Background: Larotrectinib is a selective tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of NTRK fusion-positive tumors. Although its efficacy has been demonstrated in clinical trials, particularly in infantile fibrosarcoma (IFS), real-world data in pediatric populations remain limited. Methods: We conducted a prospective observational study within the SACHA- France study, including patients < 25 years treated with larotrectinib outside clinical trials between April 2019 and September 2025. Clinical characteristics, molecular data, treatment indications, responses, survival outcomes, toxicity, treatment discontinuation, and resistance were analyzed. Results: Twenty-five patients were included (median age 2.8 years): IFS (n = 9), extra-CNS tumors (n = 10) and CNS tumors (n = 6). Twelve patients were treated at progression, nine to avoid mutilating surgery, two for multifocal/metastatic disease, and two as maintenance for high relapse risk; five received upfront larotrectinib. The overall response rate was 70% (95% CI: 47-87), with a median time to best response of 2 months. Two-year event-free and overall survival rates were 61.3% (95% CI: 38.3-77.7) and 74.9% (95% CI: 52.4-87.9) respectively. A trend toward higher 2-year EFS was observed in IFS versus CNS tumors (72.9% [95% CI: 26.7-92.9] vs 33% [95% CI: 10.5-80]). Treatment-related adverse events were reported in 8% of patients. Disease progression occurred in five patients, with acquired resistance mutations in the kinase domain confirmed in two. Conclusion: Larotrectinib shows meaningful efficacy and favorable tolerance across NTRK fusion-positive malignancies beyond IFS. These real-world data support early molecular testing, highlight histology-dependent outcomes, and inform clinical management strategies.

Background. DICER1 syndrome is an autosomal dominant disorder predisposing to a broad spectrum of malignant and benign neoplasms, caused by germline pathogenic variants (PVs) in the DICER1 gene. We aimed to characterize the clinical features of DICER1 syndrome in a national referral cohort and to estimate neoplasm risk.Materials and Methods. This retrospective study was conducted in a cohort of 945 patients who underwent DICER1 genetic testing at Institut Curie, Paris, using Sanger sequencing from 2012 to 2014 and Next Generation Sequencing from 2015 to 2023.Results. Among 584 index cases evaluated for DICER1 syndrome, 91 (16%) carried a germline DICER1 PV and 31 (5%) harbored only somatic DICER1 PVs. Several tumors that were not previously part of the DICER1 tumor spectrum were identified. ETMR-like brain tumor and testicular Sertoli cell tumor are now recognized as DICER1-related neoplasms, and schwannoma is a strong candidate. The neoplasm risk was estimated in 170 relatives carrying a germline DICER1 PV. The cumulative incidence of malignant neoplasms was 4.8% [95% CI: 2.1% – 9.1%] at 10 years and 15.8% [95% CI: 8.9% – 24.7%] at 50 years. Overall neoplasm risk was significantly higher in females, primarily driven by the higher incidence of multinodular goiter.Conclusion. This large cohort study provides a comprehensive overview of the distribution of neoplasms associated with DICER1 syndrome. Broader genetic testing identified additional DICER1-related neoplasms, and schwannoma emerged as a candidate association. Finally, this study confirms the moderate penetrance of germline DICER1 PVs.

OBJECTIVE:To map real-world management of paediatric differentiated thyroid carcinoma (DTC) across Europe and identify targets for harmonization. DESIGN:Cross-sectional, web-based survey of centres providing paediatric DTC care. SETTING & PARTICIPANTS:One consolidated response per centre was requested from a clinician overseeing paediatric DTC. The instrument covered centre profile/multidisciplinary tumour (MDT) board organization; staging and guideline use; risk stratification and dynamic response; diagnostics; surgery/lymph node management; radioactive iodine therapy (RAIT) policy and activity selection; and thyroid-stimulating hormone targets, follow-up, shared-care/transition. Analyses were descriptive at centre level. RESULTS:Forty-two centres from 18 countries participated in the survey. Response denominators varied by item. Among responding centres, ≈75% were university or academic hospitals, ≈70% used a paediatric age cut-off of ≤18 years, and ≈60% reported having a dedicated MDT board. Staging and guideline use were heterogeneous: centres most often reported mixed or centre-specific guidance, followed by the American Thyroid Association (ATA) 2015 guideline, national guidelines, and the European Thyroid Association (ETA) 2022 guideline. Dynamic response-to-therapy categories were commonly used. For unilateral presumed low-risk disease, hemithyroidectomy was the usual initial surgery in approximately two-thirds to three-quarters of centres, whereas total thyroidectomy was less common. For low-risk patients, RAIT policy were split between de-escalation and risk-adapted use. When administered, RAIT activity was determined using weight-based, dosimetric, or fixed empirical approaches. Country-level patterns suggested clustering around ETA-leaning, ATA-leaning, and national guideline frameworks. CONCLUSIONS:Across Europe, centres broadly endorse risk-adapted care but diverge at key decision nodes-extent of surgery, formal risk framework, and RAIT in low-risk disease-reflecting guidance plurality and organizational context. Leveraging existing infrastructures offers pragmatic avenues to reduce unwarranted variation while generating paediatric-specific evidence to refine recommendations.

