Peritoneal mesothelioma (PM) is a rare aggressive cancer with limited therapeutic options upon progression. Two genomic profiling initiatives were launched to implement personalized medicine in rare cancers: the EURACAN molecular profiling and personalized medicine pathway and the France Genomic Medicine 2025 plan (AURAGEN). The aim of this study was to describe initial findings in PM and to compare these approaches in a real-world implementation setting. Herein, we present the results from a cohort of 56 patients with PM. Females represented 55.4% of patients; mean age was 55.9 years. The European (Arcagen) study profiled 26 patients and the AURAGEN platform profiled 42 patients. Genomic sequencing was performed using Foundation Medicine for the Arcagen cohort and whole-genome sequencing (WGS) for the AURAGEN cohort. Arcagen used FFPE tissue or blood depending on material availability, whereas AURAGEN relied on fresh frozen tumor tissue with paired blood (and RNA sequencing when feasible). Both cohorts displayed a predominance of alterations in BAP1, NF2, and CDKN2A/B. One patient with an ALK::STRN fusion was treated with Alectinib. AURAGEN identified a larger number of altered genes overall, while the proportion of therapeutic targets was similar between approaches. In conclusion, comprehensive molecular profiling offers potential therapeutic strategies for PM patients. Panel-based profiling and pan-genomic WGS appear complementary in real-world practice, each with distinct strengths and limitations.

Tenosynovial giant cell tumors (TGCT) are rare, locally aggressive neoplasms causing pain, stiffness, swelling, limited range of motion, and joint degeneration, which can be debilitating. Therapeutic options include surgery or systemic therapy with colony-stimulating factor 1 receptor (CSF-1R) pathway inhibitors. However, many are not amenable to surgery or have high postsurgical recurrence rates. Available systemic therapies require long-term administration and can have burdensome side effects. Emactuzumab is a novel, potent, CSF-1R inhibiting monoclonal antibody with a unique mechanism of action targeting the receptor dimerization interface of the CSF-1R to reduce tumor-associated macrophages and inflammation within the TGCT microenvironment. It is the only short-course, intravenous therapy in development for TGCT. In a phase I study, emactuzumab resulted in robust and durable responses, and a manageable safety profile in patients with TGCT, supporting further research as a treatment option to address unmet need and improve quality of life in patients with TGCT. TANGENT is a randomized, double-blind, global, phase III study (NCT05417789) to investigate the safety and efficacy of intravenous emactuzumab versus placebo in patients with TGCT not amenable to surgery.Clinical trial registration: www.clinicaltrials.gov identifier is NCT05417789 initially registered on 1 June 2022.

11570 Background: Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft-tissue sarcomas frequently associated with neurofibromatosis type 1 (NF1). Prospective trials are scarce, and prognostic factors and treatment effects remain incompletely defined. Methods: We conducted a retrospective observational cohort study of 200 patients (215 tumor episodes) with histologically confirmed MPNST treated at a national sarcoma referral center between 2000 and 2025. Overall survival (OS) and progression-free survival (PFS) were estimated via Kaplan–Meier methods. Multivariable Cox models with multiple imputation (MICE, m=40) were adjusted for clinical factors. Restricted mean survival time (RMST) at 5 years quantified absolute survival differences. Interaction analyses assessed heterogeneity of radiotherapy (RT) effects. Results: Median age was 40 years; 51.5% of patients had NF1. Median OS and PFS were 74.6 and 9.1 months, respectively. NF1-associated MPNST had significantly shorter OS (28.5 vs 141.0m; p=0.012), with a 5-year RMST reduction of 8.5 months (95% CI -15.0 to -2.3; p=0.01). In the multivariable Cox model with multiple imputation, advanced stage (HR 2.28; 95% CI 1.68–3.09; p<0.001), higher FNCLCC grade (HR 1.95; 95% CI 1.39–2.75; p<0.001), NF1 status (HR 1.67; 95% CI 1.11–2.51; p=0.014), central tumor location (HR 1.63; 95% CI 1.02–2.60; p=0.041), and increasing age (HR 1.04 per year; 95% CI 1.02–1.05; p<0.001) were independently associated with inferior OS, whereas female sex was strongly protective (HR 0.43; 95% CI 0.29–0.66; p<0.001). Major biopsy-surgery histologic discordance occurred in 21.6% of cases, and diagnostic delays > 60 days in 28.4%. A significant interaction was observed between RT and surgical margins (p_int=0.028): RT markedly improved OS in R1/R2 resections (HR 0.31, 95% CI 0.16–0.61) and in locally advanced disease, but not after R0 resection. In NF1 patients, imaging-detected tumors had better surgical margins and lower risk of synchronous metastasis despite similar tumor size. Conclusions: MPNST outcomes remain poor, particularly in NF1. Radiotherapy confers a clear survival benefit in high-risk surgical contexts. Optimizing diagnostic pathways, especially in NF1 patients, may improve outcomes. Survival Predictors (Multivariable OS) Hazard Ratio (95% CI) p-value Stage 2.28 (1.68–3.09) <0.001 FNCLCC Grade 1.95 (1.39–2.75) <0.001 NF1-associated 1.67 (1.11–2.51) 0.014 Central Location 1.63 (1.02–2.60) 0.041 Female Sex 0.43 (0.29–0.66) <0.001 RT Benefit in R1/R2 Resection 0.31 (0.16–0.61) 0.001

