Daniel Orbach

• Head of Department at Institut Curie

Background: Larotrectinib is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer; approval was based on a robust and durable objective response rate in both adult and pediatric patients with various cancers. Here, we report long-term efficacy and...

Background The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) is a potential biomarker for treatment response in pediatric rhabdomyosarcoma. Due to its rarity, investigations into this marker require multicenter approaches, which can result in variability in acquisition parameters. Objective To evaluate the impa...

3148 Background: NTRK gene fusions are oncogenic drivers in various tumor types. Larotrectinib (laro) is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients (pts) with TRK fusion cancer based on a robust and durable objective response rate in pts with various cancers. H...

3066 Background: Larotrectinib (laro) is the first-in-class, highly selective, TRK inhibitor approved for tumor- and age-agnostic use in TRK fusion cancers. This is the seminal report of primary and secondary laro resistance based on an analysis of the regulatory dataset that supported drug approval across multiple countries. Methods: Genomic data...

Purpose Carcinoid neoplasms, even rare, are the most common pulmonary tumors during childhood. They are classically divided into typical and atypical tumors according to pathology pattern. Cornerstone therapy is to obtain a complete tumor resection. The aim was to describe clinical characteristics and treatment of young patients diagnosed with bron...

Background Maintenance treatment with vinorelbine and oral cyclophosphamide (oral‐CPM) improves outcome of nonmetastatic high‐risk (HR) and very‐high risk (VHR) rhabdomyosarcoma (RMS) patients. However, gonadal toxicity of maintenance was not yet investigated. Methods The authors focused their analysis on male gonadal toxicity in HR/VHR groups of...

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 fo...

Purpose of review Maintenance therapy (MT), particularly antiangiogenic approaches such metronomic chemotherapy (MC), correspond to the continuous administration of low-dose anticancer agents in a context of minimal residual disease. While widely used in pediatric acute lymphoblastic leukemia for decades, MT has recently shown promise in solid tumo...

The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 trial evaluated maintenance chemotherapy in high-risk rhabdomyosarcoma (RMS). Patients were randomly assigned to either discontinue treatment (standard arm) or receive six 28-day cycles of vinorelbine (25 mg/m ² ) once per day on days 1, 8, and 15, plus once daily low-dose cyc...

Background The epidemiology of childhood cancer in Afro-descendant (AD) populations is poorly described. We performed a descriptive study of the distribution, incidence, and survival of children with cancer in the French West Indies (FWI) and French Guiana (FG). Methods We included all patients aged 0–17 diagnosed with cancer or benign intracrania...

Background and Aims Pediatric salivary gland malignancies (SGM) present challenges in managing cervical nodes. We aimed to characterize lymph node invasion to inform decisions regarding the need of systematic wide lymph node dissection (WLND). Methods International retrospective study, conducted across seven large French and American pediatric cen...

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with...

Accurate staging of nodal involvement in pediatric sarcoma patients is important to determine correct systemic and local therapy, with the goal to reduce subsequent recurrences. However, differences in lymph node staging strategies, definitions, and treatment protocols between the Children's Oncology Group (COG), European paediatric Soft tissue sar...

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...

Keratocystoma is a rare benign salivary gland tumor described in 1999. Only 14 cases have been reported in the histopathological literature, with three of them having had a preoperative fine needle aspiration (FNA) performed. All cytological diagnoses were not specific. We have seen a 12‐month‐old boy presenting a left parotid mass with facial nerv...

Background Orbital rhabdomyosarcoma (RMS) is often limited to the orbital cavity and has a favorable prognosis. In some cases, the tumor can erode the orbital bone and behave as a parameningeal RMS (PM-RMS); thus, it is treated more intensively. However, the current protocols do not provide any guidance on how to consider different grades of bone e...

Purpose Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. Experimental Design We conducted an international retrospective cohort study of patients with TRK fusion–driven central nervous system tumors. Results A total of 119 p...

Background The prognosis for patients with relapse of localized rhabdomyosarcoma (RMS) remains poor, with limited evidence for optimal second‐line therapy. This study describes the management and outcomes of relapsed RMS patients in France. Methods We retrospectively reviewed all nonmetastatic RMS patients enrolled in France in the RMS 2005 study...

Background Parameningeal (PM) site is an unfavorable characteristic in rhabdomyosarcoma (RMS). We described the treatment and outcome for patients with PM RMS and investigated the prognostic value of risk factors. We scored PM site by originating site and by highest risk extension. Methods Patients with PM RMS were treated within the European pedi...

Purpose Within the Paediatric Rare Tumours Network—European Registry (PARTNER) project, we aimed to evaluate the situation on the registration and management of paediatric patients affected by very rare tumours (VRT) in the European low health expenditure average rates (LHEAR) countries. Methods A survey regarding infrastructure, organisation, and...