Background Management of bilateral Wilms tumor (BWT) to achieve complete tumor control and maintain good long-term renal function is challenging. Nephron-sparing surgery (NSS) allows preservation of renal parenchyma and reduces the risk of renal failure in selected cases. However, there is no standardized surgical strategy. This study analyzed the surgical management for patients included in the SIOP2001 trial and its outcomes. Methods This retrospective review analyzed French patients included in the SIOP 2001 protocol for synchronous BWT. Data regarding imaging, surgical strategy, complications, histology, oncologic outcomes, and renal function were collected. Results The study included 96 patients (median age, 15 months; range, 0-143 months). They received surgery for 122 Wilms tumors, and 56 (45.9 %) kidneys benefited from NSS. Total nephrectomy (TN) was performed in 27/35 (77.1 %) and 33/76 (43.4 %) of the histologies non-sensitive to chemotherapy (stromal and diffuse anaplasia, respectively). For bilateral surgery, the study found a trend to more TNs, tumoral rupture, and death among the patients who had surgery in a single stage (p > 0.05). Tumor rupture was associated with higher tumoral volume (p < 0.05). In a review of preoperative images, vascular contact was the main factor associated with TN. Additional chemotherapy did not seem to significantly reduce this contact or the number of TNs in these patients. Conclusion Whenever possible, NSS should be prioritized for patients with BWT. In this study, the most limiting factor was contact with vascular structures. Additional chemotherapy for tumors with non-sensitive histology or extensive vascular contact had little impact on the final surgical strategy. Staged surgery should be considered as it appeared to reduce surgical morbidity.

BACKGROUND:Larotrectinib is a selective tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of NTRK fusion-positive tumors. Although its efficacy has been demonstrated in clinical trials, particularly in infantile fibrosarcoma (IFS), real-world data in pediatric populations remain limited. METHODS:We conducted a prospective observational study within the SACHA- France study, including patients < 25 years treated with larotrectinib outside clinical trials between April 2019 and September 2025. Clinical characteristics, molecular data, treatment indications, responses, survival outcomes, toxicity, treatment discontinuation, and resistance were analyzed. RESULTS:Twenty-five patients were included (median age 2.8 years): IFS (n = 9), extra-CNS tumors (n = 10) and CNS tumors (n = 6). Twelve patients were treated at progression, nine to avoid mutilating surgery, two for multifocal/metastatic disease, and two as maintenance for high relapse risk; five received upfront larotrectinib. The overall response rate was 70% (95% CI: 47-87), with a median time to best response of 2 months. Two-year event-free and overall survival rates were 61.3% (95% CI: 38.3-77.7) and 74.9% (95% CI: 52.4-87.9) respectively. A trend toward higher 2-year EFS was observed in IFS versus CNS tumors (72.9% [95% CI: 26.7-92.9] vs 33% [95% CI: 10.5-80]). Treatment-related adverse events were reported in 8% of patients. Disease progression occurred in five patients, with acquired resistance mutations in the kinase domain confirmed in two. CONCLUSION:Larotrectinib shows meaningful efficacy and favorable tolerance across NTRK fusion-positive malignancies beyond IFS. These real-world data support early molecular testing, highlight histology-dependent outcomes, and inform clinical management strategies.