11505 Background: Afamitresgene autoleucel (afami-cel) is a melanoma-associated antigen A4 (MAGEA4)-directed genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating lentiviral vector (LV) expressing an affinity-enhanced T cell receptor (TCR) specific for the human MAGE-A4. Here we report the pooled results of afami-cel in phase 1 and phase 2 trials in patients (pts) with advanced (unresectable/metastatic) synovial sarcoma (SyS). Methods: Pts who were HLA-A*02 positive with previously treated, advanced SyS positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The pooled analyses evaluated overall response rate (ORR) per RECIST v1.1 by investigator review, duration of response (DoR), ORR in sub-populations, overall survival (OS), safety and pharmacokinetics. Results: As of May 2025, 153 pts with advanced SyS received afami-cel (1.00 –9.99×10 9 MAGE-A4 TCR positive T cells). The median age was 40 years (range: 13–76 years), 54% of pts were male, and 86% of pts were white. The median MAGE-A4 expression by H-score was 256.0 (range: 60–300). All pts received prior anthracycline and/or ifosfamide therapy and received a median of 2 prior lines of therapy (range: 1–12). ORR by investigator review was 43.8% (95% CI 35.8, 52.0). Responses were observed across all subgroups, including pediatric SyS pts. The median DoR was 7.1 months (95% CI 4.7, 10.6) and ranged from 1 to 58+ months. Median OS was 18.7 months (95% CI: 14.1, 22.5) with 44% of pts censored at the data cut-off. The 12-month or longer and 24-month or longer OS probabilities were 64.4% and 40.5%, respectively. Among the 67 pts who had a RECIST response, the median OS was 37.5 months (95% CI 26.3, 50.5). The most common any-grade non-laboratory TEAEs (≥20% of pts) were cytokine release syndrome (CRS) (73.2%), nausea (64.1%), fatigue (45.8%), pyrexia (33.3%), vomiting (29.4%), constipation (28.1%), diarrhea (27.1%), headache (26.8%), and cough (20.9%). The most common Grade ≥3 laboratory TEAEs (≥20% of pts) were lymphopenia, neutropenia, leukopenia, and anemia. Afami-cel persisted long-term, including >3 years. Conclusions: To the best of our knowledge, this is the largest dataset of T-cell therapy treated pts with advanced SyS. The magnitude of ORR supported by DOR demonstrated with afami-cel treatment is considered clinically meaningful in this rare pt population with a poor prognosis and limited effective therapies. CRS and cytopenias were common and manageable. Pts with advanced SyS treated with afami-cel had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 , NCT03132922

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.

