ABSTRACT Metastatic Ewing sarcoma (MES) has a poor prognosis. This multicenter observational study provides real‐world data on treatment patterns of patients with MES in France. Treatment characteristics, outcomes such as time to next treatment (TTNT) and overall survival (OS), and prognostic factors of patients aged ≥ 12 years treated for a MES in 11 French reference network centers were retrieved from our national database. From 2008 to 2018, 156 patients with MES were included: 82 were metastatic at diagnosis (upfront metastatic cohort), 74 had developed secondary metastases after treatment of a localized disease (metastatic relapse cohort). 94% of patients received systemic treatment, with a median of three lines (1–11), 61% had at least one loco‐regional procedure and 42% of patients participated in a clinical trial in the metastatic setting. Median OS from metastatic diagnosis was 20.3 months [95% CI 14.0; 27.7] in the metastatic relapse cohort and 31.4 months [95% CI 26.5; 42.5] in the upfront metastatic cohort (p = 0.02). Median TTNT in first metastatic line was 16.8 months [95% CI 12.9; 21.3] in the upfront metastatic cohort and 7.4 months [95% CI 5.0; 11.1] in the metastatic relapse cohort, 5.8 months [95% CI 3.6; 7.3] in 2nd line and 3.8 months [95% CI 2.8; 5.7] in 3rd line, without significant difference between cohorts and treatment regimens. Patients with upfront MES have a longer OS than patients with relapsing disease, mainly due to first metastatic line dose‐dense polychemotherapy and loco‐regional procedures in selected patients. Main regimens used at relapse are associated with the same range of benefit and survival, while TKIs such as regorafenib or cabozantinib have modest activity. Inclusion in clinical trials should be prioritized.

INTRODUCTION:Data about intra-abdominal desmoid-type fibromatosis (IA-DTFs) are limited. METHODS:We examined patients with IA-DTFs enrolled in the ALTITUDES study (NCT02867033). We compared their characteristics with those of other locations using chi-square and Wilcoxon tests, as appropriate, and assessed their outcomes using event-free survival (EFS). Association between primary location and EFS was determined using a Cox univariate model. Subgroup analysis was performed for patients initially managed with active surveillance (AS). RESULTS:95/610 tumors (15.5%) enrolled in ALTITUDES were intra-abdominal. Compared with other locations, patients with IA-DTFs were older (p < 0.001), more often men (p < 0.001), had more frequently a history of polyposis (p = 0.001), larger tumors (p = 0.003), different CTNNB1 mutation profiles (p = 0.004), and a diagnosis established more frequently on surgical specimens (p < 0.001). These patients reported less pain (p = 0.01) and fewer emotional difficulties (p = 0.001), but more constipation (p = 0.004). Surgery was the most common first-line approach (51.6%); AS accounted for the management of only 29.5%. Overall, we observed no significant difference between IA-DTFs and other locations in terms of EFS (hazard ratio, HR = 0.84; 95%CI, 0.56-1.26) and overall survival (HR = 1.84; 0.50-6.80). Among patients managed by AS, EFS was similar between both groups (HR = 1.05; 0.55-2.00). CONCLUSION:One third of IA-DTFs patients were managed using AS, and their outcome was similar to those of patients with other locations. These observational data may help to discuss SA as a first-line approach in the management of IA-DTFs patients.

