First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.The trial was sponsored by Fundación de Investigacion Biomedica del Hospital Nino Jesus (EudraCT 2008-000364-16; NCT01844661). This work was funded by grants EC11/061, EC08/00094, and EC07/90591 from Instituto de Salud Carlos III and Fondos FEDER. M.R is supported by Asociación Pablo Ugarte, Asociación NEN, and Fundación Neuroblastoma.S

Situación de la preservación de fertilidad en pacientes con cáncer en nuestro medio: grado de conocimiento, información e implicación de los profesionales.

The estimated risks of infertility in childhood cancer due to radiation, chemotherapy and surgery are well known. The involvement of professionals and advances in the different methods of preservation are increasing. However, many patients do not receive information or perform any method of preservation. Questionnaires to paediatric onco-haematology institutions throughout Spain. The questionnaire consisted of 22 questions assessing their usual practices and knowledge about fertility preservation. Fifty members of the Spanish Society of Paediatric Haematology and Oncology, representing 24 of 43 centres, responded. These represented 82% of centres that treated higher numbers of patients. The effect of treatment on fertility was known by 78% of those who responded, with 76% admitting not knowing any guideline on fertility in children or adolescents. As for the ideal time and place to inform the patient and/or family, only 14% thought it should be done in the same cancer diagnosis interview. In clinical practice, 12% of those surveyed never referred patients to Human Reproduction Units, another 12% only did so if the patients showed interest, and 38% only refer patients in puberty. Just over one-third (34%) of those referrals were going to receive highly gonadotoxic treatment. There are clear differences between pre-puberty and puberty patients. The frequency with which some method of fertility preservation is performed in patients is low. All respondents believe that the existence of national guidelines on the matter would be of interest

Thyroid abnormalities in patients with Hodgkin lymphoma: The importance of close surveillance

Introduction: Survival in paediatric patients with Hodgkin lymphoma (HL) has increased over the last decades. However, these patients are at increased risk of developing late thyroid sequelae due to the treatment with irradiation and alkylating agents. Methods: We conducted an observational and retrospective study in patients with a diagnosis of HL between 2007 and 2022, in a hospital that is a paediatric oncology reference centre, through the review of electronic health records. We collected data on demographic (age, sex), clinical, radiological and histopathological variables, the dosage of alkylating agents and radiotherapy (RT) and on thyroid disorders using Microsoft Excel. The data analysis was conducted with SPSS version 17, using the Fisher exact test for qualitative data, a nonparametric test for quantitative data and Kaplan-Meier curves. Results: Sixty patients received a diagnosis of HL from 2007 to 2022. The median duration of follow-up was 78.5 months. There were 4 detected cases of hypothyroidism, 5 of thyroid nodules and 1 of subclinical hyperthyroidism. Treatment with RT was significantly associated with the development of hypothyroidism (P= .026), thyroid nodules (P= .01) and thyroid disease overall (P= .003). We estimated that the risk of thyroid disease increased 8-fold with each additional Grey received (hazard ratio, 1.081; 95% CI, 1.014–1.152; P= .017). Conclusion: Hodgkin lymphoma patients treated with RT are at increased risk of late thyroid disorders, mainly hypothyroidism and malignancy. This risk is greater the higher the RT dosage and the longer the follow-up. We did not find evidence of an association between the use of alkylating agents and an increase in the risk of thyroid disease. Resumen: Introducción: La supervivencia de pacientes con linfoma de Hodgkin (LH) se ha incrementado en las últimas décadas. Sin embargo, el tratamiento con radioterapia (RT) y alquilantes aumenta el riesgo de desarrollo de patología tiroidea a largo plazo. Métodos: Se realizó un estudio observacional y retrospectivo en un hospital de referencia para oncología pediátrica, de pacientes diagnosticados de LH desde 2007-2022 mediante revisión de historias clínicas del sistema “Historia Clínica Electrónica” (HCIS). Se recogieron en Microsoft Excel datos demográficos (edad, sexo), clínicos, radiológicos y anatomopatológicos, así como dosis de RT y alquilantes recibidas, y alteraciones tiroideas encontradas. Estos datos fueron analizados mediante el sistema estadístico SPSS17, utilizando test de Fisher para análisis cualitativo y pruebas no paramétricas para las variables cuantitativas, así como curvas de Kaplan-Meier. Resultados: Se diagnosticaron 60 pacientes con LH, con una mediana de seguimiento de 78,5 meses. Se detectaron 4 casos de hipotiroidismo, 5 nódulos y un caso de hipertiroidismo subclínico. El tratamiento con RT resultó estadísticamente significativo para el desarrollo de hipotiroidismo (p=0,026), nódulos tiroideos (p=0,01) y patología tiroidea total (p=0,003). Este riesgo aumenta a razón de un 8% por cada grey administrado (p = 0,017, HR = 1,081, IC95% = 1,014–1,152). Conclusiones: Los pacientes con LH tratados con RT presentan un mayor riesgo de desarrollo de patología tiroidea a largo plazo, principalmente hipotiroidismo y neoplasias. Este riesgo aumenta cuanto mayor es la dosis recibida y mayor el tiempo de seguimiento. No se ha podido demostrar que los agentes alquilantes aumenten el riesgo de desarrollo de patología tiroidea

Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification