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Soft tissue sarcomas are a group of rare and aggressive connective tissue neoplasms for which curative therapeutic opportunities are limited in advanced phase. Clinical trials assessing immunotherapy in these tumors have so far reported limited efficacy. The objective of this study is to provide a description of the immunologic landscape of sarcomas to guide the next clinical trials of immunotherapy in these diseases. The gene expression profile of 93 immune checkpoint (ICP) and membrane markers (MM) of immune cells was analyzed in a series of 253 soft tissue sarcoma (synovial sarcoma, myxoid liposarcoma, sarcoma with complex genomic and GIST) using Agilent Whole Human Genome Microarrays. The unsupervised hierarchical clustering of gene expression level was found able to properly group patients according to the histological subgroup of sarcoma, indicating that each sarcoma subgroup is associated with a specific immune signature defined by its gene expression pattern. Using the prognostic impact of CIBERSORT signature on metastatic-free survival in each subgroup, specific target could be proposed for each of the four groups: Treg through ICOS and GITR in GIST, M0 macrophages in all four sarcoma subtypes, OX40 in SS, CD40 in GIST and SS. The immune landscape of sarcoma was found to be as heterogeneous as the histotypes and molecular subtypes, but strongly correlated to the histotype. Histotype adapted immunotherapeutic approaches in each sarcoma subtypes must be considered in view of these results, consistently with the already reported specific response of histotypes of ICPs.

Background: The administration of adjuvant imatinib during 3 years is indicated after resection of primary localized GIST at high risk of recurrence, but many patients relapse afterwards., Methods: IMADGIST (NCT02260505) was a multicenter, open-label, randomized phase III study evaluating the maintenance of imatinib for 3 more years (6-year arm) compared with interruption (3-year arm) from the day of randomization, conducted in the French Sarcoma Group. The primary endpoint was intent-to-treat disease-free survival. Secondary endpoints included overall survival, time to imatinib resistance, response after imatinib reintroduction at relapse, and safety., Results: From 24 December 2014 to 4 April 2023, 136 patients aged ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, with a localized gastrointestinal stromal tumor with an R0 or R1 surgery, and a risk of tumor recurrence ≥35% according to National Comprehensive Cancer Network (NCCN) risk classification were randomized in 14 centers. Sixty-five patients were randomized to the 3-year arm versus 71 to the 6-year arm. There were 68 males and females. Primary sites were gastric and small bowel in 60 (44%) and 64 (47%) patients, respectively. Respectively, 52 (38%) and 71 (52%) patients had a risk of relapse of 35%-70% and >70%. With a median follow-up of 55 months (interquartile range 46-59 months) after randomization, disease-free survival was significantly superior in the 6-year arm [hazard ratio: 0.40 (0.20-0.69), P = 0.0008]. Time to imatinib resistance, survival, adverse events, and quality of life were not different in the two arms., Conclusions: Three additional years of adjuvant imatinib reduces the risk of relapse in patients who have received 3 years of adjuvant imatinib with an acceptable tolerance., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Undifferentiated pleomorphic sarcomas (UPS) represent a prevalent and aggressive subtype of soft tissue sarcomas (STS) in adults. Despite advancements in loco regional treatments, many patients with high grade STS, including UPS, develop metastatic disease. Neoadjuvant chemotherapy is a standard approach to mitigate this risk, but response variability necessitates refined patient selection strategies. This study investigated the correlation between UPS microenvironment and neoadjuvant chemotherapy response in resectable UPS. The NEOSARCOMICS study (NCT02789384) enrolled patients with resectable STS from six sarcoma centers in France. Patients received anthracycline based chemotherapy, followed by surgery. Histological response, gene expression profiling, and multiplex immunohistofluorescence were performed on baseline and post treatment tumor samples. Plasma proteomics was analyzed to identify biomarkers. Good responders to neoadjuvant chemotherapy showed enrichment in genes related to stemness and cell cycle regulation, while poor responders exhibited immune related gene enrichment. Proteomic profiling revealed immune pathway activation and downregulation of cell cycle pathways in non responders. Despite being associated with a good prognosis, high immune infiltration, particularly of CD8 + T cells and CD20 + B cells, predicts a poor response to neoadjuvant chemotherapy in UPS, suggesting the need for alternative therapeutic strategies for patients with inflamed UPS.Ongoing clinical trials are exploring the efficacy of combining chemotherapy with immune checkpoint inhibitors to improve outcomes., (© 2024. The Author(s).)