The DeFi trial revealed a significant improvement in progression-free survival (PFS) with nirogacestat in patients with desmoid tumors. The DeNi study reports outcomes of patients treated with nirogacestat through the French compassionate use program. DeNi is a retrospective, real-world study. Outcomes included objective response, pain improvement, 1-year PFS, and toxicity. Between February and June 2024, 55 patients with desmoid tumors were included (37 women). Data were updated until November 2025. The median age was 38.6 years (range: 18.0-66.7). The median number of previous therapies was 2, including local therapies. The median follow-up was 21.4 months [95% CI: 19.5; 25.6]. The estimated median duration of nirogacestat treatment was 16 months. Partial response and stable disease were observed in 33 (60%) and 17 patients (31%), respectively. The 1-year PFS rate was 76.2%, and 77.0% of patients remained without treatment change at 1 year, including patients with dose reductions. Of the 49 patients with baseline pain, 38 (78%) experienced pain improvement under nirogacestat; 35 (71%) reduced or discontinued analgesics. The most frequent side effects (all grades) were diarrhea (53%), fatigue (47%), and rash (29%). Thirteen patients (24%) required dose reduction: 11 for digestive adverse events (85%), 1 for mucositis, and 1 for fatigue with hypertension. The DeNi study confirms the clinical benefits of nirogacestat in patients with desmoid tumors, with improvements in pain and tumor shrinkage observed in 60% of patients and PFS consistent with that reported in the phase III DeFi trial.

Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent MITF rearrangements involving actin gene partners (ACTA2, ACTG1 and ACTB). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for TFE3/MITF rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs-melanocytic, mesenchymal, or adipogenic-as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for TP53/RB1 mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.

PURPOSE:Euro-EWING99 study was a large, international, prospective study recruiting patients with Ewing sarcoma (EWS) between 1999 and 2015. It assessed three different clinical questions through randomized trials. We report here the characteristics and outcomes of all patients. METHODS:Patients younger than 50 years with EWS were included in the study. They received induction chemotherapy (six courses of vincristine [day 1], ifosfamide [day 1-3], doxorubicin [day 1-3], and etoposide [day 1-3; VIDE], administered every 3 weeks), local therapy (surgery/radiotherapy), and different consolidation treatments according to clinical risk group and trial.The objectives of the study were to describe the entire cohort according to the initial staging group, to describe the survival outcomes (overall survival [OS]; progression-free survival [PFS]; and local control), and to evaluate prognostic factors associated with OS and PFS. RESULTS:Three thousand three hundred ninety-five patients were included in the study, including 2,267 with a localized disease, 614 with pleuropulmonary metastases, and 514 with extrapulmonary metastases. Ninety-eight percent of patients received ≥4 neoadjuvant VIDE courses. The modalities of local treatment and consolidation therapy differed among the three staging groups. With a median follow-up of 7.2 years, PFS of the entire cohort was 60.2% and 55.4% at 3 and 5 years, respectively. OS was 72.6% and 64.6% at 3 and 5 years, respectively. In addition to metastatic status at diagnosis, main prognostic factors included patient age, tumor volume, and histologic response both for PFS and OS, independent of metastatic status. CONCLUSION:To our knowledge, this study is the largest published series of patients with EWS and may serve as a landmark paper for EWS. It confirms the major prognostic value of the complete histologic response after neoadjuvant therapy.

PURPOSE:Genomic instability (GIN) plays a critical role in cancer progression and treatment responses. Soft tissue sarcomas (STSs) are characterized by extensive chromosomal rearrangements and transcription-associated stress, both of which contribute to poor clinical outcomes. Current standard grading systems including fédération nationale des centres de lutte contre le cancer (FNCLCC) have limited prognostic accuracy for STS, necessitating improved risk stratification. To address this gap, we developed the Mixed Transcription- and Replication-Associated GIN Classifier (MAGIC) and assessed its translatability from whole-genome sequencing to RNA sequencing (RNA-seq). METHODS:This study analyzed RNA-seq from 226 localized STS tumors to analyze the fusion transcript breakpoint distribution and assess GIN. We computed MAGIC indices transcription association chromosomal instability index (iTRAC) and Replication-Associated Chromosomal INstability index (iRACIN), which are based on GIN linked to transcription and replication processes, respectively. The iTRAC biomarker was evaluated using FNCLCC and Complexity INdex in SARComas (CINSARC) for metastatic risk stratification. Kaplan-Meier and iterative multi-thresholds partitioning analyses assessed prognostic relevance. RESULTS:iTRAC significantly stratified patients with distinct metastatic outcomes, outperforming the FNCLCC and CINSARC grading systems. STS patients with medium iTRAC levels showed the poorest metastasis-free survival. Patients classified into iTRAC-high and iTRAC-low groups achieved a better prognosis. Furthermore, iTRAC stratified patients' metastatic risk in treated and nontreated patients, indicating poorer prognosis with chemotherapy in patients with low iTRAC and better prognosis for those with medium iTRAC. By contrast, iRACIN was not measurable in the RNA-seq-based analysis. CONCLUSION:iTRAC demonstrates superior prognostic utility in STS over the current grading systems, effectively stratifying metastatic risk for patients who might benefit from alternative therapeutic strategies. iTRAC holds the potential for personalizing chemotherapeutic approaches, paving the way for a new precision oncology approach in STS.

