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.

Distribution of segmental chromosomal alterations in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is a heterogeneous tumor with extremely diverse prognosis according to clinical and genetic factors such as specific combinations of chromosomal imbalances. METHODS: Molecular karyotyping data from a national neuroblastic tumor database of 155 NB samples were analyzed and related to clinical data. RESULTS: Segmental chromosomal alterations (SCA) were detected in 102 NB, whereas 45 only displayed numerical alterations. Incidence of SCA was higher in stage M (92%) and MYCN amplified (MNA) NB (96%). Presence of SCA was associated with older age, especially 1q gain and 3p deletion. 96% of the deaths were observed in the SCA group and 85% of the relapsed NB contained SCA. The alteration most commonly associated with a higher number of other segmental rearrangements was 11q deletion, followed by 4p deletion. Whole-chromosome 19 gain was associated with lower stages, absence of SCA and better outcome. CONCLUSIONS: SCA are not randomly distributed and are concentrated on recurrent chromosomes. The most frequently affected chromosomes identify prognostic factors in specific risk groups. SCA are associated with older age and MNA. We have identified a small subset of patients with better outcome that share whole-chromosome 19 numeric gain, suggesting its use as a prognostic biomarker in NB.

Precision medicine in Ewing sarcoma: a translational point of view.

Ewing sarcoma is a rare tumor that arises in bones of children and teenagers but, in 15% of the patients it is presented as a primary soft tissue tumor. Balanced reciprocal chimeric translocation t(11;22)(q24;q12), which encodes an oncogenic protein fusion (EWSR1/FLI1), is the most generalized and characteristic molecular event. Using conventional treatments, (chemotherapy, surgery and radiotherapy) long-term overall survival rate is 30% for patients with disseminated disease and 65-75% for patients with localized tumors. Urgent new effective drug development is a challenge. This review summarizes the preclinical and clinical investigational knowledge about prognostic and targetable biomarkers in Ewing sarcoma, finally suggesting a workflow for precision medicine committees.

Li-Fraumeni syndrome heterogeneity.

Clinical variability is commonly seen in Li-Fraumeni syndrome. Phenotypic heterogeneity is present among different families affected by the same pathogenic variant in TP53 gene and among members of the same family. However, causes of this huge clinical spectrum have not been studied in depth. TP53 type mutation, polymorphic variants in TP53 gene or in TP53-related genes, copy number variations in particular regions, and/or epigenetic deregulation of TP53 expression might be responsible for clinical heterogeneity. In this review, recent advances in the understanding of genetic and epigenetic aspects influencing Li-Fraumeni phenotype are discussed.

Retinoblastoma: towards an earlier diagnosis. / Retinoblastoma: hacia un diagnóstico más precoz.

OBJECTIVES: The number of enucleations and visual sequels due to retinoblastoma is high. The aim of this study was to evaluate the different diagnostic aspects and propose strategies that might improve the clinical management of this condition. METHOD: A retrospective study was conducted on 38 patients with retinoblastoma studied genetically (29 unilateral, 9 bilateral). The evaluation included: age of onset, clinical signs, and time since onset, number of enucleations, time to diagnosis, and survival at 5 years. RESULTS: Leukocoria was the main clinical sign (present in 90% of cases). The mean diagnostic delay was 3.2 months. Among the unilateral cases, the eyes were enucleated in 76%, and 55% in the bilateral forms. Only one death was found among the 25 patients followed-up for at least 5 years. CONCLUSIONS: Retinoblastoma diagnostic and treatment strategies need to be updated. Good coordination between paediatricians and ophthalmologists is essential for this. Its management in reference centres, which have the necessary technology and experience, should contribute to increase the rate of organ preservation.

[Assessment of behavioral dependence with the Glover-Nilsson test in smoking cessation treatment]. / Evaluación de la dependencia psicológica mediante el test de Glover-Nilsson en el tratamiento del tabaquismo.

OBJECTIVE: To assess behavioral dependence using the Glover-Nilsson test and determine its association with successful smoking cessation. MATERIAL AND METHODS: An analytical longitudinal study was carried out, the target population of which consisted of smokers who enrolled in a smoking cessation clinic for treatment. The following variables were examined: age, sex, nicotine dependence (Fagerström test), psychoactive drug use, prior attempts at quitting, and behavioral dependence measured with the Glover-Nilsson test. The most recent version of this test is an 11-item questionnaire which classifies behavioral dependence according to the scores obtained: mild (<12), moderate (12-22), severe (23-33), and very severe (>33). Successful cessation was defined as self-reported abstinence confirmed by measurement of expired CO level (< or =10 ppm). Results were expressed as means (SD) for quantitative variables and percentages and absolute frequencies for qualitative variables. RESULTS: The study population consisted of 167 smokers--89 men (53.3%) and 78 women (46.7%)--with a mean age of 43.5 (9.9) years, a nicotine dependence score (Fagerström test) of 6.5 (2.2) points, and a Glover-Nilsson score of 23.3 (6.6). Of the study population, 65.9% (n=110) had made previous attempts at quitting. Abstinence at 3 months was 55.1% (n=92). Differences between the sexes were found for age and previous attempts at quitting. Younger patients had higher scores on the Glover-Nilsson test and the Fagerström test and lower abstinence rates. CONCLUSIONS: Severe behavioral dependence can result in less successful cessation outcome. All aspects related to dependence must be assessed to help select the most adequate pharmacological and psychological treatment for results to be optimized.

[Predictors of success at 6-month follow-up for smokers treated at a smoking cessation clinic]. / Factores predictores de éxito a los 6 meses en fumadores tratados en una unidad de tabaquismo.

OBJECTIVE: To identify the predictors of successful outcome in a smoking cessation program at 6-month follow-up. MATERIAL AND METHODS: Cross-sectional descriptive study of a sample of smokers who attended a smoking cessation clinic for combined medical and cognitive-behavioral group therapy. The independent variables assessed included age, sex, level of education, nicotine dependence (Fagerström test), prior attempts to quit smoking, medication prescribed, compliance with group therapy regimen, and success at one week and 3 months. Success was defined as self-reported abstinence, confirmed by CO-oximetry (carbon monoxide <10 ppm). Odds ratios (with 95% confidence intervals) were calculated for the categorical variables and a test of statistical significance of differences between means was performed for quantitative variables. Univariate logistic regression analysis was performed and significant variables were entered into a multivariate logistic regression model. RESULTS: The study population comprised 248 individuals, 67.7% male and 32.3% female, with a mean (SD) age of 43.1 (10.5) years. The mean score on the Fagerström test was 6.3 (2.1) points and 84.7% of the individuals complied with the treatment regimen. Success rates were as follows: 77% at one week, 30.2% at 3 months, and 31.9% at 6 months. Three variables--success at 3 months, age, and nicotine dependence--were entered into the multivariate logistic regression model; the only variable predictive of successful smoking cessation at 6 months was success at 3 months. CONCLUSIONS: Individuals who fully comply with treatment and abstain from smoking during the first weeks are more likely to be successful at 6 months.

[Multi-level treatment for obstructive sleep apnea syndrome: comparative study of four different surgical techniques of palate]. / Tratamiento multinivel en el síndrome de apnea obstructiva del sueño: estudio comparativo de cuatro técnicas quirúrgicas del paladar.

Palatopharyngeal surgery is a therapeutic option for Obstructive Sleep Apnea Syndrome. This surgery is based on the assumption that the soft palate is the principal apneogenic area of the upper airway. We report a comparison of four techniques of palatopharyneal surgery. In the other hand, the effectiveness of palatopharyngeal surgery for correcting other obstructions when present, was also evaluated.

[Surgical tongue-base suspension for obstructive sleep apnea syndrome. Our experience]. / Estabilización quirúrgica de la base de la lengua en el síndrome de apnea obstructiva del sueño. Nuestra experiencia.

There are a lot of techniques involves to surgical treatment of the Obstructive Sleep Apnea Syndrome. Surgical treatments of tongue-base and hypopharyngeal colapse include glossectomy, hyoid suspension, mandibular osteotomy with genioglossal advancement and maxillay-mandibular advancement. Many or these procedures are associated with extreme morbidity. In this paper is evaluated the effectiveness of a minimally invasive technique for tongue-base suspension. The procedure was performed in 12 male patients whit O.S.A.S. that were evaluated with cefalometric and fiberoptic analysis. These preliminary results show the initial efficacy of this new surgical procedure.

Cryptic t(4;11) encoding MLL-AF4 due to insertion of 5' MLL sequences in chromosome 4.

The t(4;11) translocation is the cytogenetic hallmark of a subset of acute lymphoblastic leukemias characterized by pro-B immunophenotype and a dismal prognosis. This translocation fuses the MLL gene on chromosome band 11q23 and the AF4 gene on 4q21, resulting in the expression of fusion transcripts from both translocated chromosomes. The MLL-AF4 chimeric transcript is thought to mediate the leukemic transformation. The MLL genomic disruption detected by Southern blot and the RT-PCR for the MLL-AF4 chimeric transcript expression are molecular evidence of this chromosomal translocation. However, similar molecular rearrangements have also been identified in cases without the cytogenetic t(4;11). We report a 30-year-old patient with high risk ALL, a normal karyotype, and molecular evidence of MLL-AF4 fusion. Using a double color FISH assay with MLL specific PAC probes, a cryptic t(4;11) due to insertion of 5' MLL sequences in chromosome 4q21 was demonstrated. Consequently the MLL-AF4 was encoded by der(4). This insertion mechanism precludes the genomic recombination of AF4-MLL and supports the crucial role played by MLL-AF4 in leukemogenesis. The findings of our case, along with others, show the importance of complementing the karyotype with molecular and FISH techniques.

[Antisense oligonucleotides increase the apoptotic effect of idarubicin in K-562 cell line]. / Los oligonucleotidos antisense potencian la apoptosis inducida por la idarubicina en la linea celular K-562.

The cell line K-562, which carries bcr/abl rearrangement of type b3a2 is resistant to apoptosis induced by topoisomerase II inhibitors. K-562 cells were treated with complexes of cationic liposomes (DMRIE-DOPE and Dcchol-DOPE) and antisense oligonucleotides (AS-ODNs) directed against the b3a2 type of bcr/abl mRNA and non sense oligonucleotides (NS-ODNs), in a 3:1 lipid/DNA ratio during 72 hours, then they were incubated for a further 24 hours with idarubicin (IDA), 0.5 microgram/ml, to induce apoptosis. It was evaluated by morphology to the microscope of fluorescence. Cells treated with the complexes DMRIE-DOPE and Dcchol/DOPE with the specific AS-ODN showed a higher apoptosis percentage induced by IDA (mean +/- SD: 14.74 +/- 2.07 and 20.43 +/- 4.58, respectively) compared with controls not treated with ODNs (mean +/- SD: 8.08 +/- 0.82); (p < 0.05). These data indicate that the AS-ODNs directed against the b3a2 type of bcr-abl mRNA renders the cell line K-562 sensitive to IDA at the mentioned concentration.