Pancreatic neuroendocrine neoplasms (pNENs) diagnosed in childhood are very rare, with few data available. The aim was to describe the clinical presentation and behavior of children with pNENs at a national level. Methods National multicenter retrospective study of all patients, aged from 0 to 17 years at diagnosis, treated from 2011 to 2020 for a...

Background The authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA‐RMS). Patients and Methods Localized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA‐RMS at favorabl...

Importance Desmoid tumor (DT) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Previously, surgery was the standard primary treatment modality; however, within the past decade, a paradigm shift toward less-invasive management has been introduced and an effor...

Choriocarcinoma in neonates and infants (N‐CC) is an extremely rare, but aggressive cancer, frequently observed with concomitant maternal disease. A retrospective, bi‐national study of patients treated in France and Poland for infantile choriocarcinoma analysed eight cases of N‐CC, median age of 6 weeks. All tumours were diffuse. Six patients recei...

Purpose Though the prognosis for pediatric patients with localised synovial sarcoma (SS) is generally good, the chances of being cured after relapse are limited. This study describes a retrospective multi‐institutional series of relapsing SS patients treated at six selected European referral centers for pediatric sarcoma. Patients and methods The...

Background Patients with infantile fibrosarcoma (IFS) have shown strong and long-lasting responses to larotrectinib, a tropomyosin receptor kinase inhibitor (TRKi), in single-arm clinical trials. Conventional chemotherapy has also shown important efficacy. But, until now, no comparative data exist. This study aims to assess the therapeutic benefit...

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3 / 7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infa...

Background The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event‐free survival and provide a rationale for risk stratification in future trials. Methods The authors used data from patients enrolled i...

Rationale Sex cord‐stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes. Method Patients (< 19 years) registered in the TGM13 registry between 2014 and 2021 for SCST were selected. Results Sixty‐three ovarian SCST (juvenile granulosa tumor (JGT) n = 34, Sertoli‐Leydig cell...

Objectives The neurotrophic tyrosine receptor kinase (NTRK) fusion transcript (FT) is a major genetic landmark of infantile fibrosarcoma (IFS) and cellular congenital mesoblastic nephroma (cCMN) but is also described in other tumours. The recent availability of NTRK-targeted drugs enhances the need for better identification. We aimed to describe th...

Melanotic neuroectodermal tumor of infancy (MNTI) is a very rare benign neoplasm of probable neurocristic origin. It primarily affects children in the first year of life, with the median age at diagnosis of 4.5 months (range 0-804 months). It usually presents as a fast-growing, painless tumor developing within maxilla, skull bones or mandible but o...

Rhabdomyosarcoma (RMS) is the main form of pediatric soft-tissue sarcoma. Its cure rate has not notably improved in the last 20 years following relapse, and the lack of reliable preclinical models has hampered the design of new therapies. This is particularly true for highly heterogeneous fusion-negative RMS (FNRMS). Although methods have been prop...

BACKGROUND TRK fusions are detected in less than 2% of central nervous system (CNS) tumors. There are limited data on the clinical course of affected patients. METHODS We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatm...

While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there...

Background The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5 mm or one nodule measuring between 5 and less than 10 mm by computed tomography [CT]) in children and adolescents with adult‐type non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis. Me...

Purpose Vaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment. Methods We included children treated for vaginal MGCT according to the French TGM‐95/2013 regimen. Patients were classified as standard risk (SR: localized disease and alpha‐fetoprotein (AFP...

The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS platforms in order to assess the best genomic approach of using liquid biopsy in future prospective clinical trials. Moreover, we investigate 35 paired p...

Objective To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma. Material and methods We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Inter...

PURPOSE Inflammatory myofibroblastic tumors (IMTs) are often driven by anaplastic lymphoma kinase fusions and less frequently by alternative fusions such as ROS1. We describe the clinical characteristics, treatment approach, and outcome for a series of young patients with IMTs and ROS1 alterations. METHODS This was a retrospective, international,...

Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of “maintaining” tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low...

Very rare tumors (VRTs) in pediatric age represent many different diseases. They present an annual incidence < 2/1000,000 and correspond to about 11% of all cancers in patients aged 0–14 years. They can be roughly divided into two groups: one including tumors that are also rare in adults, and the other group includes adult-type tumors rarely encoun...

Background: NTRK gene fusions have been identified in various tumors; some requiring aggressive therapy and sometimes new TRK inhibitors (TRKi). We aimed to describe a national, unselected, retrospective, multicenter cohort. Research design and methods: Patients were identified through the French sarcoma diagnostic laboratory at Institut Curie t...

Primary vaginal malignancies are rare, comprising only 2% of all female genital tract malignancies in adults and 4.5% in children. As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) jointly with the European Society for Radiotherapy & Oncol...

Purpose: To confirm the overall benignity of fat-containing soft tissue tumors (STT) on a pediatric cohort and to define the clinical and imaging features that warrant a biopsy. Methods: A retrospective monocentric study was conducted on patients aged less than 25 years consecutively referred for fat-containing STT to our Comprehensive Cancer Ce...

