Institut Curie

Aims In this study, we explore whether neoadjuvant chemotherapy influences the surgical resection strategy devised by surgeons for high-grade soft-tissue sarcoma. Methods A total of 12 experienced soft-tissue sarcoma surgeons rated patients who underwent neoadjuvant chemotherapy for a soft-tissue sarcoma of the thigh. Cases were randomly assigned to surgeons, such that each surgeon rated three out of the 12 cases, and each case was rated by three out of 12 surgeons (n = 36 ratings before and after chemotherapy). Surgeons were asked which surgical technique they would use: amputation; and if not, resection or dissection of critical anatomical structures in close proximity to the tumour (sciatic nerve, femoral artery, and femur). Pre- and post-chemotherapy ratings were then compared to test if chemotherapy changed the surgery aggressiveness anticipated by the surgeons. Results Tumour volume increased in 9/12 cases (75%). Ratings as amputation were discordant in 5/36 cases (14%) before and after chemotherapy. The surgical technique planned by surgeons before and after chemotherapy regarding critical anatomical structures were discordant in five (14%), eight (22%), and six of 36 ratings (17%) for the sciatic nerve, the femoral artery, and the femur, respectively. Overall, a similarly aggressive surgery was planned by surgeons in nine, six, and eight cases for the sciatic nerve, the femoral artery, and the femur, respectively, which is significantly more than that expected due to chance alone. A more aggressive surgery was anticipated in five of 36 cases (14%). Conclusion Despite tumour growth being observed in 75% of cases, the surgical resection strategy devised after neoadjuvant chemotherapy remained notably similar to the one devised prior to neoadjuvant chemotherapy for critical anatomical structures. However, ‘switchers’, namely patients identified as being at risk of needing an amputation if the tumour experiences slight growth, should undergo conservative surgery initially, followed by chemotherapy. Cite this article: Bone Jt Open 2025;6(5):553–559.

The survival rate for high-risk neuroblastoma remains below 50%. Current monitoring methods are costly, invasive, and stressful for patients. MONALISA will evaluate liquid biopsies as a minimally invasive alternative, to enable frequent sampling and consequently early detection of genetic tumour markers. MONALISA leverages an advanced privacy-preserving data management infrastructure, including the SIOPEN BIOPORTAL, the EUPID Services, and patient reported outcome measures, providing a model for other paediatric cancers.

CD8⁺ T cells shape the antitumor immune response. Here, we evaluated CD8⁺ T cells expressing different levels of PD-1, their functional status, and distribution in different tissues of luminal breast cancer (BC) patients. We characterized the exhaustion stages of CD8⁺ T cells in tumors, juxtatumoral tissues (JTs), and tumor-draining lymph nodes (TDLNs). Terminal exhausted CD8⁺ T cells (PD-1High CD8⁺) were predominant in tumors and nearly absent in other tissues. However, in all tissues evaluated, most CD8⁺ T cells exhibited a pre-exhausted phenotype (PD-1Int CD8⁺) or did not express PD-1. PD-1High and PD-1Int CD8⁺ T cells from tumors and JTs presented central and effector memory phenotypes, while in TDLNs were primarily central memory. TCR-β sequencing revealed higher clonality among CD8⁺ T cells from tumor than TDLNs, with tumor-enriched clones also detected in TDLNs. Analysis of scRNA-seq datasets from tumors and JTs of colorectal and non-small cell lung cancer patients, identified a CD8⁺ terminal exhaustion and a CD8⁺ pre-exhausted signatures. High expression of exhaustion-associated genes in BC tumors correlated with improved overall survival. Overall, PD-1 expression effectively distinguishes exhaustion stages in CD8⁺ T cells. PD-1Int cells found in tumors, JTs, and TDLNs represent a promising therapeutic target for cancer immunotherapy.

