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.

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.

Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

Clinical features of influenza disease in admitted children during the first postpandemic season and risk factors for hospitalization: a multicentre Spanish experience.

The main objectives of this study were to describe the characteristics of children with influenza infection during the postpandemic outbreak, and to compare sociodemographic and clinical data between patients who required hospitalization and those managed on an outpatient basis with a matched case-control study design. This is a multicentre paediatric study in Spain that included patients aged 6 month to 18 years in whom influenza infection was confirmed by real-time reverse transcription-polymerase chain reaction between December 2010 and March 2011. Among the 143 admitted patients, the main reason for admission was respiratory failure (123/143). In 55 there was some previously known disease. The median age was lower in patients without comorbidity (1.8 years: interquartile range 1.0-3.0 versus 5.3 years: interquartile range 1.3-10.7); p <0.01). The lag time from onset of symptoms to starting antiviral treatment was correlated with the length of hospital stay (Rho Spearman = + 0.32; p 0.01). Twenty patients required admission to the paediatric intensive care units, all due to respiratory failure. Children with chest X-ray opacities in more than one quadrant more frequently required admission to intensive care. Having a neurological disease conferred the highest risk of requiring hospitalization (OR 17.18) in a multivariate analysis. This study concludes that influenza in the paediatric population requiring hospitalization during the postpandemic season affected mainly children with neurological or pulmonary comorbidities and children of parents with a lower educational level. Most of the influenza infections caused respiratory symptoms, although neurological manifestations were also observed. Early initiation of oseltamivir was associated with a shorter length of hospital stay.

[Protocol for the study and treatment of immune thrombocytopenic purpura (ITP). ITP-2010]. / Protocolo de estudio y tratamiento de la trombocitopenia inmune primaria (PTI-2010).

Primary immune thrombocytopenia (ITP), formerly known as immune thrombocytopenic purpura, is a disease in which clinical and therapeutic management has always been controversial. The ITP working group of the Spanish Society of Paediatric Haematology and Oncology has updated its guidelines for diagnosis and treatment of ITP in children based on current guidelines, literature review, clinical trials and member consensus. The primary objective was to lessen clinical variability in diagnostic and therapeutic procedures in order to obtain best clinical results with minimal adverse events and good quality of life.

Hemophagocytic lymphohistiocytosis in a pancreas-kidney transplant recipient: response to dexamethasone and cyclosporine.

We describe a severe case of hemophagocytic lymphohistiocytosis (HLH), secondary to a candida glabrata retroperitoneal abscess in a 41-year-old simultaneous pancreas-kidney transplantation (SPKT) recipient. Despite percutaneous abscess drainage and antifungal therapy, general status deteriorated with persistent fever, severe pancytopenia and liver dysfunction. Presence of hypertriglyceridemia, very high serum levels of ferritin and hemophagocytosis in a bone-marrow aspirate gave the diagnosis of HLH. Of note, change from tacrolimus to cyclosporine together with dexamethasone produced rapid response with status improvement. We concluded that HLH, a rare but often fatal condition characterized by excessive activation of lymphocytes and macrophages, is a diagnostic and therapeutic challenge in solid-organ transplanted patients and must be suspected in the presence of fever, blood cytopenia and liver dysfunction. Specific antiinfectious therapy together with cyclosporine and dexamethasone may be a therapeutic approach.

[Ophthalmological findings in pediatric brain neoplasms: 58 cases]. / Manifestaciones oftalmológicas en tumores cerebrales pediátricos: 58 casos.

PURPOSES: To describe the visual manifestations of brain neoplasms, and to analyze the effect of tumor control on these. METHODS: This is a descriptive retrospective study, which includes patients under 14 years of age, suffering from different brain neoplasms in our hospital between 1996 and 2005 inclusive. RESULTS: In the group of patients with low visual acuity, 44% had organic amblyopias. In 28% of cases, the amblyopia was secondary to the strabismus/nystagmus produced by the developing tumor. Corrective treatment was successful in some cases of partial or total organic amblyopia. Ophthalmologic evaluation (including perimetry and fundoscopy) enabled detection of 3 tumor relapses. CONCLUSIONS: Visual analysis (visual acuity, perimetry, fundoscopy) should be an essential component of assessment during brain neoplasm treatment and follow-up. Corrective treatment is sometimes successful in organic amblyopias

[Kikuchi-Fujimoto disease: review of four cases]. / Enfermedad de Kikuchi-Fujimoto: estudio de cuatro casos.

Kikuchi-Fujimoto disease is an uncommon form of lymphadenitis, firstly described in Japan. Etiology is unknown. It affects mainly young women. It commonly manifests as a painful cervical lymphadenitis usually associated with fever and leukopenia. Clinical course users to be benign, leading spontaneously to a complete recovery. Histological findings include necrotizing changes with cariorrhesis, partial loss of ganglionar architecture and foci of histiocytic infiltrates in the cortical and/or paracortical zones of the lymph nodes. A common finding is the absence of neutrophil granulocytes in the inflammatory infiltrates, in contrast to other necrotizing lymphadenitis. We report four cases of Kikuchi-Fujimoto disease, recently identified in our hospital.

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.

Hypereosinophilia due to myiasis.

We report the case of a 2-year-old boy with hypereosinophilia who presented with fever, muscle pain and heart, CNS and skin involvement. He was treated with steroids with partial response. Six months after diagnosis of hypereosinophilia, several scalp nodules were surgically removed and Hypoderma bovis larvae were found, which led to the diagnosis of cutaneous myiasis. Following removal of the larvae, the clinical and hematological manifestations returned to normal.

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.

Use of serological markers as a screening test in family members of patients with celiac disease.

That symptomatic celiac disease (CD) can occur in several members of a family has long been recognized. Given the possible complications of untreated CD, it is also important to diagnose those family members with "silent" disease, to offer them the benefit of a gluten-free diet. We studied 642 first-degree relatives of 210 patients with CD, two of the latter belonging to the same family. IgA and IgG antigliadin antibodies and IgA antiendomysium antibodies were studied in all. Jejunal biopsy was performed in 59 subjects, 47 with positive and 12 with negative serological markers. Celiac disease was diagnosed de novo in 18 cases (2.8%). Diagnosis in a symptomatic mother was made by jejunal biopsy despite the negativity of all immunological markers. We conclude that the risk of having CD is higher in siblings than in parents of patients with CD, that the most useful marker for diagnosis is the study of IgA antiendomysium antibodies, and that the absence of positive serological markers does not completely exclude the diagnosis of CD.

[Intolerance to cow's milk proteins. An epidemiologic study]. / Intolerancia a proteínas de leche de vaca. Estudio epidemiológico.

The incidence of cow's milk protein intolerance (CMPI) varies depending on the series. The aim of the present investigation was to determine the incidence of this disease in our population and its change over the past the years. Over the period January 1977 to December 1986, 217 patients suspected to have the disease were submitted to a cow's milk challenge test. Diagnosis was confirmed clinically and/or pathologically in 121 patients and was ruled out in 96 patients. The incidence for the whole period was 0.78 cases/1,000 alive newborn infants. However, it fell significantly over the ten years, with a maximum of 1.36/1,000 alive newborn infants in 1979 and a minimum of 0.17/1,000 alive newborn infants in 1986 (r = 0.76, p less than 0.001). We conclude that, similarly to the observation in other diseases of nutritional origin, the incidence in our population of CMPI has clearly decreased, probably as a consequence of changes in the dietary habits.