Background: Adolescents (15-19 years) with sarcoma are known to have significantly worse survival than children (0-14 years). One possible reason may be that the adolescent sarcomas exhibit specific biological characteristics resulting in differences in clinical presentation and treatment resistance behaviors. The BIOSCA project aims to further ex...

Background: This study describes the clinical findings of a consecutive series of pediatric and adolescent patients with a diagnosis of intra-abdominal desmoplastic small round cell tumor (DSRCT) prospectively enrolled in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols: the BERNIE study, the EpSSG MTS 2008 study, and the EpSSG...

Background: In certain rare undifferentiated small round cell sarcomas new specific molecular CIC-DUX4/other partner, BCOR-CCNB3/other partner, YWHAE fusions, or BCOR-ITD (internal tandem duplication) were identified. These new "CIC fused" (CIC-fused/ATXN1::NUTM1) and "BCOR rearranged" (BCOR fused/ITD/ YWHAE) soft tissue sarcomas (STS) are not wel...

The EPI VITRAKVI study is a retrospective study designed to place the results of the single-arm Phase I/II larotrectinib SCOUT trial into context by comparison with external historical controls. Its primary objective is to compare the time to medical treatment failure between larotrectinib and the historical standard of care (chemotherapy) in patie...

Primary vaginal malignancies are rare, comprising only 2% of all female genital tract malignancies in adults and 4.5% in children. As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) jointly with the European Society for Radiotherapy & Oncol...

Background: Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic advanced or progressive forms is recommended. Following promising results in adult patients, oral vinorelbine is investigated in young patients. Methods: A retrospective rev...

Background: To assess the outcomes of pediatric patients with undifferentiated embryonal sarcoma of the liver (UESL) and treatment including at least surgery and systemic chemotherapy. Methods: This study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three European trials...

Background Limited data exist on the clinical behavior of pediatric non‐rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined. Methods This cohort study reports on pediatric adult‐type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the...

Introduction: Desmoplastic small round cell tumor (DSRCT) is an extremely rare and highly aggressive soft tissue sarcoma, presenting mainly in male adolescents and young adults with multiple nodules disseminated within the abdominopelvic cavity. Despite a multimodal approach including aggressive cytoreductive surgery, intensive multi-agent chemoth...

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 QL...

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO...

Objective: To describe hypothalamic-pituitary-gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumour more than 5 years earlier, in order to identify risk factors for HPGA impairment. Methods: We retrospectively included 204 patients diagnosed with a primary brain tumour before 18 years of age and monitored at th...

Background: Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Onc...

Background Hospitalization rates can be used as an indirect indicator of the burden and severity of adverse health outcomes in childhood cancer survivors (CCS). We aimed to determine the long-term risks of hospitalization related to renal and urinary diseases among 5-year CCS. Methods The French Childhood Cancer Survivor Study cohort was linked wi...

Background The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods NETSARC database...

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make...

Background: The prognosis of patients with metastatic rhabdomyosarcoma (RMS) is not uniformly poor. Tumors with nodal involvement beyond the first lymph node station are currently considered to have distant metastases. The aim of this study is to evaluate the characteristics and outcome of RMS patients with distal nodal involvement as the only sit...

Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients with pediatric-type RMS, exploring possible underlying factors which may...

Background: The only French center for pediatric oncology and hematology outside of the metropolitan territory is in the Indian Ocean, in Saint Denis, on Reunion Island. It welcomes children from Reunion Island but also from Mayotte and neighboring countries. A quarter of them requires a secondary medical transfer to metropolitan France for specif...

The Cancer Bulletin continues its tradition. At the beginning of 2023, the members of the editorial committee would like to share with you their analyses of the highlights of 2022. The objective remains to highlight what will change our practices and lead to different diagnostic or therapeutic options. Our synthesis will therefore focus on publishe...

Background: Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more. Procedure: Patients less than 19 year...

Malignant ectomesenchymoma (MEM) is an extremely rare soft tissue tumor typical of young children, currently included in the category of skeletal muscle malignancies and characterized by a neuroblastic component. This study describes a series of 10 patients prospectively registered in the European paediatric Soft tissue sarcoma Study Group (EpSSG)...

Background Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1–0.2/1,000,000 per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of th...

Background and aims: Nuclear protein of the testis (NUT) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and you...

Background To assess the outcomes of pediatric patients with Undifferentiated Embryonal Sarcoma of the Liver (UESL) and treatment including at least surgery and systemic chemotherapy. Methods This study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three european trials focus...

Introduction: Very rare pediatric tumors (VRTs), defined by an annual incidence ≤2 per million inhabitants, represent a heterogeneous group of cancers. Due to their extremely low incidence, knowledge on these tumors is scant. Since 2012, the French Very Rare Tumors Committee (FRACTURE) database has recorded clinical data about VRTs in France. This...