Young breast cancer patients with germline radiosensitivity mutations, such as in TP53 and ATM, face an increased risk of radiation-induced toxicities and secondary malignancies. Proton therapy offers dosimetric advantages by reducing the radiation exposure of healthy tissues, potentially mitigating these risks. However, clinical data on the use of proton therapy in this specific population are limited. We conducted a single-center retrospective study in patients with non-metastatic breast cancer with germline TP53 or ATM mutations treated with intensity-modulated proton therapy (IMPT) at the Institut Curie Proton Therapy Center between June 2019 and November 2024. Patient demographics, treatment characteristics, and toxicity profiles were analyzed. Acute and late toxicities were graded according to CTCAE v5.0. Survival outcomes were calculated from the date of histological diagnosis. Four young patients (median age 25 years; range 24–29) with TP53 (n = 2) or ATM (n = 2) mutations received IMPT targeting the chest wall and regional lymph nodes. All patients had hormone receptor-positive, node-positive breast cancer; one patient was also HER2 positive. Treatments included chemotherapy, surgery, and adjuvant hormonal therapy; three patients received additional targeted therapies. The median mean heart dose was 1.25 Gy (range 0.5–1.5 Gy). One patient experienced acute grade 2 radiodermatitis, while two patients had grade 1 radiodermatitis. After a median follow-up of 18 months (range 11–49 months), one patient exhibited persistent grade 1 skin pigmentation. No other late toxicities, including cardiac or pulmonary complications, were observed. There were no secondary malignancies or recurrences, resulting in 100% overall and recurrence-free survival. Proton therapy was well tolerated in this small cohort of young breast cancer patients with germline TP53 or ATM mutations, demonstrating minimal acute toxicity and no significant late effects over a median follow-up of 18 months. These preliminary findings suggest that proton therapy may be a safe treatment option for this high-risk population. Larger studies with extended follow-up are necessary to confirm these results and to inform clinical guidelines.

Background Based on results of randomized clinical trials, polyADP-ribose polymerase inhibitors (PARPi) have become the standard of care in patients with platinum-sensitive recurrent ovarian cancer (OvC) in patients responding to platinum chemotherapy. However, little is known about their impact on survival in a real-world setting. Patients and methods This retrospective French multicenter observational study included women with platinum-sensitive recurrent OvC (not limited to the first platinum-sensitive relapse) receiving PARPi as maintenance after response to platinum-based chemotherapy. They were compared to patients with similar characteristics undergoing observation after chemotherapy completion. Data were collected in the Ovarian Cancer Epidemiological Strategy and Medical Economics (ESME-OC) database between 2011 and 2021. We explored progression-free survival (PFS) and overall survival (OS) benefits with PARPi maintenance. Results One hundred and twenty-three patients matching the selection criteria were included in the PARPi group and 397 patients in the control group. Median PFS was 19.9 months (95CI [15.0-21.9]) in the PARPi group vs 13.4 months (95CI [11.8-15.0]) in the control group, with a HR = 0.71 (95CI [0.55-0.93]), P = .01). Median OS was 82.0 months (95CI [48.6-Not Estimable]) in the PARPi group vs 44.7 months (95CI [38.8-53.7]) in the control group (HR = 0.47, 95CI [0.30-0.74], P < .001). Multivariate analyses including performance status, histological subtype, achievement of cytoreductive surgery at relapse, and platinum-free interval, confirmed the independent prognostic impact of PARPi treatment. Conclusion This first national study focusing on the efficacy of PARPi in a real-world population shows similar benefits than in randomized clinical trials, supporting their use in clinical routine practice. Database registration clinicaltrials.gov Identifier NCT03275298.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis¹. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2, 3–4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work⁵. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron—fentomycin-1—to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states¹⁰.

Background Isolated nodal recurrence (INR) after localized breast cancer is rare, with an incidence of less than 1%. Curative management typically includes surgical resection, often with axillary lymph node dissection (ALND), followed by regional nodal radiotherapy. However, evidence-based guidelines remain limited due to the rarity of this clinical scenario. The aim of this study was to evaluate survival determinants and the acute and long-term toxicities associated with second-course regional nodal irradiation as part of curative strategies for INR after localized breast cancer. Materials and methods This retrospective study included 11 patients with localized breast cancer who developed ipsilateral, nonmetastatic INR between 2003 and 2019. All patients were treated with curative intent, including regional nodal irradiation. Overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), local control, and treatment toxicities were analyzed. Survival probabilities were calculated using the Kaplan–Meier method, and Cox regression was used to assess prognostic factors. Results The 5‑year OS and CSS were 71.6%, while MFS was 62.3%. Inclusion of internal mammary chain (IMC) irradiation significantly improved OS, CSS, and MFS (p < 0.01). Triple-negative breast cancer (TNBC) INRs were associated with worse survival outcomes. Acute grade 2 toxicities included radiodermatitis (36.4%), and late grade 2 toxicities were limited to fibrosis (18.2%). No cardiac, pulmonary, or grade 3 or higher toxicities were reported. Conclusion This study highlights the favorable survival outcomes and safety profile of contemporary curative strategies for INRs following localized breast cancer, with a 5-year OS rate exceeding historical benchmarks. Internal mammary chain irradiation appears to improve survival without increased toxicity. However, the poor prognosis associated with TNBC INR underscores the need for effective systemic therapies. Prospective multicenter trials are essential to validate these findings and optimize treatment protocols.