Background and Aims: Alveolar soft part sarcoma (ASPS) is an ultra-rare chemo-resistant sarcoma in children, occurring preferentially in young adults. We aimed to describe and compare its clinical presentation and behaviour in children and young adults to determine whether the same therapeutic strategy should be addressed for both populations., Methods: National retrospective multicentre study of children (0-18 years) vs. young adults (19-30 years) included in the "ConticaBase" sarcoma database, treated for ASPS between 2010 and 2019 with pathology reviewed via the NETSARC + network., Results: Overall, 45 patients were identified, 19 children (42%) and 26 young adults (58%). All ASPS diagnoses were confirmed with TFE3 rearrangement by immunohistochemistry or FISH. All clinical characteristics were balanced between both populations with frequent metastases at diagnosis (8/19 vs. 10/26). The therapeutic strategy was based on surgery (17/19 vs. 21/26), radiotherapy (8/19 vs. 12/26) ± systemic treatment (8/19 vs. 9/26). In patients with initially localized disease, metastatic relapse occurred only in adults (8/16), whereas metastatic progression was present in both metastatic groups (5/8 vs. 8/10). After a median follow-up of 5.2 years (range, 0.2-12.2), 5-year EFS was 74% [95%CI, 56-96] vs. 47% [30-74] (p = 0.071) respectively, and 5-year OS was 95% [85-100] vs. 85% [70-100] (p = 0.84). For localized tumours, 5-year MFS was 100% [100-100] vs. 60% [39-91] (p = 0.005). The 5-year OS of all patients with metastasis at diagnosis was 80.2% (62.2%-100%)., Conclusions: ASPS appears to have the overall same clinical characteristics, but a more aggressive behaviour in young adults than in children. However, despite frequent metastases at diagnosis, long-term survival is high in both groups. Overall, the same therapeutic strategies may be considered for both populations., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up., Patients and Methods: This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m 2 and CDDP 100 mg/m 2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives., Results: From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16-63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3-4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months., Conclusion: Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial., Methods: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861., Findings: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib., Funding: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis., Competing Interests: Declaration of interests J-YB reports grants from NETSARC+, INTERSARC+, and LYRICAN+ from INCA (to the institution), DEpGyn RHU and LYRICAN+ from the Agence Nationale de la Recherche (to the institution), and ERN EURACAN from the EU commission (to the institution); research support from Novartis, Deciphera, and Bayer (to the institution); membership of steering committees for the Intrigue and Motion studies for Deciphera; and membership of the supervisory boards of Transgène and Innate Pharma. IR-C reports research grants from Bristol Myers Squibb (BMS); consulting fees from and participation on data safety boards of Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis, Daiichi Sankyo, Deciphera, Eisai, EQRX, GSK, MacroGenics, Merck Serono, Mersana, MSD, Novartis, Onxeo, Roche, and Sutro Biopharma. NP reports research grants from Bayer. DP reports travel grants from Roche and Novartis. ALC reports honoraria from Deciphera and Pharmamar. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: To better understand the importance of the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and human leukocyte antigen (HLA) subtypes in treatment decision-making, further investigation of their prevalence and prognostic impact among patients with metastatic synovial sarcoma (mSS) is needed., Patients and Methods: This was a retrospective clinico-biological cohort study of adults with mSS. Patient data were collected from the French Sarcoma Group NetSARC database and supplemented by electronic medical records. Primary tumor samples were collected and analyzed for NY-ESO-1 expression by immunohistochemistry (IHC) and HLA-A∗02 status by RNA sequencing (RNA-seq). The primary cohort included patients with available primary tumor samples; the impact of a larger sample size was explored by including patients who had either a primary or metastatic sample (termed the exploratory cohort). P values are provided for descriptive purposes., Results: In 92 patients with primary tumor samples, ∼25% (n = 23) were positive for NY-ESO-1 and HLA-A∗02 expression (dual positive). Among 106 patients with IHC data, 61% (n = 65) were NY-ESO-1 positive, and among 94 patients with RNA-seq data, 45% (n = 42) were HLA-A∗02 positive. The median overall survival (OS) for positive versus negative NY-ESO-1 status was 35.3 and 21.7 months, respectively (unadjusted P = 0.0428). We observed no difference in median OS for HLA-A∗02-positive versus -negative and dual-positive patients versus others (both unadjusted P > 0.05). Multivariate analyses of OS showed no prognostic impact for NY-ESO-1 among primary tumor samples and in the exploratory cohort. However, in the latter we observed an association between NY-ESO-1 expression and OS in the first-line (P = 0.0041) but not in the second-line setting., Conclusions: The primary tumor cohort showed no association between NY-ESO-1 expression and OS (including stratification by HLA-A∗02 subtype and treatment line) when adjusting for important prognostic factors, possibly due to small sample sizes., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value., Methods: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2)., Results: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%)., Conclusions: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Our objective was to capture subgroups of soft-tissue sarcoma (STS) using handcraft and deep radiomics approaches to understand their relationship with histopathology, gene-expression profiles, and metastatic relapse-free survival (MFS). We included all consecutive adults with newly diagnosed locally advanced STS (N = 225, 120 men, median age: 62 years) managed at our sarcoma reference center between 2008 and 2020, with contrast-enhanced baseline MRI. After MRI postprocessing, segmentation, and reproducibility assessment, 175 handcrafted radiomics features (h-RFs) were calculated. Convolutional autoencoder neural network (CAE) and half-supervised CAE (HSCAE) were trained in repeated cross-validation on representative contrast-enhanced slices to extract 1024 deep radiomics features (d-RFs). Gene-expression levels were calculated following RNA sequencing (RNAseq) of 110 untreated samples from the same cohort. Unsupervised classifications based on h-RFs, CAE, HSCAE, and RNAseq were built. The h-RFs, CAE, and HSCAE grouping were not associated with the transcriptomics groups but with prognostic radiological features known to correlate with lower survivals and higher grade and SARCULATOR groups (a validated prognostic clinical-histological nomogram). HSCAE and h-RF groups were also associated with MFS in multivariable Cox regressions. Combining HSCAE and transcriptomics groups significantly improved the prognostic performances compared to each group alone, according to the concordance index. The combined radiomic-transcriptomic group with worse MFS was characterized by the up-regulation of 707 genes and 292 genesets related to inflammation, hypoxia, apoptosis, and cell differentiation. Overall, subgroups of STS identified on pre-treatment MRI using handcrafted and deep radiomics were associated with meaningful clinical, histological, and radiological characteristics, and could strengthen the prognostic value of transcriptomics signatures., (© 2024. The Author(s).)

