Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma

Dinutuximab beta; Pacients pediàtrics; NeuroblastomaDinutuximab beta; Pacientes pediátricos; NeuroblastomaDinutuximab beta; Pediatric patients; NeuroblastomaThe anti-GD2 antibody dinutuximab beta (Qarziba®) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. Topics such as the mode of preparation and administration, the concomitant use of interleukin-2, the recommended pediatric age and dose for its use, or the adequate management of possible toxicities are important aspects to review. The objective of this article was to update the clinical guide to management with dinutuximab beta of children with neuroblastoma based on the most recent published evidence and our own experience in clinical practice

Multidisciplinary consensus on optimising the detection of NTRK gene alterations in tumours

Fusions de gens; Oncologia molecular; NeoplàsiaFusiones de genes; Oncología molecular; NeoplasiaGene fusions; Molecular oncology; NeoplasmThe recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System.SEOM, SEAP and SEHOP have received financial support for this project in the form of unrestricted collaboration in the logistics of expert meeting from Bayer and Roche

The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Precision Medicine; Pediatric and Adolescent Patients; Recurrent MalignanciesMedicina de Precisión; Pacientes pediátricos y adolescentes; Neoplasias malignas recurrentesMedicina de precisió; Pacients pediàtrics i adolescents; Neoplasmes malignes recurrentsMAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/ refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA)

A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Cancer models; Paediatric cancerModelos de cáncer; Cáncer pediátricoModels de càncer; Càncer pediàtricPediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies.This work was supported by grants from Fondation Gustave Roussy; Fédération Enfants Cancers et Santé, Société Française de lutte contre les Cancers et les leucémies de l’Enfant et l’adolescent (SFCE), Association AREMIG and Thibault BRIET; Parrainage médecin-chercheur of Gustave Roussy; INSERM; Canceropôle Ile-de-France; Ligue Nationale Contre le Cancer (Equipe labellisée); Fondation ARC for the European projects ERA-NET on Translational Cancer Research (TRANSCAN 2) Joint Transnational Call 2014 (JTC 2014) ‘Targeting Of Resistance in PEDiatric Oncology (TORPEDO)’, ERA-NET TRANSCAN JTC 2014 (TRAN201501238), and TRANSCAN JTC 2017 (TRANS201801292); Agence Nationale de la Recherche (ANR-10-EQPX-03, Institut Curie Génomique d’Excellence (ICGex); IMI ITCC-P4; The Child Cancer Research Foundation (CCRF), Cancer Council Western Australia (CCWA); PAIR-Pédiatrie/CONECT-AML (INCa-ARC-LIGUE_11905 and Association Laurette Fugain), Ligue contre le cancer (Equipe labellisée, since 2016), OPALE Carnot institute; Dell; Fondation Bristol-Myers Squibb; Association Imagine for Margo; Association Manon Hope; L’Etoile de Martin; La Course de l’Espoir; M la vie avec Lisa; ADAM; Couleur Jade; Dans les pas du Géant; Courir pour Mathieu; Marabout de Ficelle; Olivier Chape; Les Bagouz à Manon; Association Hubert Gouin Enfance et Cancer; Les Amis de Claire; Kurt-und Senta Hermann Stiftung; Holcim Stiftung Wissen; Gertrud-Hagmann-Stiftung für Malignom-Forschung; Heidi Ras Grant Forschungszentrum fürs Kind; Children’s Liver Tumor European Research Network (ChiLTERN) EU H2020 projet (668596); Fundación FERO and the Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Sassella-Stiftung, Berger-Janser Stiftung and Krebsliga Zürich, Deutschland Gemeindienst e.V. and others from Barcelona and province, and No Limits Contra el Cáncer Infantil Association

Improved collection of hematopoietic stem cells and progenitors from Fanconi anemia patients for gene therapy purposes