Neurodegeneration (ND) is a severe complication of Langerhans cell histiocytosis (LCH), often leading to progressive neurological decline. We evaluated the usefulness of using plasma and cerebrospinal fluid neurofilament light chain (p- and CSF-NFL) levels as biomarkers to identify and monitor ND-LCH. NFL levels were measured using the single-molecule array for a subset of patients from the French National LCH Registry. NFL levels in 692 plasma and 115 CSF samples from 273 registry-enrolled children were analysed. Based on 84 paired plasma and CSF samples from 67 patients, p- and CSF-NFL levels were strongly correlated (p < 0.0001). The areas under the receiver operating characteristics curves for ND-LCH were 72% (95% confidence interval [CI], 64%-78%) for p-NFL and 94% (95% CI, 88%-98%) for CSF-NFL. The highest p-NFL (13.7 vs. 7.2 pg/mL; z-score 2.3 vs. 0.6) and CSF-NFL (436.9 vs. 65.2 pg/mL) levels were significantly higher for ND-LCH than in no-ND-LCH patients, respectively (p < 0.0001). Plasma NFL levels were not elevated at LCH diagnosis. At LCH diagnosis, p-NFL was not predictive of ND, but it may serve as a minimally invasive screening tool for ND in LCH, although optimal timing remains to be determined.

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

BACKGROUND:Desmoid-type fibromatosis (DTF) is a rare intermediate malignancy with high local aggressiveness and recurrence in children after first-line methotrexate-vinblastine (Mtx-Vbl) regimen. The objective is to describe refractory DTF to standardize second-line therapy. METHODS:This national multicenter retrospective study included patients (<25 years) with progressive/refractory DTF after Mtx-Vbl first-line. The primary objective was to evaluate response rate (RR: complete/partial response [CR/PR]) and progression-free survival (PFS2) following second-line treatments. Secondary objectives included overall burden of therapy and predictive factors for therapeutic efficacy analysis. RESULTS:From 2000 to 2022, 50 patients fulfilled inclusion criteria. Median age at first relapse was 15.6 years [range: 0.9-24.8]. Second-line treatments included exclusive medical treatment for 86%-majority alkaloid-based re-challenge (60%)-exclusive local therapy in 8%, both (4%) and observation (2%). RR to any medical therapy was 30% [95% CI: 16-44], specifically 35% [95% CI: 15-55] for alkaloid-based regimens with clinical benefit (CR/PR or stabilization) in 85%. The 5-year PFS2 was 44% [95% CI: 30-58]. Limb location was the only significant predictive factor for PFS2 (p < 0.01). Overall treatment load comprised a median of three lines [range: 2-8] over 27 months median duration [range: 4-90]. Local therapy was done for 50% of patients. One patient died from secondary digestive infection. CONCLUSIONS:Refractory DTF should be considered as a chronic disease with significant treatment burden where objectives should be regularly reassessed. Even for refractory disease, local therapy might be avoided in half of cases. Authors propose a second-line treatment algorithm for pediatric refractory DTF.

Background Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into 4 molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis. It is critical to establish effective subtyping methods for accurate diagnosis and patient's management that strikes a delicate balance between improving outcomes and minimizing the risk of comorbidities.Methods We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB. Nanopore sequencing was applied to an EPIC cohort of 44 frozen MB, benchmarked against the gold standard EPIC array, and further evaluated on an integrated diagnosis cohort of 116 MB.Results Most MB of both cohorts (42/44; 95.5% and 106/116; 91.4%, respectively) were accurately subgrouped by Nanopore sequencing. Employing Flongle flow cells for 18 MB allowed a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Nanopore sequencing enabled us to accurately subtype 28/30 (93.3%) MB.Conclusion This study, conducted on the largest cohort of MB analyzed with Nanopore sequencing to date, establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. Nanopore sequencing demonstrates a robust capacity for precise subtyping of MB, a critical advancement that holds significant potential for enhancing patient stratification in future clinical trials. Its ability to deliver quick and cost-effective results firmly establishes it as a game-changer in the field of MB classification.

ABSTRACT Background and aims Primary lung tumors (PLTs) in children are rare, and surgery remains the key to ensure remission. Here we describe the PLTs clinical characteristics, their management, and the pulmonary outcome following surgery. Methods We carried out a French national cohort of pediatric PLTs from 2013 to 2023 from the FRACTURE rare pediatric tumors national database. We included children under 18 years at diagnosis who underwent surgery for a histologically proven PLT, with a minimum of 6 months of follow‐up (FU) post surgery. Results Sixty‐two patients were included. The median age at diagnosis was 3.6 years [3; 11], sex ratio 1.07. Pleuropulmonary blastoma was the most frequent tumor retrieved ( n = 31). Sixty patients underwent surgery: 32 lobectomies, 15 wedges, five segmentectomies, and five pneumectomies. A thoracoscopic approach was carried out in 14% of the cases. At 6 months post surgery and at the last follow‐up (median time of 5.7 years [3.4; 7.6]), respectively, 11 and eight patients presented with pulmonary symptoms, and 10 and three patients presented with surgical complications. During the post‐surgery period, 22 children benefited from an evaluation of their respiratory function by pulmonary function tests, and four of them remained with abnormal results. Conclusions Surgery is key to ensure remission in PLTs and seems secure. However, respiratory symptoms are noted in 13% of children during the FU, and this rate is probably underestimated. Therefore, we suggest a systematic pulmonary FU to optimize postoperative pulmonary rehabilitation and, therefore, the child's pulmonary outcome.