Patients who develop Ewing sarcoma with extra-pulmonary metastasis have a poor prognosis. A recent French protocol, CombinaiR3, was set up to evaluate the efficacy of induction chemotherapy followed by high-dose chemotherapy and metronomic maintenance treatment. It is now closed for inclusions and while waiting for the results, we propose a French consensus guideline for the management of patients diagnosed with Ewing sarcoma with extra-pulmonary dissemination. Main recommendations include induction chemotherapy with nine cycles of vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide. In case of insufficient response, other chemotherapy combination or inclusion in a clinical trial should be considered. Induction chemotherapy should be followed by local treatment, consisting of surgery and/or radiotherapy. Optimal local treatment is a milestone in the management of patients with Ewing sarcoma and should be discussed with experts and surgeons/radiotherapists working in the sarcoma network. High-dose chemotherapy (HDC) containing busulfan and melphalan followed by autologous stem-cell transplantation is still unclear, with contradictory results. HDC will then be discussed in national tumor board and administered to patients when compatible with local treatment. Given the high relapse rate observed among these metastatic patients, maintenance chemotherapy (so called metronomic regimen) will then be given for two years.

Ewing sarcoma (ES) is a rare tumour with metastatic spread in 25

Background:Liposarcomas (LPS) are among the most common sarcomas, but gather a diversity of rare to ultrarare molecular subtypes whose presentations and natural histories are partially characterized. The aim of the work was to describe the presentation and outcome of the different LPS histotypes from the NETSARC+ registry. Methods:NETSARC+ (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB), funded by the French INCA since 2010 aiming to improve the quality of care of sarcoma patients. Patients' characteristics, treatment and outcomes are collected in a nationwide database. This work describes the outcome of all LPS confirmed by central review pathology review and integrated between 2010 and 2023 in the NETSARC+ database. Findings:11,132 liposarcomas are included in the database for an estimated incidence of 11.5/106/y. Median age was 65 (Q1-Q3: 53-74, range 0-97 y), with 6529 males (58.7%), with 4220 (37.9%) dedifferentiated (DDLPS), 1838 (16.5%) well differentiated LPS (WDLPS) & 2424 (21.8%) atypical lipomatous tumours (ALT), 1371 (12.3%) myxoid LPS (MyxLPS), 450 (4.0%) pleomorphic LPS (PLPS), 177 (1.6%) high grade myxoid LPS (HGMLPS), 24 (0.2%) mixed type liposarcomas (MTLPS), 14 (0.1%) myxoid pleomorphic LPS (MPLPS) and 614 (5.5%) non classified LPS (NCLPS). Age, sex and sites differed across histotypes, but overall, all histotypes were represent in all age groups and sites. We report first on a difference in the sex ratio of liposarcoma in different age groups. Women were less frequently affected with liposarcomas after 50, in DDLPS, MyxLPS and HGMLPS. The median overall survival of DDLPS was 144 months, significantly worse than that of MyxLPS (HR: 0.26 [95% CI 0.21-0.33]), PLPS (HR: 0.76 [95% CI 0.59-0.98]), HGMLPS (HR: 0.30 [95% CI 0.18-0.50]), WDLPS (HR: 0.30 [95% CI 0.24-0.37]), unclassified LPS (HR: 0.53 [95% CI 0.37-0.75]). In addition to a lower incidence, women aged >50 had a better relapse free and overall survival than male, while this was not observed in the group aged 50 or under. In multivariate analyses, size and age were independent prognostic factors for the most common subgroups, but specific prognostic parameters were observed in each molecular subgroup. Female >50 was an independent favorable prognostic factor for the largest groups of DDLPS. Interpretation:In this nationwide series of pathology-confirmed LPS, the clinical presentation, management and survival of histotypes are very different with age-related sex differences favoring women >50. DDLPS is the subtype with the worse prognosis. Funding:This work was supported by the following grants: NetSARC+ (INCA), RREPS (INCA), RESOS (INCA), INTERSARC+ (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), LYriCAN+ (INCa-DGOS-INSERM-ITMO cancer_18,003), Ligue Nationale contre le Cancer, Ligue Contre le Cancer (Comité de l'Ain), Fondation ARC, and EURACAN (EU project 739521).