OBJECTIVE:The efficacy of adjuvant chemotherapy (AC) in improving survival for patients with sarcoma is debated. We performed a cost-effectiveness analysis (CEA) comparing AC vs. no AC for non-metastatic sarcoma based on the nationwide retrospective study DEEPSARC. METHODS:The CEA was carried out over a 1-, 3-, and five-year horizon, using data from the French NETSARC+ database linked to the French national health data system (SNDS).There was no age limit and no specific histological type selection in the reference case analysis. Costs (expressed in 2021 EUR) were provided by the SNDS from the French national health insurance perspective. Incremental cost effectiveness ratios (ICER) were expressed in cost per life-year gained (LYG). Propensity score analysis with 1:1 matching was undertaken. Sensitivity and subgroup analyses were performed. RESULTS:Of the 33,548 patients from the French NETSARC+ database, 24,539 were linked to the SNDS. A total of 14,808 patients diagnosed between 2012 and 2017 were included in the reference case analysis with 2,784 patients after propensity score matching. Mean costs (SD) [95% CI] differences per patient between AC and no AC were €12,826 (36,758) [10,883-14,719], €15,706 (49,849) [13,330-18,383], and €16,841 (56,060) [13,590-19,657] at 1, 3, and 5 years, respectively. Mean overall survival differences per patient (in years) were 0.0066 (0.1685) [-0.0021 to 0.0157], -0.0728 (0.9336) [-0.1237 to -0.0229], and -0.1204 (1.3595) [-0.1926 to -0.0475] at 1, 3, and 5 years, respectively. ICER was €1,934,511 [-11,767,351-15,829,959] per LYG at 1 year. AC lagged behind at 3 and 5 years. CONCLUSIONS:In the reference case analysis, AC outperformed its use in terms of outcomes at 1 year, but a high level of willingness to pay would be required for AC to be cost-effective. At 3 and 5 years, AC was deemed to be not cost-effective for patients with non-metastatic sarcoma.

Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft-tissue sarcomas frequently associated with neurofibromatosis type 1 (NF1). Prognostic factors and optimal treatment strategies remain poorly defined. METHODS:Retrospective cohort study including all MPNST patients managed at Centre Léon Bérard (2000-2025). Overall survival (OS) was estimated using Kaplan-Meier and multivariable Cox models with multiple imputation. Transcriptional heterogeneity was explored via bulk RNA sequencing in a tumor subset. RESULTS:The cohort comprised 206 patients and 219 tumor episodes. Median OS was 53.6 months. NF1-associated tumors had inferior OS compared with sporadic tumors (median OS 26.6 vs 141.0 months, p = 0.012), with a 5-year restricted mean survival time (RMST) reduction of 7.6 months (95% CI -13.8 to -1.2; p = 0.025). Independent predictors of worse OS were higher stage (HR 2.37, p < 0.001), FNCLCC grade (HR 1.79, p < 0.001), NF1 status (HR 1.74, p = 0.006), central location (HR 1.75, p = 0.013) and older age (HR 1.41 per 10 years, p < 0.001); female sex was protective (HR 0.46, p < 0.001). Major biopsy-surgical histologic discordance occurred in 21.3% of cases. Radiotherapy showed context-dependent survival associations, with benefit in grade 3 tumors (HR 0.39, p < 0.001), locally advanced disease (HR 0.32, p = 0.003) and after macroscopically incomplete resections (HR 0.34, p = 0.027). Exploratory transcriptomic analysis identified two NF1-independent expression states defined by Schwann-lineage/immune versus proliferative programs. CONCLUSIONS:Outcomes remain poor, particularly in NF1. Discordance supports centralized expert review. Disease extent and anatomical location are major prognostic drivers. Radiotherapy may be beneficial in selected high-risk contexts. The transcriptomic landscape supports hypothesis-generating biomarker development based on tumor-state biology beyond NF1 status alone.

Patients with rare diseases are particularly vulnerable during emergencies due to dependence on specialised care pathways, medicines, and expertise. European Reference Networks (ERNs) for rare and complex diseases have operated since 2017 and were confronted with two major crises: the COVID-19 pandemic and the war in Ukraine. To assess ERN experiences, responses, and preparedness for crisis and disaster situations, we conducted a cross-sectional survey of all 24 ERN coordinators between July and September 2025. Only 2 (8·3%) ERNs reported pre-existing preparedness plans, while 70% lack structured frameworks. Major bottlenecks included patient access to healthcare facilities, drug and device shortages, bed shortage, staff unavailability, and diagnostic service interruption. Our findings highlight the need to formally integrate and mandate ERNs into European health emergency preparedness and response mechanisms. We propose a 10-point global crisis preparedness plan for rare diseases emphasizing cross-border coordination, digital infrastructure, patient education, and integration with national emergency services and non-governmental organizations.

BACKGROUND:Alveolar soft part sarcoma (ASPS) is an ultra-rare sarcoma with limited chemotherapy sensitivity affecting mostly young patients. Tyrosine kinase inhibitors (TKIs) and immunotherapy are therapeutic advances with promising results in this disease. The aim of this study was to describe the characteristics, management and survival of patients with ASPS in France. PATIENTS AND METHODS:The French NETSARC+ database was screened for all adult patients with ASPS managed in French sarcoma centers between 2010 and 2023. RESULTS:Sixty-four patients from 18 centers were analyzed. The 5-year overall survival (OS) of the entire cohort was 87.3 % (95 % CI, 75.0-93.8 %). Fifty-six percent of patients had localized tumors at diagnosis; all were treated surgically, and 47 % received perioperative radiotherapy. With a median follow-up of 91 months, their 5-year OS was 96.3 % (95 % CI, 76.5-99.5 %). Half of the patients experienced metastatic recurrence with a median metastasis-free survival of 87.9 months (95 % CI, 29.6-NE). In patients with metastases, the first-line systemic treatment yielded an overall response rate of 7 %, 26 %, and 40 % for chemotherapy, TKIs, and immunotherapy, respectively. The 5-year OS after metastasis diagnosis was 67.7 % (95 % CI: 50.5-80.0 %). CONCLUSION:Our cohort reinforces existing data on clinical characteristics and demonstrated prolonged survival in both localized and metastatic stages. Among systemic treatments, immunotherapy achieved the highest response rates. We confirmed that ASPS may follow an indolent course in some cases and highlighted recent advances in its management, driven by standardized local treatments in reference centers and innovative systemic therapies.

BACKGROUND:The growing population of cancer survivors is increasingly exposed to the long-term risk of second primary cancers (SPCs), which represents a major source of morbidity and mortality. While current prevention mainly relies on surveillance and screening, pharmacological and immunological strategies may offer opportunities to reduce SPC incidence in selected high-risk populations. METHODS:This narrative review synthesises current evidence on pharmacological prevention strategies for SPCs, including endocrine therapy, aspirin and non-steroidal anti-inflammatory drugs, PARP inhibitors, metformin, GLP-1 receptor agonists, statins, nicotinamide, immune checkpoint inhibitors, cancer vaccines, and microbiome modulation. Evidence from randomised trials, observational studies, translational research, and ongoing clinical trials was reviewed, with particular attention to SPC-specific endpoints, biological rationale, safety, and clinical applicability. RESULTS:The strongest evidence currently supports endocrine therapy for reducing contralateral breast cancer in patients with hormone receptor-positive breast cancer, and aspirin in selected populations such as Lynch syndrome carriers or patients with molecularly defined colorectal cancer. Other repurposed agents, including metformin, statins, GLP-1 receptor agonists, and nicotinamide, remain investigational, with most available data addressing incident cancer, recurrence, or surrogate endpoints rather than SPC prevention specifically. Immunological approaches are emerging as particularly promising strategies. Retrospective studies and exploratory analyses of randomised trials suggest that immune checkpoint inhibitors may reduce the occurrence of new malignancies, while neoantigen-based vaccines, especially in Lynch syndrome, provide an early proof of concept for cancer immunoprevention. CONCLUSIONS:Pharmacological prevention of SPCs is an expanding but remains a heterogeneous field. Current evidence supports a shift from broad chemoprevention toward biologically informed, risk-adapted prevention strategies. Future progress will depend on dedicated SPC-focused trials, biomarker-driven patient selection, long-term safety evaluation, and integration of pharmacological prevention into broader cancer interception programmes.