Anèmia de Fanconi; Mozobil; Teràpia gènicaAnemia de Fanconi; Mozobil; Terapia génicaFanconi anemia; Mozobil; Gene therapyDifficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols.This work was supported by grants from the European Commission’s Seventh Framework Program (HEALTH-F5-2012-305421 to the EUROFANCOLEN Consortium, J.A.B., J. Sevilla, C.D.-d.-H., J. Soulier, and J. Surralles), Ministerio de Sanidad, Servicios Sociales e Igualdad (EC11/060 and EC11/550 to C.D.-d.-H., J. Sevilla, J.A.B., and J. Surralles), Ministerio de Economía, Comercio y Competitividad and Fondo Europeo de Desarrollo Regional (SAF2015-68073-R, RTI2018-097125-B-I00 to P.R. and RTI2018-098419-B-I00 to J. Surralles), Fondo de Investigaciones Sanitarias at the Instituto de Salud Carlos III (RD12/0019/0023 to J.C.S.), and Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid (AvanCell Project; B2017/BMD3692). CIBERER is an initiative of the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional. J. Surralles is supported by ICREA Academia and FARF

Targeting the Hedgehog Pathway in Rhabdomyosarcoma

Embryonic pathways; Paediatric cancer; Soft tissue sarcomasVies embrionàries; Càncer pediàtric; Sarcomes de teixits tousVías embrionarias; Cáncer pediátrico; Sarcomas de tejidos blandosAberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours—among them sarcomas—mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting.This article was funded by grants from: Institut Català d’Oncologia (ICO); Instituto de Salud Carlos III (PI18/00398 and FI18/00178); ACCIÓ (COMRDI15-1-0014); Fundació la Marató de TV3; Fundació Albert Bosch; Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst e.V. and others from Barcelona and province; Fundation Amics Joan Petit; Del Hospital a la cathedral Initiative by Xavi Vallès; and Mi compañero de viaje Association

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma

Dissemination; Paediatric cancer; Solid tumoursDiseminación; Cáncer pediátrico; Tumores sólidosDisseminació; Càncer pediàtric; Tumors sòlidsThe majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.This research was supported by grants from: Institut Català d’Oncologia (ICO); Instituto de Salud Carlos III (PI18/00398 and FI18/00178); ACCIÓ (COMRDI15-1-0014); Fundació la Marató de TV3; Fundació A. BOSCH; Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst e.V. and others from Barcelona and province; Eric Abidal Foundation; Del Hospital a la catedral Initiative by Xavi Vallès; and Mi compañero de viaje Association

Determinacions del perfil genètic del càncer pediàtric

Oncologia; Perfil genètic; Càncer pediàtric; PrecisióOncología; Perfil genético; Cáncer pediátrico; PrecisiónOncology; Genetic profile; Pediatric cancer; AccuracyL'àmbit d'aquest grup de treball és la implementació de panels NGS per a diagnòstic / pronòstic / tractament de càncer en pacients menors de 18 anys (oncologia i hematologia). Els casos de predisposició genètica en pacients pediàtrics es tractaran en el grup de predisposició genètica. El càncer infantil comprèn més de 40 entitats entre leucèmies, limfomes, tumors cerebrals i sòlids extracranials; per la qual cosa no és possible tècnicament o operativament fer panels específics per a cada un d'aquests càncers. Serà necessari utilitzar panels comercials o acadèmics dissenyats específicament per a càncer infantil

Determinacions del perfil genètic del càncer pediàtric

Oncologia; Perfil genètic; Càncer pediàtric; PrecisióOncología; Perfil genético; Cáncer pediátrico; PrecisiónOncology; Genetic profile; Pediatric cancer; AccuracyL'àmbit d'aquest grup de treball és la implementació de panels NGS per a diagnòstic / pronòstic / tractament de càncer en pacients menors de 18 anys (oncologia i hematologia). Els casos de predisposició genètica en pacients pediàtrics es tractaran en el grup de predisposició genètica. El càncer infantil comprèn més de 40 entitats entre leucèmies, limfomes, tumors cerebrals i sòlids extracranials; per la qual cosa no és possible tècnicament o operativament fer panels específics per a cada un d'aquests càncers. Serà necessari utilitzar panels comercials o acadèmics dissenyats específicament per a càncer infantil

A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient's tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies