Aurora Navajas

Hyperfractionated Versus Conventional Radiotherapy Followed by Chemotherapy in Standard-Risk Medulloblastoma: Results From the Randomized Multicenter HIT-SIOP PNET 4 Trial

PURPOSE To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. PATIENTS AND METHODS In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. RESULTS After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. CONCLUSION In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.

Mir-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia

Objectives Methotrexate (MTX), the key drug in childhood B-cell acute lymphoblastic leukemia (B-ALL) therapy, often causes toxicity. An association between genetic variants in MTX transport genes and toxicity has been found. It is known that these transporters are regulated by microRNAs (miRNAs), and miRNA single nucleotide polymorphisms (SNPs) interfere with miRNA levels or function. With regard to B-cell ALL, we have previously found rs56103835 in miR-323b that targets ABCC4 associated with MTX plasma levels. Despite these evidences and that nowadays a large amount of new miRNAs have been annotated, studies of miRNA polymorphisms and MTX toxicity are almost absent. Therefore, the aim of this study was to determine whether there are other variants in miRNAs associated with MTX levels. Patients and methods Blood samples of 167 Spanish patients with pediatric B-cell ALL treated with the LAL-SHOP protocol were analyzed. We selected all the SNPs described in pre-miRNAs with a minor allele frequency more than 1% (213 SNPs in 206 miRNAs) that could regulate MTX transporters because the miRNAs that target MTX transporter genes are not completely defined. Genotyping was performed with VeraCode GoldenGate platform. Results Among the most significant results, we found rs56292801 in miR-5189, rs4909237 in miR-595, and rs78790512 in miR-6083 to be associated with MTX plasma levels. These miRNAs were predicted, in silico, to regulate genes involved in MTX uptake: SLC46A1, SLC19A1, and SLCO1A2. Conclusion In this study, we detected three SNPs in miR-5189, miR-595, and miR-6083 that might affect SLC46A1, SLC19A1, and SLCO1A2 MTX transport gene regulation and could affect MTX levels in patients with pediatric B-cell ALL.

Efficacy and safety of liposomal cytarabine in children with primary CNS tumours with leptomeningeal involvement

PurposeTo assess the efficacy and safety of liposomal cytarabine in the treatment of de novo and relapsed leptomeningeal involvement in children with primary CNS tumours.MethodsData from clinical charts were entered into a database for consecutive unselected patients (n=20) from nine Spanish centres. Diagnosis of leptomeningeal involvement was confirmed by cytology, MRI and/or CT scan. The dose of liposomal cytarabine used varied from 20 to 50 mg, by age.ResultsThere were 8 females and 12 males, mean age 7.3 years (range 8 months to 18 years). The tumours were: 10 medulloblastomas, 4 ependymomas, 3 primitive neuroectodermal tumours and 3 other tumours. Fourteen had undergone previous chemotherapy and 12 radiotherapy. Nine received concurrent chemotherapy and 2 concurrent radiotherapy. Median follow-up was 244.5 days (range 12–869). Patients received a median of 5 doses (range 1–9) of liposomal cytarabine. A neurological response (complete or partial) was seen in 11/19 (58%) and a cytological response in 7/10 (64%). Median time to neurological progression exceeded 180 days (range 12–869). Adverse effects were reported in 11/20 patients, but none was grade IV.DiscussionLiposomal cytarabine was well tolerated and efficacious in this patient group, but prospective randomised trials are needed.

Reversible Cardiomyopathy Secondary to α-Interferon in an Infant

Abstract. Interferon-α (IFN-α) 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-α 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-α 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-α in infancy.

Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

Confirmation of involvement of new variants at CDKN2A/B in pediatric acute lymphoblastic leukemia susceptibility in the Spanish population

The locus CDKN2A/B (9p21.3), which comprises the tumor suppressors genes CDKN2A and CDKN2B and the long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS), was associated with childhood acute lymphoblastic leukemia (ALL) susceptibility in several genome wide association studies (GWAS). However, the variants associated in the diverse studies were different. Recently, new and independent SNPs deregulating the locus function were also identified in association with ALL risk. This diversity in the results may be explained because different variants in each population could alter CDKN2A/B locus function through diverse mechanisms. Therefore, the aim of this study was to determine whether the annotated risk variants in the CDKN2A/B locus affect the susceptibility of B cell precursor ALL (B-ALL) in our Spanish population and explore if other SNPs altering additional regulatory mechanisms could be also involved. We analyzed the four SNPs proposed by GWAs and two additional SNPs in miRNA binding sites in 217 pediatric patients with B-ALL and 330 healthy controls. The SNPs rs2811712, rs3731249, rs3217992 and rs2811709 were associated with B-ALL susceptibility in our Spanish population. ALL subtypes analyses showed that rs2811712 was associated with B-hyperdiploid ALL. These results provide evidence for the influence of genetic variants at CDKN2A/B locus with the risk of developing B-ALL.

Evidence in medulloblastomas

Medulloblastoma is the most common infratentorial malignant tumour under 15 years of age. In recent protocols, the patients are stratified for treatment in standard risk or high risk, according to the clinical variables as age, localized or disseminated disease, degree of surgical resection and more recently expected biological behaviour based on retrospective and prospective studies of former samples analyzed. The objectives for future treatments are reduce morbidity without jeopardizing survival.

Involvement of SNPs in miR-3117 and miR-3689d2 in childhood acute lymphoblastic leukemia risk

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by in silico analysis. SNPs rs12402181 in miR-3117 and rs62571442 in miR-3689d2 were associated with ALL risk in both cohorts, possibly through their effect on MAPK signalling pathway. These SNPs could be novel markers for ALL susceptibility.

Pharmacoepigenetics in childhood acute lymphoblastic leukemia: involvement of miRNA polymorphisms in hepatotoxicity

AIM Hepatotoxicity is one of the most common drug-related toxicities during the treatment of childhood acute lymphoblastic leukemia (ALL). Many genes involved in liver-specific signaling pathways are tightly controlled by miRNAs, and miRNA function could be modulated by SNPs. As a consequence, we hypothesized that variants in miRNAs could be associated with drug-induced hepatotoxicity. METHODS We analyzed 213 SNPs in 206 miRNAs in a cohort of 179 children with ALL homogeneously treated. RESULTS rs2648841 in miR-1208 was the most significant SNP during consolidation phase after false discovery rate correction, probably through an effect on its target genes DHFR, MTR and MTHFR. CONCLUSION These results point out the possible involvement of SNPs in miRNAs in toxicity to chemotherapy in children with ALL.

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

IntroductionThe 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 methodsThe 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.ResultsThe 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.ConclusionsThe 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.