Abstract Purpose: The phase II/III Brightline-1 trial (NCT05218499) assessed the mouse double minute 2 homolog (MDM2)–p53 antagonist brigimadlin versus standard-of-care doxorubicin as first-line treatment for MDM2-amplified, locally advanced/metastatic dedifferentiated liposarcoma (DDLPS). Patients and Methods: Patients with MDM2-amplified, locally advanced or metastatic, unresectable, progressive, or recurrent DDLPS were eligible. In phase II, patients received oral brigimadlin 30 or 45 mg or intravenous doxorubicin 75 mg/m2 (all once every 3 weeks). Following a preplanned analysis, in phase III patients received brigimadlin 45 mg or doxorubicin 75 mg/m2. The primary endpoint was progression-free survival (PFS) by blinded central independent review. Results: Between April 13, 2022, and August 22, 2023, 148 patients received brigimadlin 45 mg, and 162 received doxorubicin. At data cutoff, the median PFS was 8.4 months with brigimadlin versus 7.2 months with doxorubicin (hazard ratio, 0.79; 95% confidence interval, 0.6–1.06; P = 0.096); the primary endpoint was not met. The confirmed objective response rate was 22.3% with brigimadlin and 8.6% with doxorubicin. The most common grade ≥3 adverse events with brigimadlin were neutropenia (n = 54, 36.7%) and thrombocytopenia (n = 41, 27.9%). Translational analysis demonstrated that brigimadlin activated the TP53 pathway, but no biomarkers predictive of efficacy were identified. Conclusions: Although brigimadlin showed activity in this patient population, the median PFS with doxorubicin was substantially longer than anticipated, and the primary endpoint of PFS was not met. The safety profile of brigimadlin also did not seem to be more manageable than that of doxorubicin. The translational results will guide future clinical investigations of MDM2–p53 antagonists.

11573 Background: Randomized trials of perioperative chemotherapy in high-risk localized extremity/truncal soft tissue sarcoma (etSTS) show modest average survival benefits, leaving uncertainty about which patients derive clinically meaningful benefit. Conventional hazard ratio-based reporting reflects population-level effects but offers limited guidance for individual decisions. Counterfactual approaches, such as the virtual twin framework, enable estimation of patient-specific outcomes under alternative treatment strategies, translating randomized evidence into clinically interpretable absolute benefit measures. Methods: Individual patient data from the ISG-STS 1001 randomized trial in high-risk localized etSTS with updated follow-up were analyzed using a virtual-twin framework with counterfactual predictions to estimate each patient’s outcomes under alternative treatment scenarios: standard epirubicin-ifosfamide (EI) vs histotype-tailored (HT) chemotherapy (proxy for no effective chemotherapy). Patients with myxoid liposarcoma were excluded. Cox proportional hazards models for overall survival (OS) and disease-free survival (DFS) were adjusted for pretreatment covariates. For each patient, counterfactual 5-year OS and DFS probabilities under EI and HT were estimated and individualized absolute treatment effects were defined as the difference between counterfactual predictions. Bootstrap resampling was used to quantify uncertainty and treatment benefit explored across levels of baseline risk and tumor characteristics. Results: The cohort included 218 pts (median follow-up 116 months). In covariate-adjusted models, mean absolute improvement in 5-year OS with EI was 7.5% (95%CI: 4.5%-10.2%). Absolute OS benefit was inversely correlated with Sarculator-predicted 10-year survival, indicating greater benefit among patients with poorer baseline prognoses. Pts in the highest Sarculator-predicted survival quartile (pOS >69%) had a mean 5-year OS benefit of 5.9% (95%CI: 3.5%-9.0%), with 63% achieving ≥5% benefit. In contrast, pts in the lowest predicted survival quartile (pOS <46%) had a mean benefit of 8.7% (95%CI: 5.3%-10.4%), with 98% achieving ≥5% benefit. Benefits varied by histology (undifferentiated pleomorphic sarcoma = 6.6%, leiomyosarcoma = 7.2%, synovial sarcoma = 8.3%, malignant peripheral nerve sheath tumor = 8.9%) and, within each subtype, was inversely correlated with Sarculator-predicted survival. Conclusions: Individualized counterfactual prediction reveals substantial heterogeneity in the absolute benefit of chemotherapy in high-risk localized etSTS, driven by baseline prognostic risk and histology. This framework provides clinically relevant, patient-centered estimates that support risk-adaptive decision-making and clarify chemotherapy benefits across risk groups beyond average trial effects.