ABSTRACT:Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL, platelets <100 × 109/L, leukopenia (white blood cell count <4 × 109/L), and/or neutrophils <1.5 × 109/L. Among the 2313 patients aged <18 years enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis, 1 year); median follow-up lasted 8.1 years. Bone marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis, or myelofibrosis but never confirm the diagnosis. Fifty-eight patients (17%) developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 × 109/L, respectively) and severe HI (SHI; ≤7 g/dL and/or ≤20 × 109/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities, and outcomes (MHI and SHI 10-year survival rates, 98% and 73%, respectively). Since 1998, mortality first declined with combination cladribine-cytarabine therapy and then with MAPK inhibitors since 2014. Forty-one patients (12%) developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, because it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted therapy approaches would be better adapted for these patients, whereas MHI can be managed with classic therapies.

Neuroblastoma is a common childhood tumor originating from neural crest progenitors with variable clinical behavior. Despite improved overall survival, factors such as stage, histoprognosis, MYCN status, and age still influence outcome. MCM6 regulates DNA replication and contributes to cancer progression. PRAME, first identified in melanoma, also acts on cell replication, epithelial-mesenchymal transition, and cell migration and has been associated with poor outcomes in several cancers, including neuroblastoma, using molecular biology techniques. The study aims to investigate MCM6 and PRAME expression and prognostic roles in neuroblastoma. A retrospective study was conducted, which included data of 84 patients with neuroblastoma diagnosed between 2000 and 2022, sourced from the pediatric tumor registry. Patient's characteristics and prognostic tumor factors were collected. Expression of MCM6 and PRAME proteins was evaluated using digital image analysis techniques. Univariate and multivariate analyses were performed using Cox regression to assess the impact of protein expression on survival and their associations with these prognostic factors. A total of 84 children diagnosed with neuroblastoma were included. MCM6 and PRAME were associated with unfavorable histologies (p = 0.03). PRAME was associated with bone marrow metastases (p < 0.01), high mitotic-karyorrhectic index (p = 0.04), and poor histoprognosis (p < 0.01). PRAME and MCM6 expression was correlated with several neuroblastoma prognostic factors. PRAME was significantly (p = 0.05) associated with poor event-free survival (EFS) and not significantly (p = 0.08) associated with overall survival (OS). Although statistical significance was not reached in multivariate analysis, the trends strongly suggested that the overexpression of MCM6 and PRAME was correlated with decreased survival.

Background ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome.Methods We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB.Results All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (n = 26); moreover, all tested familial trio (n = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms.Conclusions The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request.

Background Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet uniformly approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE). Methods Dinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤25 years old as compassionate or off-label use. Results Between February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1-24) were treated with dB+TopoCyclo (n=24) or dB+TOTEM/TEMIRI (n=15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22-63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16-68%). Conclusion Similar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone.