Background Liposarcomas (LPS) are among the most common sarcomas, but gather a diversity of rare to ultrarare molecular subtypes whose presentations and natural histories are partially characterized. The aim of the work was to describe the presentation and outcome of the different LPS histotypes from the NETSARC+ registry. Methods NETSARC+ (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB), funded by the French INCA since 2010 aiming to improve the quality of care of sarcoma patients. Patients’ characteristics, treatment and outcomes are collected in a nationwide database. This work describes the outcome of all LPS confirmed by central review pathology review and integrated between 2010 and 2023 in the NETSARC+ database. Findings 11,132 liposarcomas are included in the database for an estimated incidence of 11.5/106/y. Median age was 65 (Q1–Q3: 53–74, range 0–97 y), with 6529 males (58.7%), with 4220 (37.9%) dedifferentiated (DDLPS), 1838 (16.5%) well differentiated LPS (WDLPS) & 2424 (21.8%) atypical lipomatous tumours (ALT), 1371 (12.3%) myxoid LPS (MyxLPS), 450 (4.0%) pleomorphic LPS (PLPS), 177 (1.6%) high grade myxoid LPS (HGMLPS), 24 (0.2%) mixed type liposarcomas (MTLPS), 14 (0.1%) myxoid pleomorphic LPS (MPLPS) and 614 (5.5%) non classified LPS (NCLPS). Age, sex and sites differed across histotypes, but overall, all histotypes were represent in all age groups and sites. We report first on a difference in the sex ratio of liposarcoma in different age groups. Women were less frequently affected with liposarcomas after 50, in DDLPS, MyxLPS and HGMLPS. The median overall survival of DDLPS was 144 months, significantly worse than that of MyxLPS (HR: 0.26 [95% CI 0.21–0.33]), PLPS (HR: 0.76 [95% CI 0.59–0.98]), HGMLPS (HR: 0.30 [95% CI 0.18–0.50]), WDLPS (HR: 0.30 [95% CI 0.24–0.37]), unclassified LPS (HR: 0.53 [95% CI 0.37–0.75]). In addition to a lower incidence, women aged >50 had a better relapse free and overall survival than male, while this was not observed in the group aged 50 or under. In multivariate analyses, size and age were independent prognostic factors for the most common subgroups, but specific prognostic parameters were observed in each molecular subgroup. Female >50 was an independent favorable prognostic factor for the largest groups of DDLPS. Interpretation In this nationwide series of pathology-confirmed LPS, the clinical presentation, management and survival of histotypes are very different with age-related sex differences favoring women >50. DDLPS is the subtype with the worse prognosis. Funding This work was supported by the following grants: NetSARC+ (INCA), RREPS (INCA), RESOS (INCA), INTERSARC+ (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), LYriCAN+ (INCa-DGOS-INSERM-ITMO cancer_18,003), Ligue Nationale contre le Cancer, Ligue Contre le Cancer (Comité de l’Ain), Fondation ARC, and EURACAN (EU project 739521).