Immune checkpoint inhibitors such as anti-PD1 antibodies are essential in cancer therapy. Emerging data suggest that lower doses may be effective and more economical, though further evidence is needed. We conducted a retrospective study at Centre Leon Berard to assess the efficacy and safety of low-dose nivolumab (20 mg every three weeks) in patients with advanced cancer, mainly squamous cell carcinomas (SCC). Between 2023 and 2024, 53 patients were treated, with a median age of 74 years; 39.6% were over 80. Most were male (64%) and had ECOG >1 (69.9%). Primary tumor sites included cutaneous SCC (34%), head and neck SCC (32%), and soft tissue sarcoma (15%). After a median follow-up of 8.3 months, median overall survival was 7.5 months. The objective response rate (ORR) was 20.8% overall, rising to 35.3% in cutaneous SCC and 23.5% in head and neck SCC-comparable to standard-dose nivolumab. Toxicity was manageable: 18.7% experienced immune-related adverse events, with only 3.7% grade 3. Low-dose nivolumab demonstrates encouraging efficacy and tolerability in a frail population, supporting its potential role in resource-limited settings. Prospective trials are warranted to confirm these findings in broader populations. ### Competing Interest Statement Jerome Fayette: Honoraria and consulting for Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Sanofi, Seagen, AstraZeneca, Takeda, Merus NV. Travel and accommodations supported by Merck Sharp & Dohme, Merck Serono. Mehdi Brahmi: Honoraria and consulting for Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Seagen, AstraZeneca, Takeda, Merus NV. Travel and accommodations supported by Merck Sharp & Dohme, Merck Serono. Jean-Yves Blay: Honoraria, consulting, research funding, and travel support from Roche, AstraZeneca, PharmaMar, MSD, BMS, Bayer, Ignyta, Deciphera, GlaxoSmithKline, Novartis, OSE Pharma, Lilly. Isabelle Ray-Coquard: Honoraria, consulting, research funding, and travel support from GSK, MSD, Roche, BMS, AstraZeneca. Pierre Etienne Heudel: Grants and personal fees from Pfizer, Lilly, Daiichi, AstraZeneca, Novartis, Roche, Seagen, Gilead, MSD. Axel De Bernardi: Financial relationships with Chugai, Daiichi-Sankyo, Netris Pharma, Novocure, Servier. Clelia Coutzac: Honoraria and advisory board participation for Amgen, MSD, BMS, Merck Serono, Daiichi Sankyo, AstraZeneca, Pierre Fabre, Servier. Other authors: No conflicts to declare. ### Funding Statement The study was supported and funded by academic grants, NetSARC+ (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS), LYRICAN+ (INCA-DGOS-INSERM 12563), InterSARC+ (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), EURACAN (EC 739521), SHAPEMED, la Fondation ARC, Infosarcome, Ligue de L Ain contre le Cancer, La Ligue contre le Cancer. ### 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: Ethics Committee of the Centre Leon Berard, Lyon, France waived ethical approval for this work in accordance with French regulation MR004. 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 study are available upon reasonable request to the corresponding author. Data include anonymized patient records from the Centre Leon Berard.

Abstract Background Although individual rare and complex diseases (RDs) affect small patient populations, together they impact an estimated 27–36 million people across the European Union. Addressing this major public health challenge has been a long-term priority for the European Union, leading to the establishment of the European Reference Networks (ERNs) in 2017. Main body ERNs are cross-border networks connecting clinical expert centres to share knowledge, improve and harmonise diagnosis and care for patients with rare and complex diseases. Since their inception, 24 ERNs have united 1,606 expert centres across 375 hospitals in all EU Member States and Norway. Their activities span multidisciplinary clinical collaboration, patient-centred governance, education and training, and the development of clinical guidelines. Over 4900 extremely rare or difficult cases have been discussed among experts without requiring the patients to travel abroad when expertise was not available in their own countries. A key factor for this success is the cross-border IT platform - known as the Clinical Patient Management System 2.0 - provided by the European Commission for medical discussions, which enables experts to share patient data, including medical images and lab results, in a secure and protected environment that is fully compliant with all relevant security and data privacy requirements. ERNs have demonstrated resilience in crises such as the COVID-19 pandemic and the war in Ukraine, providing rapid, coordinated responses to sustain care for vulnerable patient groups. The first formal evaluation in 2023 confirmed that more than 95% of member centres met quality standards, underscoring the networks’ maturity and effectiveness. Moving into the next phase, the Joint Action JARDIN (2024–2027) aims to integrate ERNs into national healthcare systems to ensure sustainability and equitable access to high-quality RD care. Conclusions ERNs exemplify European solidarity and innovation in healthcare, transforming how rare disease expertise is shared and applied across borders. Their continued integration into national systems will be pivotal to achieving a truly cohesive European Health Union that delivers improved outcomes for all patients with rare and complex diseases.

