Luis Rojas

Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies

The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.

SNPs and taxane toxicity in breast cancer patients

AIM In order to identify genetic variants associated with taxanes toxicity, a panel with 47 SNPs in 20 genes involved in taxane pathways was designed. PATIENTS & METHODS Genomic DNA of 113 breast cancer patients was analyzed (70 taking docetaxel, 43 taking paclitaxel). RESULTS Two SNPs associated with docetaxel toxicity were identified: CYP3A4*1B with infusion-related reactions; and ERCC1 Gln504Lys with mucositis (p≤0.01). Regarding paclitaxel toxicity: CYP2C8 HapC and CYP2C8 rs1934951 were associated with anemia; and ERCC1 Gln504Lys with neuropathy (p≤0.01). CONCLUSION Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients.

Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: A systematic review and meta-analysis of observational studies

The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07–2.01), 2677G>T/A at years 4–5 (OR: 1.37, 95% CI: 1.01–1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03–1.94) and 4–5 (OR: 1.42, 95% CI: 1.05–1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.

Association of SNPs with the efficacy and safety of immunosuppressant therapy after heart transplantation.

AIM Studying the possible influence of SNPs on efficacy and safety of calcineurin inhibitors upon heart transplantation. MATERIALS & METHODS In 60 heart transplant patients treated with tacrolimus or cyclosporine, we studied a panel of 36 SNPs correlated with a series of clinical parameters during the first post-transplantation year. RESULTS The presence of serious infections was correlated to ABCB1 rs1128503 (p = 0.012), CC genotype reduced the probability of infections being also associated with lower blood cyclosporine concentrations. Lower renal function levels were found in patients with rs9282564 AG (p = 0.003), related to higher blood cyclosporine blood levels. A tendency toward increased graft rejection (p = 0.05) was correlated to rs2066844 CC in NOD2/CARD15, a gene related to lymphocyte activation. CONCLUSION Pharmacogenetics can help identify patients at increased risk of clinical complications. Original submitted 30 January 2015; revision submitted 27 March 2015.

Reanimación cardiopulmonar básica: conocimiento teórico, desempeño práctico y efectividad de las maniobras en médicos generales

BACKGROUND General physicians should be adequately trained to deliver effective resuscitation during ventricular fibrillation (VF). AIM To assess the degree of knowledge, skills and practical effectiveness in cardiopulmonary resuscitation (CPR) of Chilean general physicians. MATERIALS AND METHODS Forty eight general physicians starting Anesthesiology or Internal Medicine residency programs were evaluated. They answered a modified American Heart Association Basic Life Support Course written test and individually participated in a witnessed VF cardiac arrest simulated scenario. Execution of resuscitation tasks in the correct order, the quality of the maneuvers and the use of defibrillator were registered. RESULTS All participants acknowledged the importance of uninterrupted CPR and early defibrillation. Seventy five percent knew the correct frequency of chest compressions, but only 6.25% knew all the effective chest compression characteristics. Ninety eight percent knew the recommended number of breaths per cycle. In practice, 58% performed effective ventilations, 33% performed uninterrupted compressions, 14% did them with adequate frequency and only 8% performed chest compressions adequately. Forty four percent requested a defibrillator within 30 seconds and 31% delivered the first defibrillation within 30 seconds of defibrillator arrival. Airway, breathing, circulation and defibrillation sequence was correctly performed by 12% of participants and 80% acknowledged that their medical training was inadequate or insufficient for managing a cardiac arrest. CONCLUSIONS Despite an elevated degree of knowledge about key aspects of CPR, this group of Chilean physicians displayed suboptimal practical skills while performing CPR in a simulated scenario, specially delivering effective chest compressions and promptly asking for and using the defibrillator.

Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment

Abstract Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.

Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia

Abstract Anthracycline uptake could be affected by efflux pumps of the ABC family. The influence of 7 SNPs of ABC genes was evaluated in 225 adult de novo acute myeloid leukemia (AML) patients. After multivariate logistic regression there were no significant differences in complete remission, though induction death was associated to ABCB1 triple variant haplotype (p = .020). The ABCB1 triple variant haplotype was related to higher nephrotoxicity (p = .016), as well as this haplotype and the variant allele of ABCB1 rs1128503, rs2032582 to hepatotoxicity (p = .001; p = .049; p < .001). Furthermore, the variant allele of ABCC1 rs4148350 was related to severe hepatotoxicity (p = .044), and the variant allele of ABCG2 rs2231142 was associated to greater cardiac (p = .004) and lung toxicities (p = .038). Delayed time to neutropenia recovery was observed with ABCB1 rs2032582 variant (p = .047). This study shows the impact of ABC polymorphisms in AML chemotherapy safety. Further prospective studies with larger population are needed to validate these associations.

A systematic review and meta-analysis of the impact of WT1 polymorphism rs16754 in the effectiveness of standard chemotherapy in patients with acute myeloid leukemia

The polymorphism rs16754 of the WT1 gene has been described as a possible prognostic marker in different acute myeloid leukemia (AML) cohorts; however, it is not supported by all the studies. We performed the first meta-analysis evaluating the effect of this polymorphism upon the effectiveness of standard AML therapy. Fourteen cohort studies were included (3618 patients). Patients with the variant allele showed a significant higher overall survival (OS) at 5 years (OR:1.24, 95% CI: 1.06–1.45, P=0.007, with dominant model). WT1 did not influence complete remission, but a higher disease-free survival was observed with the variant allele. In the subgroup analysis, Caucasians, pediatric and patients treated with idarubicin and etoposide carrying the variant allele showed consistent results in OS, whereas patients with cytogenetically normal AML did not show differences. To verify the effect of this polymorphism upon other outcomes, studies in larger and multiracial populations are needed.

Positive impact of ABCB1 polymorphisms in overall survival and complete remission in acute myeloid leukemia: a systematic review and meta-analysis.

Positive impact of ABCB1 polymorphisms in overall survival and complete remission in acute myeloid leukemia: a systematic review and meta-analysis

Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy

Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.