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Impact of single nucleotide polymorphisms on the efficacy and toxicity of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.

Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients.

Chemotherapy based on platinum compounds is the standard treatment for NSCLC patients with EGFR wild type, and is also used as second line in mutated EGFR patients. Nevertheless, this therapy presents poor clinical outcomes. ERCC1, ERCC2, XRCC1, MDM2, MTHFR, MTR, and SLC19A1 gene polymorphisms may contribute to individual variation in response and survival to platinum-based chemotherapy. The aim of this study was to investigate the influence of these polymorphisms on response and survival of NSCLC patients treated with platinum-based chemotherapy. A retrospective-prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR real-time with Taqman® probes. Patients with ERCC1 rs3212986-GG (p = 0.0268; OR = 2.50; CI95% = 1.12-5.69) and XRCC1 rs25487-GG (p = 0.0161; OR = 2.99; CI95% = 1.26-7.62) genotype showed significantly better ORR. Cox survival analysis revealed that patients carrying the MDM2 rs1690924-GG genotype (p = 0.0345; HR = 1.99; CI95% = 1.05-3.80) presented higher risk of death. Furthermore, carriers of MTR rs1805087-A alleles (p = 0.0060; HR = 8.91; CI95% = 1.87-42.42) and SLC19A1 rs1051266-AA genotype (p = 0.0130; HR = 1.74; CI95% = 1.12-2.68) showed greater risk of progression. No influence of ERCC1 rs11615, ERCC2 rs13181, ERCC2 rs1799793, XRCC1 rs1799782, MDM2 rs1470383, MTHFR rs1801131, and MTHFR rs1801133 on platinum-based chemotherapy clinical outcomes was found. In conclusion, our results suggest that ERCC1 rs3212986, XRCC1 rs25487, MDM2 rs1690924, MTR rs1805087, and SLC19A1 rs1051266 gene polymorphisms may significantly act as predictive factors in NSCLC patients treated with platinum-based chemotherapy.

Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer.

Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.

Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer.

BACKGROUND: Surgery is the standard treatment for early-stage NSCLC, and platinum-based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naïve EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients. METHODS: A prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time. RESULTS: Patients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13-2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06-18.99). The rest of polymorphisms showed no effect of on outcomes. CONCLUSIONS: Our results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients.

Medication adherence and persistence in type 2 diabetes mellitus: perspectives of patients, physicians and pharmacists on the Spanish health care system.

OBJECTIVE: A good relationship between diabetes patients and their health care team is crucial to ensure patients' medication adherence and self-management. To this end, we aimed to identify and compare the views of type 2 diabetes mellitus (T2DM) patients, physicians and pharmacists concerning the factors and strategies that may be associated with, or could improve, medication adherence and persistence. METHODS: An observational, cross-sectional study was conducted using an electronic self-administered questionnaire comprising 11 questions (5-point Likert scale) concerning factors and strategies related to medication adherence. The survey was designed for T2DM patients and Spanish National Health System professionals. RESULTS: A total of 963 T2DM patients, 998 physicians and 419 pharmacists participated in the study. Overall, a lower proportion of pharmacists considered the proposed factors associated with medication adherence important as compared to patients and physicians. It should be noted that a higher percentage of physicians in comparison to pharmacists perceived that "complexity of medication" (97% vs 76.6%, respectively) and "adverse events" (97.5% vs 72.2%, respectively) were important medication-related factors affecting adherence. In addition, both patients (80.8%) and physicians (80.8%) agreed on the importance of "cost and co-payment" for adherence, whereas only 48.6% of pharmacists considered this factor important. It is also noteworthy that nearly half of patients (43%) agreed that "to adjust medication to activities of daily living" was the best strategy to reduce therapeutic complexity, whereas physicians believed that "reducing the frequency of administration" (47.9%) followed by "reducing the number of tablets" (28.5%) was the most effective strategy to improve patients' adherence. CONCLUSION: Our results highlight the need for pharmacists to build a stronger relationship with physicians in order to improve patients monitoring and adherence rates. Additionally, these findings may help to incorporate greater patient-centeredness when developing management strategies, focusing on adjusting medication regimens to patients' daily lives.

Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.

Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-ß pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-ß, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.

Liquid biopsy in early stage lung cancer.

