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.

[Long-term renal function in Wilms tumor survivors]. / Función renal a largo plazo en supervivientes de tumor de Wilms.

OBJETIVE: To evaluate long-term renal function and morbimortality in non-syndromic Wilms tumor (WT) survivors. METHODS: Retrospective study about WT patients treated in 1993-2017, according to SIOP protocols. Mortality, glomerular filtration rate (GFR), prevalence of hypertension and requirement of dialysis and renal transplant were evaluated. Chronic kidney disease (CKD) was defined as GFR <90 ml/min/1.73 m2. RESULTS: Thirty-nine children were treated in the 25 analyzed years. Median time of follow-up was 6 years (0.5-21 years). 48% (19 patients) debuted with stage I or II. Four cases had high-grade histo-logy. Mortality rate was 10%. GFR data were found in 37 patients. Chronic kidney disease (grade I-II) turned up in 6 patients (16%). No patient required renal replacement therapy or renal transplant. 16% of patients developed CKD in both unilateral and bilateral WT, (p>0.05); OR 1.04 (IC 95% 0.09-10.9). Identical results were obtained comparing patients treated with or without radiotherapy (16%). Children with stage I-III had CKD in 11% vs. 40% of patients with stage IV (p=0.12); OR 5.3 (IC 95% 0.61-45). None of them presented hypertension in addition. CONCLUSIONS: In the current study the prevalence of CKD was low but not negligible, although no patients required renal replacement therapy or renal transplant. Bilateral renal involvement and radiotherapy were not associated with CKD development. Metastatic disease determines a higher risk of CKD.

OBJETIVOS: Evaluar la función renal y la morbimortalidad a largo plazo, en supervivientes de tumor de Wilms (TW) no sindrómico. MATERIAL Y METODOS: Estudio retrospectivo de pacientes con TW entre 1993-2017 tratados según protocolos SIOP. Evaluamos mortalidad, filtrado glomerular (FG), prevalencia de hipertensión arterial (HTA), necesidad de diálisis y trasplante renal. Se definió enfermedad renal crónica (ERC) como FG <90 ml/min/1,73 m2. RESULTADOS: En los 25 años analizados se trataron 39 pacientes con edad media diagnóstica de 3,6 años (0,3-11 años). Mediana de seguimiento 6 años (0,5-21 años). El 48% (19 pacientes) debutaron con estadio I o II. Cuatro pacientes presentaron histología de alto riesgo (10%). La mortalidad fue del 10%. El 16% (6 pacientes) desarrolló ERC (grados I-II). Ningún paciente precisó terapia renal sustitutoria (TRS) o trasplante. La presencia de ERC tanto en enfermedad unilateral como bilateral fue del 16%, p>0,05; OR 1,04 (IC 95% 0,09-10,9). Se obtuvieron idénticos resultados (16%) comparando pacientes que recibieron radioterapia frente a aquellos que no. Los pacientes en estadio I, II y III presentaron una prevalencia de ERC del 11% vs. 40% en estadio IV (p=0,12); OR 5,3 (IC 95% 0,61-45). Ningún paciente asoció HTA crónica. CONCLUSIONES: En el presente estudio la prevalencia de ERC en supervivientes de TW no sindrómico es baja pero no desdeñable, aunque ninguno precisó trasplante renal o TRS. La presencia de enfermedad bilateral y la radioterapia no se asociaron al desarrollo de ERC. La enfermedad metastásica condiciona un riesgo mayor de ERC.

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia.

There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n=49) or T-ALL (n=5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1+ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4+ B-ALL but also ETV6-RUNX1+, BCR-ABL+ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P=0.002) and disease-free survival (DFS; 0 vs 43%; P=0.03) in MLL-AF4+ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age>14 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4+ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4+ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

Cavernomas in children with brain tumors: a late complication of radiotherapy.

BACKGROUND: Delayed complications of radiation therapy comprise cerebral atrophy, radionecrosis and induction of tumors. Recent reports indicate the possibility of the "de-novo" formation of intracranial cavernomas in patients submitted to radiation therapy to the brain. OBJECTIVES: To report three children, two with medulloblastomas and one with a pineal germinoma, treated with radiotherapy that developed intracerebral cavernous hemangiomas some years after treatment. With this work, we aim to draw attention to this occurrence in the neurosurgical community. RESULTS: The patients were two girls and one boy with ages comprised between 2.5 and 7 years (mean 5.2 years). The average interval from irradiation to the appearance of cavernoma was of 5.3 years (range 5-6 years). The lesions were found during the routine neuroimaging studies performed for the follow-up of their primary neoplasms. No patient showed signs or symptoms related to the cavernomas. However, the three children will need both clinical and neuroimaging surveillance to monitor the evolution of these incidentally discovered lesions. CONCLUSIONS: Intracranial cavernomas can occur years after cerebral radiation therapy. In spite of previous reports that show a high incidence of bleeding lesions, cavernomas may be found incidentally during the neuroimaging surveillance studies that are performed to children with brain tumors previously treated with radiotherapy. In these cases, a conservative attitude seems to be advisable, reserving surgery only for those lesions that grow or bleed.

Toxicity to topical dimethyl sulfoxide in a pediatric patient with anthracycline extravasation.

Accidental extravasation of vesicant chemotherapy may cause important tissue injuries. Nowadays, the majority of authors propose topical dimethyl sulfoxide (DMSO), with or without local cooling, as the treatment of choise efor anthracyclines extravasation. No significant toxicity has been reported when DMSO is used as topical treatment. This report describes a case of local toxicity consisting of severe pain after its use in a pediatric patient. An illustration shows the extravasation area.