Canine olfaction is increasingly studied as a tool for detecting cancer and other diseases. Previous pilot studies have demonstrated that dogs can effectively distinguish positive samples from negative samples in humans with breast cancer, achieving sensitivity rates as high as 100%. However, questions remain about dogs’ ability to detect low concentrations of volatile organic compounds in complex medium. While dogs’ detection thresholds for isoamyl acetate using a mineral oil substrate have been studied, there are no current studies on their detection limits using more complex substrates like urine, relevant in clinical settings. This pilot study aimed to evaluate the olfactory threshold of dogs using artificial urine with various concentrations of isoamyl acetate. Two dogs were trained to detect isoamyl acetate, initially using water as the substrate during the training phase, and subsequently using artificial urine during the testing phase, under single and double-blinded conditions. The dogs were trained to indicate the presence of isoamyl acetate solutions by sitting in front of the positive sample and ignoring controls. Training and testing occurred in a controlled environment, maintaining consistency with the same two handlers, a standardized methodology, and positive reinforcement with toy rewards. Based on double-blind performances, results showed a minimum detection threshold of 6.7 x 10-9 Molar (M) for Nougaro (Springer Spaniel) one dog and 2.1 x 10-7M for Prince (Labrador Retriever). The sample age did not affect performance. However, the position of the cone did, with higher failure rates for the first cone compared to the other three. These findings underscore the potential of trained dogs to detect volatile organic compounds at very low concentrations in complex substrates, supporting their use in clinical diagnostics.

Anti-CD19 chimeric antigen receptor (CAR) T cells have shown impressive results in the treatment of relapsed/refractory aggressive large B-cell lymphomas (LBCLs). However, the prognostic value of the LBCL histological subtype in the context of CAR T cell therapy is unclear. Here, we report the prognostic value of transformed indolent non-Hodgkin lymphoma (TriNHL) (n=110) confirmed by an expert pathologic review (LYMPHOPATH) vs. de novo LBCL (n=391) in the context of CAR T cell therapy from 4 centers of the French DESCAR-T registry. After 1:1 propensity score matching (N=170, 85 TriNHL patients and 85 de novo LBCL patients), the median follow-up was 19.4 months (95% CI, 12.0-25.1) for TriNHL patients and 18.5 months (95% CI, 13.8-24.8) for LBCL patients. The 1-year progression-free survival rate was significantly better (55.8%, [95% CI, 43.6-66.4]) in the TriNHL group than in the de novo LBCL group (31.7%, [95% CI, 21.4-42.6]) (hazard ratio=0.54, [95% CI, 0.36-0.82], p=0.0034). The best overall response rate/complete response rate was 82.4%/63.5%, whereas it was 63.5%/50.6% for the TriNHL group compared with the de novo LBCL group. The 1-year overall survival was also longer in the TriNHL group than in the de novo LBCL group (72.1%, [95% CI, 59.6-81.4] vs. 50.7%, [95% CI, 38.2-62.0], p=0.031). Similar findings were found via an inverse probability weighting statistical approach. No difference was observed in terms of toxicity. In conclusion, our matched-comparison study revealed a greater efficacy of CAR T cell therapy, with a comparable toxicity profile for TriNHL patients than for LBCL patients.

Background and aims Head and neck germ cell tumors (HN‐GCTs), excluding the central nervous system, are rare and frequently contain mature or immature teratoma (MIT) compounds. The aims of this study were to analyze the risk of malignant transformation after MIT HN‐GCTs, to describe treatments and sequelae, and to propose recommendations for the follow up of these patients. Methods National multicentric retrospective study of all patients aged from birth to 17 years, treated in France between 2000 and 2021 for a HN‐GCT of all histotypes. Patients were selected from various sources: French National Registry of Childhood Cancers, SFCE ( Société Française des Cancers de l'Enfant ) centers and pediatric ENT (ear, nose and throat) surgical centers. Results A total of 152 patients were selected. Median age at diagnosis was 9 months (range, 0–190), with 34 diagnosed antenatally. Overall, 150 tumors contained MIT and two were malignant yolk sac GCT (YST). All patients, except for two cases with early postpartum death, underwent surgery, preceded in 12 cases by an EXIT (Ex Utero Intra Partum) procedure. After a median follow‐up of 47 months (range, 11–124), four patients with MIT developed a localized mature teratoma relapse, three developed a localized secreting malignant HN‐GCT (including two malignant degenerations after MIT), and one had a thoracic neuroblastoma. All patients survived. 9% of survivors developed moderate to severe sequelae. Conclusions Due to the low rate of malignant degeneration (two out of 148, 1.3%), this study does not support systematic oncologic long‐term monitoring after neonatal MIT HN‐GCT. However, regular clinical examination is required to detect and treat locoregional sequelae.