11534 Background: Soft Tissue Sarcomas (STS), known for their extensive Genomic instability (GIN), often result in poor clinical outcomes. Grading systems, such as FNCLCC, have limited prognostic accuracy in stratifying metastatic risk for STS patients. We introduce transcription-associated GIN indice (iTRAC) to improve prognostic precision and guide treatment decisions. Methods: This study analyzed 226 STS tumor samples using RNA sequencing (RNAseq) to assess breakpoint distribution from fusion transcripts as a surrogate for GIN. We calculated iTRAC to quantify transcription-associated GIN. Kaplan-Meier survival analysis were used to evaluate prognostic relevance in patients receiving or not chemotherapy. Multivariate analysis was performed to evaluate the iTRAC compared to FNCLCC and CINSARC for metastatic risk stratification. Results: STS patients with medium iTRAC level had the poorest metastasis-free survival (MFS) compared to low and high iTRAC levels. Importantly, patients with low iTRAC have a poorer outcome when treated with chemotherapy than those untreated, but at the contrary patients with medium iTRAC and treated by chemotherapy have a better outcome, raising the question of the potential predictive value of iTRAC for adjuvant chemotherapy in STS patients. FNCLCC and CINSARC groups did not show significant difference in MFS between treated and not treated patients. Conclusions: iTRAC is a novel biomarker for stratifying metastatic risk and guiding personalized treatment in STS. It outperforms molecular and histological prognosis systems like CINSARC and FNCLCC grade by revealing distinct MFS between patients receiving or not chemotherapy. This could enable better identification of patients who may benefit from chemotherapy and alternative options for those with poor responses. Prospective clinical trials are needed for validation and integration for patients care.

(1) Background: Genomic Instability (GIN) plays a critical role in cancer progression and treatment response. Soft tissue sarcomas (STS), are characterized by high levels of chromosomal rearrangements and transcription-associated stress, both of which contribute to poor clinical outcomes. Current standard grading systems, such as FNCLCC, are limited in prognostic accuracy for STS, necessitating novel approaches for risk stratification and treatment guidance. To address this gap, we developed a holistic classifier, the MAGIC (Mixed transcription- and replication-associated GIN classifier), combining transcription- and replication-related GIN indices (iTRAC and iRACIN) to predict metastatic risk. (2) Patients and Methods: This study utilized RNA sequencing (RNAseq) on 226 STS tumor samples to analyze fusions transcripts break points (BP) distribution and assess GIN. We computed MAGIC indices iTRAC and iRACIN, which are based on chromosomal instability linked to transcription and replication processes, respectively. iTRAC biomarker was evaluated against FNCLCC and CINSARC for metastatic risk stratification. Kaplan-Meier and iPART analyses were used to determine the prognostic relevance of iTRAC levels. (3) Results: iTRAC significantly stratified patients with distinct metastatic outcomes, outperforming FNCLCC and CINSARC grading systems. STS patients with medium level of iTRAC showed the poorest metastasis-free survival. Patients classified as iTRAC high- and low-risk groups, achieved better prognosis. Furthermore, iTRAC stratified patients' metastatic risk in treated and not treated patients, indicating poorer prognosis with chemotherapy in patients with low iTRAC and better for those with with medium iTRAC. (4) Conclusion(s): iTRAC demonstrates a superior prognostic utility in STS over current grading systems, effectively stratifying metastatic risk for patients who might benefit from alternative therapeutic strategies. iTRAC holds potential for personalizing chemotherapeutic approaches, paving the way for a new precision oncology approach in STS. ### Competing Interest Statement Ataaillah Benhaddou is a founder of Magic Genomix, which co-owns a patent application (PCT/EP2021/085491) related to the MAGIC method. Frederic Chibon is a consultant for Magic Genomix ### Funding Statement This work was supported by Region Occitanie, INCa (Institut National du Cancer), Inserm, Inserm Transfert, IUCT/ICR (Institut universitaire de cancerologie de Toulouse/Institut Claudius Regaud). We thank these institutions for their financial and strategic support of this research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The samples used in this study are part of the Biological Resources Center of Bergonie Cancer Institute (CRB-IB). Accordance with the French Public Health Code (articles L. 1243-4 and R. 1243-61), the CRB-IB has received the agreement from the French authorities to delivered samples for scientific research (number AC-2008-812). The samples come from care and are re-qualified for research as part of the ICGC program (International Cancer Genome Consortium), with patient consent. The project was approved by the Bergonie Institute ethic committee (scientific advisory board). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript

SARCOMA:A PLURAL ENTITY. Sarcoma are a heterogeneous group of 150 different histopathological entities, developed from soft tissues or bone of any anatomical location.Their estimated incidence is around 70 cases for 100 000 people. They can occur in patients of any age, including children, the median age of onset being around 60 years. Most sarcomas are sporadic, since predisposing factors are rare. In France, the treatment of patiens with sarcomas must be carried out, within a center belonging to Netsarc+ networt as soon as a diagnosis is suspected, to offer them a better prognosis, mostly explained by the quality of the surgery, a major prognostic factor in these diseases.

Background: Sarcomas do not belong to the Lynch Syndrome (LS)-tumour spectrum. A growing body literature has reported sarcomas in patients with LS. Clinical and tumour characteristics of these patients remain unknown. Patients and methods: We set up the first national retrospective study, SarcLynch, describing the pathological and clinical characteristics of sarcomas developed in patients with LS. Patients were identified from two national networks and included from 23 centres in France. Results: Eighty-one patients participated in the SarcLynch study. Sixty-seven (83 %) tumours were soft-tissue sarcomas (STS) and 14 (17 %) bone sarcomas. Among STS, 59 (88 %) showed a pleomorphic component, with undifferentiated pleomorphic sarcoma (UPS) (36 %) and pleomorphic rhabdomyosarcoma (pRMS) (21 %) being the most represented subtypes. Sarcoma was the first neoplastic event in 32 patients (40 %). Thirty-two patients (40 %) were carriers of MSH2 germline pathogenic variants. Among patients who underwent an assessment of deficient mismatch repair (dMMR) by immunohistochemistry and/or molecular biology status, 75 % were dMMR by immunohistochemistry and 45 % were microsatellite instability high (MSI-H). Eight patients received immune checkpoint inhibitors and 4 (50 %) exhibited an objective response with 3 complete radiological response including 1 patient with pathological complete response. Duration of response ranged from 6 to 20 months. Conclusions: SarcLynch, the largest multicentric series describing sarcomas developed in patients with LS, revealed an enrichment in patients with pleomorphic sarcomas - especially UPS and pRMS. This finding strongly supports screening for MMR status evaluation in these rare histotypes both for oncogenetic screening and therapeutic interest. Considering an objective response rate of 50 %, access to immunotherapy should be considered in these tumours.