Introduction : A strategy of therapeutic de-escalation has been proposed for children with localized stage nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) over the past twenty years : either local surgical treatment and watch and wait after complete resection of an isolated adenopathy or low intensity chemotherapy ±Rituximab (R). Here, we provide results on the management and efficacy of R-CVP in children with early stage NLPHL. Methods : A retrospective multicenter national study was carried out in the centers of the French Children's Cancers Society (SFCE) to evaluate the tolerability and efficacy of 3 courses of Rituximab 375 mg/m2-Cyclophosphamide (500 mg/m2 day 1), Vinblastine 6 mg/m2 day 1 and 8, Prednisolone (40 mg/m2 day 1-8) (R-CVP) treatment in NLPHL patients under 18 years of age diagnosed between January 2015 and December 2023. NLPHL diagnosis was confirmed by hematopathologist review and the staging was evaluated by FDG-TEP/CT in all patients. Results : Twelve children, median age at diagnosis 12 years, (range 7-16 years); boys n=10 received R-CVP between January 2019 and December 2023 in SFCE centers. No patient were treated by R-CVP before 2019 in France. Patients were classified as stage IA n=4 , stage IIA n=7 and stage IIIA n=1. Six patients were treated by R-CVP as first line treatment at initial diagnosis, 3 cases for residual adenopathy post initial surgery, 3 cases after relapse (median time to relapse 9 months) after primary treatment by local surgery and/or radiotherapy. All patients achieved complete remission. In 10/12 cases R-CVP course was performed every 21 days, only one patient received R-CVP every 15 days. Stage IIIA received 4 courses of R-CVP. With a median follow up of 23 months (8-45 months) EFS and OS is 100%. Forty-two percent presented neutropenia at d17 (nadir 0.3 G/l and 0.6 G/l first and third course, respectively). No patient needed blood transfusion support. Grade II mucositis and febrile neutropenia were reported as well as grade I/II peripheral sensitive neuropathy, constipation or digestive disorders Conclusion: Our results show that R-CVP is an effective chemotherapy regimen in children with localized stage NLPHL. Limited hematological toxicities and peripheral neuropathy were reported during the treatment

Abstract BACKGROUND Medulloblastomas (MB) Sonic hedgehog (SHH) subtype are associated with a cancer predisposition syndrome (CPS) in about 15% of cases, the most frequent being related to ELP1 pathogenic variant (PV). The aim of our study is to better evaluate penetrance of this CPS and detail the characteristics of the related tumors. METHODS Twenty-nine ELP1-mutated MB identified in France were retrospectively reviewed. Molecular characteristics of the tumor and clinical features of the patients were collected; whenever possible, the germline DNA from patients and their relatives were sequenced. RESULTS All patients (sex ratio 16/13) presented with SHH-MB, mostly nodular desmoplastic (n=20/28), between 3 and 15 years of age (median 7.3). All mutations are found in the germline when a constitutional DNA sample was available (n=26). Most tumors (93%) showed a biallelic inactivation of PTCH1, other recurrent alterations concerned the TP53 pathway (including 1 somatic TP53 VP) and activation of MYCN/MYCL signaling. We observed that ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups of MB, similar outcomes (5y-OS = 85%) and no unusual side effects of treatments. Three patients developed a second tumor (2 high-grade gliomas and 1 thyroid carcinoma) within the irradiation fields. All germline PV were inherited from one asymptomatic parent (11 trio). No specific morphological features were mentioned. Only two index cases from the 29 French patients had a previous familial history of MB (occurring in a cousin), with many asymptomatic carriers. Except the MB, no other cancer was significantly associated with the ELP1 PV. CONCLUSIONS the low penetrance, the ‘at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with MB, depending on the parents’ request.

Background: The Ewing Sarcoma Family of Tumors (ESFT) constitutes a group of rare malignancies, wherein approximately one-third of cases exhibit metastatic spread, particularly impacting prognosis when bone and/or bone marrow (BM) are involved. Primary extra-pulmonary metastatic ESFT often necessitates intensified therapeutic approaches. Accurate staging plays a pivotal role in clinical decision-making, with fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) currently serving as a non-invasive modality for assessing ESFT's BM extent. Methods: In the French phase II COMBINAIR3 (NCT03011528) study, a comprehensive approach for patients with extra-pulmonary ESFT metastasis was evaluated. We prospectively compared the efficacy of PET/CT to BM aspiration and biopsy (BMAB) analysis in patients undergoing initial staging. Results: Among the 42 patients analyzed (median age 14 y, 2:1 male/female ratio), 45% presented with pelvic primary tumors and 83% had bone/BM involvement at diagnosis. Our findings showed PET/CT had 100% specificity and 83.3% sensitivity in detecting initial BM involvement. Overall, PET/CT correctly classified 92.8% of patients, reaching 100% accuracy in patients identified with bone involvement, thus surpassing the standard BMAB. Discussion: These results suggest that the conventional use of BMAB in the initial staging of high-risk ESFT patients can be omitted, promoting PET/CT as a non-invasive alternative, thus improving staging accuracy and treatment decisions in ESFT management.

PURPOSE:Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas. METHODS:TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. RESULTS:Median age at first osteosarcoma diagnosis was 13.7 years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10 years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25 years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]. CONCLUSION:In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

Background Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.Methods A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.Results Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.Conclusions The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT. Graphical Abstract