Background:Whether adjuvant chemotherapy (AC) improves overall survival (OS) after complete resection in localized soft tissue sarcoma (STS) remains unproven and optional in guidelines. We measured OS in patients with operated non-metastatic STS treated with or without AC in the nationwide exhaustive NETSARC+ registry. Methods:The DEEPSARC project linked the NETSARC+ registry and the French nationwide health data system (SNDS) into a retrospective cohort. Adults with non-metastatic, undergoing primary surgical resection between 2012 and 2017 were included, excluding those with incomplete linkage data or prior neoadjuvant chemotherapy. We analysed the entire series of 8331 patients with successful linkage and a complete-case subset of 4296 patients. Survival with or without AC were compared using crude and multivariate Cox proportional hazards regression models, including adjustment for confounders and inverse probability of treatment weighting (IPTW). Sensitivity analyses and subgroups analysis in high-risk patients were performed. Findings:In the complete-case series, the commonest histotypes were liposarcoma (30%), undifferentiated pleomorphic sarcoma (23%) and leiomyosarcoma (17%). Overall, 389 (9.1%) patients received AC and, compared with those not receiving AC, had fewer comorbidities and presented more high-risk tumour features. With 5.8 years median follow-up, 5-yr OS was 61% (95%CI: 60-63) in the entire series, and 64% (95%CI: 63-66) in the complete-case analysis. 5-yr OS was inferior in patients receiving AC, both in the entire series (50% [47%-54%] vs. 63% [61%-64%]) and in the complete-case analysis (53% [48-59%] vs. 65% [64-67%]). After adjustment (HR = 1.46 [1.12-1.93]) or IPTW (HR = 1.56 [1.17-2.08]), AC remained associated with inferior OS. Findings were consistent across sensitivity and subgroup analyses. Interpretation:In this real-world nationwide study, AC was not associated with superior OS, but rather with an inferior OS in patients operated of a localized STS and did not compensate for the adverse prognostic profile of treated patients. Future research should therefore focus on identifying predictive biomarkers in order to better identify patients who are likely to derive real benefit from systemic treatment. Funding:This work was supported by the Health Data Hub; the Institut National Du Cancer and the French Ministry of Health (Direction Générale de l'Offre de Soins, DGOS) for the NETSARC, RRePS and RESOS networks; the INTERSARC+ program; the Agence Nationale de la Recherche; the LYriCAN+ program; the Ligue Nationale contre le Cancer; the Ligue contre le Cancer (Comité de l'Ain); the Fondation ARC; and the European Reference Network for Rare Adult Solid Cancers.

Chondrosarcoma (ChS) is a rare bone malignancy with heterogeneous behavior, the molecular and immunological background of which remains unknown. No effective systemic treatment for advanced ChS patients is available. The aim of this study was to develop an immune-mutational classification of ChS and to search for novel prognostic factors and molecular targets. We performed an immunological-molecular profiling of 99 patients diagnosed with primary ChS G1-G3 and dedifferentiated ChS. An expression of 20 immune response markers was assessed by IHC and targeted the next-generation sequencing of 409 genes was performed. Immunological and mutational profiles were correlated with overall survival using a multivariate LASSO-penalized Cox model. Three immunophenotypes were described-"cold" (IMP1), "hot" (IMP2), and "intermediate" (IMP3). IMP1 was the most prevalent in G1 cases, while IMP2 was the most prevalent in dedifferentiated cases. IDH1/2 or TP53 mutations were associated with high-grade ChS (FDR < 0.05). IMP2 was characterized by a higher number of immune infiltrates in the central region of the tumor (HR: 3.3; CI: 1.13-9.8; p < 0.05). IDH1 mutations were present most often in IMP2 cases (HR: 3.8; CI: 1.75-8.1; p < 0.001). Tumor size, dedifferentiated subtype, IDH1 mutation and the presence of IMP2 were identified as independent negative prognostic survival factors in ChS. An immune-mutational classification system for ChS patients was proposed, which may be used to identify those potentially suited for immunotherapy combined with IDH-mutant inhibitors in future research.