Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.

OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.

Impact of the use of molecular techniques (PCR) on detection and eradication success against Helicobacter pylori.

INTRODUCTION: Helicobacter pylori infection affects more than 50% of the world population. Increased antibiotic resistance is the main cause of treatment failure. The main objective was to analyze the eradication success after the application of the new ESPGHAN treatment recommendations and the introduction of PCR as a direct diagnosis technique, describe the evolution of the local pattern of antibiotic resistance, and assess the cost-effectiveness of PCR application, isolated or in conjunction with culture as a diagnostic strategy. PATIENTS AND METHODS: Retrospective descriptive study of all microbiological isolates of Helicobacter pylori in 2013-2019 in our center, by comparing the percentage of resistance and eradication success between the periods 2013-2016 and 2017-2019. Cost-effectiveness study of direct diagnostic tests, comparing 3 different options: culture and PCR; only culture; PCR only. RESULTS: 192 patients were included, 98 were detected by culture (2013-2016) and 94 by culture and/or PCR (2017-2019). Antibiotic treatment was established in 153 patients, 90 in the first period (2011 ESPGHAN guidelines: eradication percentage 62.2%), 63 in the second (2017 ESPGHAN guidelines: eradication percentage: 73%). An increase in resistance to clarithromycin was observed, going from 16.3% (n=16) in the first period, to 53.2% (n=48) in 2017-2019 (98% detected by PCR, 60% by culture). There were no differences in the rest of antibiotic resistances. The isolated PCR application presented a cost-effectiveness analysis ratio (CEAR) of 71.91, compared to 92.16 for the culture and 96.35 for the culture and PCR combined. CONCLUSIONS: The application of the ESPGHAN 2017 guidelines achieved greater eradication success, although less than that observed in previous publications, without reaching the target of at least 90%. An increase in resistance to macrolides was observed, without being able to discriminate whether it is a real increase or a greater diagnostic sensitivity of molecular techniques, with the isolated request for PCR being the most cost-effective strategy.

Comparison of clinical outcomes between unrelated single umbilical cord blood and "ex-vivo" T-cell depleted haploidentical transplantation in children with hematological malignancies.

BACKGROUND: Over the last two decades, umbilical cord blood (UCB) and haploidentical transplantation (HaploHSCT) have emerged as alternative sources of hematopoietic stem cell for allogeneic transplantation. There are few retrospective studies and no prospective studies comparing both types of alternative transplantation in pediatric patients. RESULTS: We analyzed the data of 134 children with hematological malignancies who received a hematopoietic stem cell transplantation from a single umbilical cord blood (UCB) (n = 42) or an "ex-vivo" T-cell depleted transplant from a haploidentical-related donor (HaploHSCT) (n = 92) between 1996 and 2014. Hematological recovery was faster after HaploHSCT than the UCB transplant group (median times to neutrophil and platelet recovery: 13 vs. 16 days, 10 vs. 57 days, respectively) (P < 0.001). The HaploHSCT group had a significantly early immune reconstitution based on NK and CD8 + T cells compared with the UCB group. However, after the first year post-transplantation, HaploHSCT had a lower number of CD4 + T and B lymphocytes compared with the UCB transplant recipients. The cumulative incidence of TRM was 29±8% in the HaploHSCT group versus 40±5% in the UCB group. Relapse incidence was 21±7% in the HaploHSCT group and 19±8% in the UCB group. Probability of DFS was 58±8% in the HaploHSCT group versus 40±9% in the UCB group (P = 0.051). CONCLUSIONS: TCD haploidentical transplant is associated with advantages in terms of engraftment and early immune reconstitution kinetics. TCD haploidentical transplant was associated with lower incidence of infectious and non-infectious complications, especially in the early phases of the transplant compared with UCB transplant recipients. However, there are no advantages in transplant outcomes compared with UCB transplant.

[Impact of the use of molecular techniques (PCR) on detection and eradication success against Helicobacter pylori]. / Impacto del uso de las técnicas moleculares (PCR) en la detección y el éxito erradicador frente a Helicobacter pylori.

INTRODUCTION: Helicobacter pylori (H. pylori) infection affects more than 50% of the world population. Increased antibiotic resistance is the main cause of treatment failure. The main objective was to analyze the eradication success after the application of the new ESPGHAN treatment recommendations and the introduction of PCR as a direct diagnosis technique, describe the evolution of the local pattern of antibiotic resistance, and assess the cost-effectiveness of PCR application, isolated or in conjunction with culture as a diagnostic strategy. PATIENTS AND METHODS: retrospective descriptive study of all microbiological isolates of H. pylori in 2013-2019 in our center, by comparing the percentage of resistance and eradication success between the periods 2013-2016 and 2017-2019. Cost-effectiveness study of direct diagnostic tests, comparing 3 different options: culture and PCR; only culture; PCR only. RESULTS: 192 patients were included, 98 were detected by culture (2013-2016) and 94 by culture and / or PCR (2017-2019). Antibiotic treatment was established in 153 patients, 90 in the first period (2011 ESPGHAN guidelines: eradication percentage 62.2%), 63 in the second (2017 ESPGHAN guidelines: eradication percentage: 73%). An increase in resistance to clarithromycin was observed, going from 16.3% (n=16) in the first period, to 53.2% (n=48) in 2017-2019 (98% detected by PCR, 60% by culture). There were no differences in the rest of antibiotic resistances. The isolated PCR application presented a cost-effectiveness analysis ratio (CEAR) of 71.91, compared to 92.16 for the culture and 96.35 for the culture and PCR combined. CONCLUSIONS: the application of the ESPGHAN 2017 guidelines achieved greater eradication success, although less than that observed in previous publications, without reaching the target of at least 90%. An increase in resistance to macrolides was observed, without being able to discriminate whether it is a real increase or a greater diagnostic sensitivity of molecular techniques, with the isolated request for PCR being the most cost-effective strategy.