2002 to December 2018 at Gustave Roussy (Villejuif, France). The primary endpoint was progression-free rate (PFR) at 4 months; secondary endpoints were: best response (according to RECIST v1.1), progression-free survival (PFS), overall survival (OS) and safety. With a median follow-up of 9.8 months, 37 patients were eligible for this analysis: 68% males, median age 42 (range: 21-75), 19% with synchronous metastases, 92% with lung metastases, median PS: 1 (range: 0-3). Median number of previous treatment lines in the metastatic setting was 1 (range: 0-4). Progression-free rate at 4 months was 40.3% (95% CI: 24.5-56.2). Best response was partial response in 11% and stable disease in 35% of patients (disease control rate: 46%). Median PFS was 3.1 months (95% CI: 2.5-4.7) and median OS was 9.8 months (95% CI: 5.1-12.3). Toxicity profile was acceptable, with 13% grade 3 haematological toxicities (anaemia and neutropenia), without any grade 3-4 non-haematological toxicity. In our experience, oral metronomic etoposide demonstrated effective palliation along with acceptable toxicity in patients with progressive metastatic osteosarcoma.

Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of CTNNB1 Mutational Status.

PURPOSE: Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments. EXPERIMENTAL DESIGN: We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included. RESULTS: From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06-4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23-6.27; P = 0.04). Toxicity profile was favorable, without grade 3-4 toxicity, except for one grade 3 neutropenia. CONCLUSIONS: Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.