BACKGROUND:Clinical practice guidelines for managing superficial non-dermatofibrosarcoma soft tissue sarcomas (NDSTS) vary depending on surgical margins. This study assessed NDSTS outcomes by margin status and re-excision (RE) in the nationwide NETSARC+ database. METHODS:This retrospective study (MR004-346) of 1773 patients used clinical data from the NETSARC database between 01/01/2010 and 12/30/2017. Analyses focused on local relapse-free survival (LRFS) and overall survival (OS). RESULTS:Pre-surgery, 31 % of patients underwent local staging with imaging, 46 % biopsy, and 17.8 % a reference center multidisciplinary tumor board (MDTB). Initial margin quality was R0, R1, R2, and unknown for 37 %, 36 %, 13 %, and 12.8 % of patients respectively. Univariate analysis positively correlated R0 surgery with preoperative biopsy (p < 0.001), adequate local imaging for tumors ≥ 5 cm (p < 0.009), case discussion within a NETSARC+ MDTB (p < 0.001), and tumor size< 5 cm (p < 0.001). Reference network surgery resulted in higher proportions of R0 margins (p < 0.001). Re-excision (RE) was performed in 9.7 %, 63 %,79 %, and 34 % of patients following initial surgery with R0, R1, R2, and unknown margins, respectively. Multivariate analysis identified several poor LRFS prognostic factors: size ≥ 5 cm (HR=1.47, p = 0.002), angiosarcoma (HR=2.95, p < 0.001), surgery outside a NETSARC network (HR=1.61, p = 0.003), old age (p < 0.001), and no final R0 margin (HR=2.60, p < 0.001). Multivariate analysis identified several poor OS prognostic factors: angiosarcoma (HR=2.03, p = 0.065), trunk/head and neck site (HR=1.57, p = 0.004), grades 2 and 3 (respectively HR=2.21, p = 0.039 and HR=4.35, p < 0.001), age (p < 0.001), and no final R0 margins (HR=2.02, p < 0.001). CONCLUSION:Sarcoma clinical practice guideline compliance was associated with better surgery quality, reduced local relapse rates, and improved survival.

Metastatic osteosarcoma (MOS) has a poor prognosis, and few treatment options. This multicentre observational study provides real-world data on treatment patterns of patients with MOS in France. The primary objective was to describe treatment modalities of patients with MOS aged ≥12 years treated in 11 reference network centers. Secondary objectives were to assess time to next treatment (TTNT), overall survival (OS) and prognostic factors for TTNT and OS. From 2008 to 2018, 262 patients with MOS were included; 88 patients were metastatic at diagnosis, and 174 patients had a metastatic relapse. Median age at diagnosis was 26 (12-86). A total of 227 (86.6%) patients received systemic treatment in the metastatic setting, and 75 (28.6%) patients received more than two lines. Overall, 153 (58.4%) patients underwent at least a loco-regional procedure, and 50 patients (19.1%) participated in a clinical trial in the metastatic setting. Median OS from metastasis diagnosis was 21.5 months [95% CI 18.9-27.0], 23.0 months [95% CI 15.0-31.1] in the synchronous cohort, and 21.4 months [95% CI 18.7-29.7] in the metachronous cohort. Median TTNT was 8.2 months [95% CI 6.7-9.9], 5.7 months [95% CI 4.2-7.2], 3.7 months [95% CI 3.0-4.3], and 2.9 months [95% CI 1.8-3.9] in first, second, third, and fourth line. It was 7.6 months [95% CI 5.1-12.5], 6 months [95% CI 3.6-8.7], and 4.8 months [95% CI 2.9-7.5] for tyrosine kinase inhibitors such as regorafenib or cabozantinib in first, second, and third line. In MOS, the benefit of chemotherapy after first line is limited. TKIs show encouraging activity from first line. Inclusion in clinical trials should be prioritized.

The EWSR1::CREM rearranged intra-abdominal malignant epithelioid neoplasm is an emerging tumor, with only a few publications describing it to date. Here, we report two new cases of this highly aggressive tumor, primarily involving the peritoneal surface. The tumors presented as a widespread diffuse peritoneal lesion associated with a 4-cm pelvic mass in a 28-year-old woman (Case 1) and as a 10-cm intra-abdominal mass infiltrating the stomach with multiple hepatic metastases in a 53-year-old woman (Case 2). The tumors shared predominant epithelioid morphology with minimal nuclear polymorphism. One of them additionally harbored spindle and rhabdoid cell populations. Both tumors displayed immunoreactivity for pan-cytokeratins, EMA, and CD99, and variable positivity for MUC4, progesterone and estrogen receptors, pan-NTRK, and synaptophysin. This misleading histology and immunophenotype give rise to a wide spectrum of differential diagnoses and highlight the crucial role of RNA sequencing in diagnostic accuracy and thus in appropriate therapeutic approaches.