Pd‐catalyzed reactions are among the most straightforward and efficient methods to proficiently build Csp²‐Csp² bonds. Nevertheless, thermal activation remains mandatory in most cases, which may decrease the compatibility with sensitive functional groups. In this context, improvements of conventional strategies must be an important source of research in order to enhance the applicability of such methods for building complex scaffolds. In this work, we contribute to this aim by implying visible‐light as the sole energy source in a Pd‐catalyzed rearrangement reaction involving N‐tosylhydrazones and aryl halides. These mild reaction conditions efficiently allow oxidative addition, aryl migration and β‐hydride elimination at room temperature, allowing the construction of various 1,1’ disubstituted olefins.

Developing new therapeutic regimens for relapsed/refractory (R/R) B non‐Hodgkin lymphoma (NHL) patients remains a significant unmet clinical need. Our objective was to evaluate atezolizumab (ATE), obinutuzumab (OBI) and venetoclax (VEN) combination in patients with R/R NHL who had received at least one prior anti‐CD20‐containing immunochemotherapy regimen. We report here the final analysis of the phase II LYSA‐promoted multicentre trial (NCT03276468) of this combination in follicular lymphoma (FL, n = 58), diffuse large B‐cell lymphoma (DLBCL, n = 58) and marginal zone lymphoma (MZL, n = 20). The primary end‐point for FL and DLBCL was not met: ATE, OBI, and VEN resulted in an overall response rate (ORR) at the end of induction (EOI) of 53.6% for FL (cohort 1) and 23.6% for DLBCL (cohort 2) when a minimum of 70% and 48% was expected respectively. The median progression‐free survival was 11.0 and 2.7 months in cohorts 1 and 2 respectively. In cohort 3 (MZL), the ORR at the EOI was evaluated at 66.7%. The most frequent adverse events (AEs) were cytopenias. We also observed 7.4% of autoimmune AE imputable to the combination. In this phase II study, ATE, OBI and VEN demonstrated moderate efficacy and a manageable toxicity profile when used as induction and maintenance therapy.

The accurate prediction of RNA secondary structure, and pseudoknots in particular, is of great importance in understanding the functions of RNAs since they give insights into their folding in three-dimensional space. However, existing approaches often face computational challenges or lack precision when dealing with long RNA sequences and/or pseudoknots. To address this, we propose a divide-and-conquer method based on deep learning, called DivideFold, for predicting the secondary structures including pseudoknots of long RNAs. Our approach is able to scale to long RNAs by recursively partitioning sequences into smaller fragments until they can be managed by an existing model able to predict RNA secondary structure including pseudoknots. We show that our approach exhibits superior performance compared to state-of-the-art methods for pseudoknot prediction and secondary structure prediction including pseudoknots for long RNAs. The source code of DivideFold, along with all the datasets used in this study, is accessible at https://evryrna.ibisc.univ-evry.fr/evryrna/dividefold/home.

This study investigated hypofractionated stereotactic radiotherapy (HSRT) for resected brain metastases and how the dose-fractionation affects local control (LC) and radionecrosis (RN). We retrospectively evaluated patients with brain metastases who were treated between 2010 and 2023. Post-operative HSRT was delivered in three or five fractions. The primary objective was to determine the effect of dose escalation and fractionation on LC. Secondary objectives included identifying factors associated with RN. Statistical analyses were conducted using Chi-square or Fisher’s exact tests for categorical data and Mann-Whitney U tests for continuous variables (significance level: p < 0.05). After a median follow-up of 19 months, 34 patients out of 212 (16%) had local recurrence. A biologically effective dose (BED10) > 28.8 Gy was associated with better LC (p = 0.002), but no benefit was found for a BED10 > 48 Gy. RN developed in 34 patients (16%). A prescription BED10 > 48 Gy was associated with an increased incidence of symptomatic RN (p = 0.002). For HSRT in three fractions, a CTV D99% ≥ 29 Gy significantly improved the LC (p = 0.04), and V30Gy, V23.1 Gy, and V18Gy were significantly associated with an increased risk of RN. The fractionation was not found to affect the LC or RN. This large, retrospective cohort study on post-operative HSRT indicates that a BED10 of 40.9–48 Gy (3 × 7,7 Gy or 5 × 6 Gy) to the planning target volume results in excellent LC while limiting the risk of RN. No difference in LC or RN was found for different fractionations.