Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

The study analyzes the current status of personalized medicine in pediatric oncology in Spain. It gathers national data on the tumor molecular studies and genomic sequencing carried out at diagnosis and at relapse, the centers that perform these studies, the technology used and the interpretation and clinical applicability of the results. Current challenges and future directions to achieve a coordinated national personalized medicine strategy in pediatric oncology are also discussed. Next generation sequencing-based (NGS) gene panels are the technology used in the majority of centers and financial limitations are the main reason for not incorporating these studies into routine care. Nowadays, the application of precision medicine in pediatric oncology is a reality in a great number of Spanish centers. However, its implementation is uneven and lacks standardization of protocols; therefore, national coordination to overcome the inequalities is required. Collaborative work within the Personalized Medicine Group of SEHOP is an adequate framework for encouraging a step forward in the effort to move precision medicine into the national healthcare system.

The paediatric cancer clinical research landscape in Spain: a 13-year multicentre experience of the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

PURPOSE: Early phase trials are crucial in developing innovative effective agents for childhood malignancies. We report the activity in early phase paediatric oncology trials in Spain from its beginning to the present time and incorporate longitudinal data to evaluate the trends in trial characteristics and recruitment rates. METHODS: Members of SEHOP were contacted to obtain information about the open trials at their institutions. The study period was split into two equal periods for analysis: 2007-2013 and 2014-2020. RESULTS: Eighty-one trials and two molecular platforms have been initiated. The number of trials has increased over the time of the study for all tumour types, with a predominance of trials available for solid tumours (66%). The number of trials addressed to tumours harbouring specific molecular alterations has doubled during the second period. The proportion of industry-sponsored compared to academic trials has increased over the same years. A total of 565 children and adolescents were included, with an increasing trend over the study period. For international trials, the median time between the first country study approval and the Spanish competent authority approval was 2 months (IQR 0-6.5). Fourteen out of 81 trials were sponsored by Spanish academic institutions. CONCLUSIONS: The number of available trials, and the number of participating patients, has increased in Spain from 2007. Studies focused on molecular-specific targets are now being implemented. Barriers to accessing new drugs for all ranges of age and cancer diseases remain. Additionally, opportunities to improve academic research are still required in Spain.

ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain.

INTRODUCTION: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. METHODS: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. RESULTS: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. CONCLUSIONS: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.

Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years

Background: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. Patients and methods 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. Results: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. Conclusions: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain

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Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years.

BACKGROUND: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. PATIENTS AND METHODS: 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. RESULTS: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. CONCLUSIONS: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain.

Revisión de los pacientes estudiados por coagulopatía en una unidad de Oncohematología / Review of patients studied for coagulopathy in a Hematology/Oncology unit

INTRODUCCIÓN: Los síntomas/signos indicativos de una coagulopatía son un motivo de consulta frecuente en las unidades de Hematología Pediátrica. Tanto la clínica como los antecedentes familiares son fundamentales para el diagnóstico. PACIENTES Y MÉTODOS: Estudio retrospectivo y descriptivo de los pacientes derivados a una consulta de Hematología Pediátrica de un hospital de tercer nivel por posible coagulopatía durante el año 2012. RESULTADOS: Se estudiaron 47 niños. El 61,7% no había presentado previamente sangrado. El motivo de derivación más frecuente fue un tiempo de tromboplastina parcial activada alargado sin hemorragia (42,5%); de estos, un 25% fue diagnosticado de una coagulopatía con riesgo real de sangrado. En los pacientes derivados por tiempo de tromboplastina parcial activada alargado con clínica hemorrágica se detecta una coagulopatía con riesgo real de sangrado con mayor frecuencia (41,7%). En los niños con antecedentes familiares de sangrado se diagnostica con más frecuencia una coagulopatía con riesgo real de sangrado: 37,5 vs. 14,3% (niños sin antecedentes familiares). Los diagnósticos han sido: sano (48,9%), enfermedad de von Willebrand tipo1 (19,1%), déficit de factor XII (19,1%), déficit de factor XI(4,2%), déficit de precalicreína/cininógeno de alto peso molecular (2,1%), déficit adquirido de factor X (2,1%) y déficit de factor IX (2,1%). CONCLUSIONES: Los antecedentes personales y familiares de sangrado orientan el diagnóstico de una coagulopatía. El motivo de derivación debería basarse en mayor medida en la clínica hemorrágica y no solo en un tiempo de laboratorio alterado. Los diagnósticos más frecuentes han sido enfermedad de von Willebrand tipo 1 y déficit de factor XII

INTRODUCTION: Symptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. PATIENTS AND METHODS: Retrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. RESULTS: A total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor XII deficiency (19.1%), factor XI deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor X (2.1%), and factor IXdeficiency (2.1%). CONCLUSIONS: A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor XII deficiency

[Review of patients studied for coagulopathy in a Hematology/Oncology unit]. / Revisión de los pacientes estudiados por coagulopatía en una unidad de Oncohematología.

INTRODUCTION: Symptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. PATIENTS AND METHODS: Retrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. RESULTS: A total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor xii deficiency (19.1%), factor xi deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor x (2.1%), and factor ix deficiency (2.1%). CONCLUSIONS: A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor xii deficiency.

A prospective biological study in relation to a family with Li-Fraumeni syndrome

INTRODUCTION: The Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disorder associated with different tumor types in childhood and young adults. Approximately 70% of LFS cases contain germline mutations in the TP53 gene. We report a case of a family suspected of LFS. MATERIALS AND METHODS: The proband and four members of the family affected were diagnosed with cancer at an early age and they all died except the proband. Exons 5-9 from TP53 gene were analysed by direct amplification and sequencing in 7 family members. RESULTS: The analysis revealed a germline nonsense mutation in exon 8 at codon 306 of the codified region of the TP53 gene, causing a change of CGA to TGA (Arg→Stop) in the proband, her mother, her cousin and her maternal uncle. Proband's maternal grandmother and aunt do not have the mutation. CONCLUSIONS: The members of this family that were studied meet the criteria of classic LFS and the described mutation increases their susceptibility to develop cancer. The proband's maternal grandfather died of lung cancer in 1993, and we believe that he was the carrier of the mutation in this family (AU)

Reversible cardiomyopathy secondary to alpha-interferon in an infant.

Interferon-alpha (IFN-alpha) is a biological response modifier with antiviral and tumoral effect that is used in the treatment of chronic myelogenous leukemias. Adverse effects are well documented and cardiovascular disturbances mostly include hypotension and tachycardia and rarely cardiomyopathy. We report on an infant with chronic myelomonocytic leukemia (CML) diagnosed at 3 months of age who was treated with increasing IFN-alpha dosage (2.5-5.5 million U/m2/day) given subcutaneously for 7.5 months. At that age, he presented anorexia, general malaise, and nocturnal sweating for about a week, followed by respiratory distress and tachycardia. Diagnosis of congestive heart failure was suspected and documented by cardiomegaly and echographic changes of left ventricular dilated cardiomyopathy, with a 40% left ventricular ejection fraction (EF) and 20% fractional shortening (FS). He was treated with digoxin, furosemide, and angiotensin converting inhibitors, and IFN-alpha was discontinued. Progressive improvement of cardiac function was observed within 7 months of the events with normalization of the echocardiographic findings (EF 60%, FS 31%). We should emphasize the possibility of severe and reversible cardiac toxicity of IFN-alpha in infancy.

[Vaccination of chickenpox in children with acute lymphoblastic leukaemia]. / Vacunación de varicela en niños con leucemia linfoblástica aguda.

Varicella vaccine has shown its efficacy to prevent the disease and complications in healthy and immunodeficient children. In this article the authors evaluate the immunologic status of acute lymphoblastic leukaemia at diagnosis and at follow up and the development of chickenpox and/or herpes zoster. Children with negative serology and continuous complete remission of acute lymphoblastic leukaemia for one year were vaccinated. Of 71 children diagnosed of acute lymphoblastic leukaemia from 1983 to 1996, 25 received the vaccine and seroconversion was obtained in 76% after one dose and 92% after the second dose. Vaccine tolerance was adequate. The incidence of herpes zoster infection was decreased in vaccinated children during chemotherapy compared to the wild-virus infected ones. Nowadays that vaccine for healthy children is recommended, we consider a priority to protect from chickenpox the children affected by leukaemia that are in continuous complete remission of the disease.

Hydrops fetalis and fibrosarcoma: case report of an uncommon association.

UNLABELLED: Fetal hydrops associated with neonatal tumours is an uncommon occurrence. The diagnosis can be established prenatally by ultrasound examination. The treatment of choice is surgery which may be curative. We report the case of a male born at 32 weeks gestation who presented with severe hydrops fetalis and a thoracic mass. The child could not be operated upon because of rapid clinical deterioration. The autopsy findings confirmed the diagnosis of congenital fibrosarcoma. This is, to our knowledge, the first case of hydrops fetalis associated with fibrosarcoma. CONCLUSION: The association of hydrops fetalis and fibrosarcoma is an exceptional observation but can be added to the long list of differential diagnoses of non-immune hydrops.

Secondary central nervous system metastases in children with neuroblastoma.

Cerebral and meningeal involvement in patients with primary extracranial neuroblastoma (NB) is unusual although it is generally present in disseminated disease. The intensification of chemotherapy that has prolonged survival in these children has changed the pattern of relapse presentation, as occurs with isolated central nervous system (CNS) disease. We report 4 patients with secondary CNS metastases. Three infants of 16, 14, and 10 months of age, diagnosed with primary abdominal NB stage 4, presented neuromeningeal metastases during maintenance chemotherapy with seizures and cranial hypertension as the first manifestation. Another 8-year-old patient diagnosed with NB stage 3 presented local relapse with later neuromeningeal metastases. All died in the following 3 months. The possibility of CNS relapse in patients with NB should be considered when neurological symptoms and signs appear. These new relapse forms overshadow the prognosis of these children.

[Acute lymphoblastic leukemia with L1 morphology arising during treatment for ALL-L3 in a child with AIDS]. / Leucemia linfoblástica aguda (LLA) con morfología L1 de aparición durante el tratamiento de LLA-L3 en niño con SIDA.

A child with AIDS is presented who developed L1-ALL while being treated for L3-AL. After achievement of complete remission of the former, he suffered a relapse with L3 morphology. Although the possibilities of a shift in both the morphology and the immunophenotype of ALL in relapse are well known, the rarity of L1-ALL in association with AIDS is stressed by the authors, along with the factors related with the morphologic and phenotypic changes shown by these patients.