Background: We investigated the impact of the implementation of a network of reference centers for sarcomas (NETSARC) on the care and survival of sarcoma patients in France since 2010., Patients and Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTBs), funded by the French National Cancer Institute (INCa) since 2010. Its aims are to improve the quality of diagnosis and care of sarcoma patients. Patients' characteristics, treatments, and outcomes are collected in a nationwide database. The objective of this analysis was to compare the survival of patients in three periods: 2010-2012 (non-exhaustive), 2013-2015, and 2016-2020., Results: A total of 43 975 patients with sarcomas, gastrointestinal stromal tumors (GISTs), or connective tissue tumors of intermediate malignancy were included in the NETSARC+ database since 2010 (n = 9266 before 2013, n = 12 274 between 2013 and 2015, n = 22 435 in 2016-2020). Median age was 56 years, 50.5% were women, and 13.2% had metastasis at diagnosis. Overall survival was significantly superior in the period 2016-2020 versus 2013-2015 versus 2010-2012 for the entire population, for patients >18 years of age, and for both metastatic and non-metastatic patients in univariate and multivariate analyses (P < 0.0001). Over the three periods, we observed a significantly improved compliance to clinical practice guidelines (CPGs) nationwide: the proportion of patients biopsied before surgery increased from 62.9% to 72.6%; the percentage of patients presented to NETSARC MDTBs before first surgery increased from 31.7% to 44.4% (P < 0.0001). The proportion of patients with R0 resection on first surgery increased (from 36.1% to 46.6%), while R2 resection rate decreased (from 10.9% to 7.9%), with a better compliance and improvement in NETSARC centers., Conclusions: The implementation of the national reference network for sarcoma was associated with an improvement of overall survival and compliance to guidelines nationwide in sarcoma patients. Referral to expert networks for sarcoma patients should be encouraged, though a better compliance to CPGs can still be achieved., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781., (© 2024. The Author(s).)

Background: Missing covariates are common in observational research and can lead to bias and loss of statistical power. Limited data regarding prognostic factors of survival outcomes of sarcomas in irradiated fields (SIF) are available. Because of the long lag time between irradiation of first cancer and scarcity of SIF, missing data are a critical issue when analyzing long-term outcomes. We assessed prognostic factors of overall (OS), progression-free (PFS), and metastatic-progression-free (MPFS) survivals in SIF using three methods to account for missing covariates., Methods: We relied on the NETSARC French Sarcoma Group database, Cox (OS/PFS), and competitive hazards (MPFS) survival models. Covariates investigated were age, sex, histological subtype, tumor size, depth and grade, metastasis, surgery, surgical resection, surgeon's expertise, imaging, and neo-adjuvant treatment. We first applied multiple imputation (MI): observed data were used to estimate the missing covariate. With the missing-data modality approach, a category missing was created for qualitative variables. With the complete-case (CC) approach, analysis was restricted to patients without missing covariates., Results: CC subjects ( N = 167; 33%) presented more often with soft-tissue sarcoma ( versus visceral sarcoma) and grade I-II tumors as compared to the 504 eligible cases. With MI ( N = 504), factors associated with the worst outcome included metastasis ( p = 0.04) and R1/R2 resection ( p < 0.001) for OS; higher grade/non-gradable tumors ( p = 0.002) and R1/R2 resection ( p < 0.001) for PFS; and metastasis ( p = 0.01) for M-PFS. The 'missing-data modality' approach ( N = 504) led to different associations, including significance reached due to variables with the modality 'missing'. The CC analysis led to different results and reduced precision., Conclusion: The CC population was not representative of the eligible population, introducing bias, in addition to worst precision. The 'missing-data modality method' results in biased estimates in non-randomized studies, as outcomes may be related to variables with missing values. Appropriate statistical methods for missing covariates, for example, MI, should therefore be considered., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Sclerosing Epithelioid Fibrosarcoma (SEF) and Low Grade Fibromyxoid Sarcoma (LGFMS) are ultrarare sarcomas sharing common translocations whose natural history are not well known. We report on the nationwide exhaustive series of 330 patients with SEF or LGFMS in NETSARC+ since 2010., Patients and Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB). Since 2010, (i) pathological review has been mandatory for sarcoma,and (ii) tumour/patients' characteristics have been collected in the NETSARC+ nationwide database. The characteristics of patients with SEF and LGFMS and their outcome are compared., Results: 35/73 (48%) and 125/257(49%) of patients with SEF and LGFMS were female. More visceral, bone and trunk primary sites were observed in SEF (p < 0.001). 30% of SEF vs 4% of LGFMS patients had metastasis at diagnosis (p < 0.0001). Median size of the primary tumor was 51 mm (range 10-90) for LGFMS vs 80 (20-320) for SEF (p < 0.001). Median age for LGFMS patients was 12 years younger than that of SEF patients (43 [range 4-98] vs 55 [range 10-91], p < 0.001). Neoadjuvant treatment was more often given to SEF (16% vs 9%, p = 0.05). More patients with LGFMS were operated first in reference centers (51% vs 26%, p < 0.001). The R0 rate on the operative specimen was 41% in LGFMS vs 16% in SEF (p < 0.001). Median event-free survival (EFS) of patients with SEF and LGFMS were 32 vs 136 months (p < 0.0001). The median overall survival (OS) was not reached. Fifty-months OS was 93% vs 81% for LGFMS vs SEF (p = 0.05). Median OS was 77 months after first relapse, similar for SEF and LGFMS. In multivariate analysis, age, tumor size, metastasis at diagnosis were independent prognostic factors for OS in LGFMS., Conclusions: Although sharing close molecular alterations, SEF and LGFMS have a different natural history, clinical presentation and outcome, with a higher risk of metastatic relapse in SEF. Survival after relapse is longer than with other sarcomas, and similar for SEF and LGFMS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Epithelioid Hemangioendothelioma: A NATIONWIDE STUDY: Epithelioid hemangioendothelioma (EHE) is an ultrarare sarcoma whose natural history and treatment is not well defined. We report on the presentation and outcome of 267 patients with EHE in the NETSARC+ network since 2010 in France., Patients and Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centres with specialised multidisciplinary tumour boards (MDTB), funded by the French National Cancer Institute (NCI), Institut National du Cancer (INCA). Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients. Patients' characteristics are collected in a nationwide database regularly monitored with stable incidence since 2013. The characteristics of patients with EHE at diagnosis are presented as well as progression-free survival (PFS), overall survival (OS), and outcome under treatment., Results: Two hundred and sixty-seven patients with EHE were included in the NETSARC+ database since 2010. Median age in the series was 51 (range 10-90) years, 58% were women. Median tumour size was 37 mm (4-220). Forty-eight percent, 42%, and 10% were visceral, soft parts, or bone primaries. The most frequent sites were liver (28%), lung (13%). 40% were reported to have systemic (i.e. multifocal or metastatic disease) at diagnosis. With a median follow-up of 20 months, OS and PFS rates at 24 months were 82% and 67%, with 10-year projected OS and PFS of 62% and 21% respectively. Male and M+ patients at diagnosis had a significantly worse OS, but not PFS. Local treatment was associated with a favourable survival in localised but not in patients with advanced stage at diagnosis. For 23 patients receiving medical treatment, PFS and OS were 50.2% and 33.2% at 60 months were respectively., Conclusions: EHE is a frequently metastatic sarcoma at diagnosis with a unique natural history. This study shows in a nationwide series over 12 years that most patients progressed but are still alive at 10 years, both in localised and metastatic stages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic was an unprecedented shock to the healthcare systems, and its consequences on managing rare cancers are unknown. We investigated COVID-19's impact on the activity of sarcoma-labeled networks by comparing key indicators in 2019-2020 (before and during the pandemic, respectively)., Methods: We compared the incidence of limb and trunk soft tissue sarcomas, surgery rate, surgery center, surgery quality, and surgery delays nationally and in various regions, focusing on the three most severely affected regions., Findings: In this study, sarcoma incidence did not decrease, and the tumor and patient characteristics were similar in both years. The number of patients who underwent surgery in the labeled centers increased significantly (63% versus 57%, p = 0.015), the rate of R0 resection increased (55% versus 47%, p = 0.004), and the rate of re-excision decreased (12% versus 21%, p < 0.0001). In the univariate analysis, the time to surgery was similar in both years. Cox regression analysis revealed that the factors associated with a longer time to surgery were age > 70 years ( p = 0.003), retroperitoneal location ( p > 0.001), tumor size ( p < 0.001), deep tumors ( p < 0.001), and regions ( p < 0.001). However, we have observed an increase in the time before surgery in the regions most stroked by the COVID-19 pandemic., Interpretation: The model of the labeled center network for managing rare tumors was resilient. Paradoxically, the quality indicators improved during the pandemic due to the direct referral of patients with sarcomas to the labeled centers., Summary: This study shows that a nationwide network organization has made it possible to maintain care for these rare tumors during the pandemic., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors characterized by KIT or PDGFRA mutations. Over three decades, significant changes in drug discovery and loco-regional (LR) procedures have impacted treatment strategies. We assessed the evolution of treatment strategies for metastatic GIST patients treated in the three national coordinating centers of NetSarc, the French network of sarcoma referral centers endorsed by the National Institute of Cancers, from 1990 to 2018. The primary objective was to describe the clinical and biological profiles as well as the treatment modalities of patients with metastatic GIST in a real-life setting, including access to clinical trials and LR procedures in the metastatic setting. Secondary objectives were to assess (1) patients' outcome in terms of time to next treatment (TNT) for each line of systemic treatment, (2) patients' overall survival (OS), (3) evolution of patients' treatment modalities and OS according to treatment access: <2002 (pre-imatinib approval), 2002-2006 (pre-sunitinib approval), 2006-2014 (pre-regorafenib approval), post 2014, and (4) the impact of clinical trials and LR procedures on TNT and OS in the metastatic setting. 1038 patients with a diagnosis of GIST made in one of the three participating centers between 1990 and 2018 were included in the national prospective database. Among them, 492 patients presented metastasis, either synchronous or metachronous. The median number of therapy lines in the metastatic setting was 3 (range 0-15). More than half of the patients (55%) participated in a clinical trial during the course of their metastatic disease and half (51%) underwent additional LR procedures on metastatic sites. The median OS in the metastatic setting was 83.4 months (95%CI [72.7; 97.9]). The median TNT was 26.7 months (95%CI [23.4; 32.3]) in first-line, 10.2 months (95%CI [8.6; 11.8]) in second line, 6.7 months (95%CI [5.3; 8.5]) in third line, and 5.5 months (95%CI [4.3; 6.7]) in fourth line, respectively. There was no statistical difference in OS in the metastatic setting between the four therapeutic periods (log rank, p = 0.18). In multivariate analysis, age, AFIP Miettinen classification, mutational status, surgery of the primary tumor, participation in a clinical trial in the first line and LR procedure to metastatic sites were associated with longer TNT in the first line, whereas age, mitotic index, mutational status, surgery of the primary tumor and LR procedure to metastatic sites were associated with longer OS. This real-life study advocates for early reference of metastatic GIST patients to expert centers to orchestrate the best access to future innovative clinical trials together with LR strategies and further improve GIST patients' survival.

The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P = .18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P = .013) and tumor site (P < .001); pain was more frequent in the neck and shoulder locations (odds ratio: 3.05 [1.27-7.29]). Pain at baseline was significantly associated with poor quality of life (P < .001), depression (P = .02), lower performance status (P = .03) and functional impairment (P = .001); we also observed a nonsignificant association with anxiety (P = .10). In the univariate analysis, baseline pain was associated with poor EFS; the 3-year EFS was 54% in patients with pain compared to 72% in those without pain. After adjustment for sex, age, size and line of treatment, pain was still associated with poor EFS (hazard ratio: 1.82 [1.23-2.68], P = .003). One third of recently diagnosed patients with DF experienced pain, especially those with larger tumors and neck/shoulder locations. Pain was associated with unfavorable EFS after adjustment for the confounders., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)