Lung cancer is the leading cause of cancer-associated deaths worldwide. Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC). However, 30% to 80% of these patients will die within 5 yearS of diagnosis. Circulating cell-free DNA (cfDNA) harbors pathologic characteristics of the original tumor, such as gene mutations or epigenetic alterations. Analysis of cfDNA has revolutionized the clinical care of advanced lung cancer patients undergoing targeted therapies. However, the low concentration of cfDNA in the blood of early-stage NSCLC patients has hampered its use for management of early disease. Continuing development of more specific and sensitive techniques for detection and analysis of cfDNA will soon enable its leverage in early stage and, perhaps, even screening settings. Therefore, cfDNA analysis may become a tool used for routine NSCLC diagnosis and for monitoring tumor burden, as well as for identifying hidden residual disease. In this review, we will focus on the current evidence of cfDNA in patients with early-stage NSCLC, new and upcoming approaches to identify circulating-tumor biomarkers, their clinical applications and future directions.

Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non-small cell lung cancer patients.

Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy.

Resultados negativos asociados a la medicación en los pacientes con fibrilación auricular permanente atendidos en un servicio de urgencias hospitalario / Medication-related negative outcomes in patients with permanent atrial fibrillation attended in a hospital emergency department

Objetivos: Detectar la frecuencia de resultados negativos asociados a la medicación (RNM) en los pacientes con fibrilación auricular permanente (FAP) atendidos en un servicio de urgencias hospitalario (SUH), y evaluar su tipología, evitabilidad y gravedad en función de su relación con la terapia farmacológica para la fibrilación auricular (FA). Metodología: Estudio observacional descriptivo de una serie de casos con análisis transversal que incluyó a los pacientes atendidos con FAP en un servicio de urgencias (SU) de un hospital de tercer nivel durante 3 meses. Un farmacéutico entrevistó a los pacientes recogiendo datos demográficos, problemas de salud, grado de dependencia y terapia farmacológica. Un grupo evaluador, formado por un urgenciólogo y un farmacéutico, revisaron los cuestionarios y las historias clínicas para la evaluación de los RNM según el método Dáder. Resultados: Del total de 210 pacientes evaluados se incluyeron finalmente 198 pacientes con una edad media de 80,5 (DE 7,3) años, de los cuales 114 (57,5%) fueron mujeres. Ciento treinta y cuatro (67,7%) pacientes sufrieron un RNM, de los cuales 61 (45,5%) estaban relacionadas con el tratamiento de la FA (RNM-RTFA). De los 61 pacientes con RNM-RTFA, 24 (39,3%) fueron RNM de seguridad y 36 (59%) estaban causados por los fármacos para el control de la frecuencia. De los 73 pacientes con RNM no relacionadas con el tratamiento de la FA (RNM-NRTFA), 34 (46,6%) fueron RNM de necesidad y 38 (52,1%) eran por antibióticos. Entre los dos grupos, hubo diferencias estadísticamente significativas en cuanto a la evitabilidad (RNM-RTFA 55,7% vs RNM-NRTFA 78,1%; p = 0,010), pero no para la gravedad (p = 0,265). Conclusiones: Casi dos tercios de los pacientes con FAP que acuden a un SUH sufren un RNM relacionado o no con la medicación específica para la FA, siendo más evitables los RNM del grupo de fármacos no relacionados con el tratamiento de esta enfermedad (AU)

Objectives: To detect the frequency of negative outcomes associated with medication in patients with permanent atrial fibrillation (AF) who are attended in a hospital emergency department, and to assess type and severity of such outcomes related to AF medications as well as the rate of preventable negative outcomes. Methods: Descriptive, observational cross-sectional study in patients with permanent AF who were attended in the emergency department of a tertiary care hospital during a 3-month period. A pharmacist interviewed the patients to record demographic characteristics, health problems, degree of functional impairment, and current drug treatments. An emergency physician and a pharmacist reviewed the patients’ questionnaires and medical histories and evaluated them using the Dader method of pharmacotherapeutic follow-up. Results: Of the 210 patients assessed, 198 entered the final analysis. They had a mean (SD) age of 80.5 (7.3) years, and 114 (57.5%) were women. One handred and thirty-four (67.7%) patients had medication-related negative outcomes; 61 (45.5%) of the outcomes were related to treatment for permanent AF. Twenty-four of these 61 patients (39.3%) had problems affecting safety; 36 (59%) of the problems were caused by drugs to control heart rate. Of the 73 patients with negative outcomes unrelated to AF medication, 34 (46.6%) were related to necessary medications and 38 (52.1%) were taking antibiotics. The frequencies of avoidable negative outcomes were significantly different between the group of patients with problems related to drug therapy for AF (where 55.7% were due to medications considered unnecessary) and those with problems unrelated to AF medications (where 78.1% were from avoidable medications) (P=.010). However, the level of seriousness was similar. Conclusions: Nearly two-thirds of patients with permanent AF who come to the emergency department have a medication-related negative outcome that may or may not be related to AF treatment. Problems from drugs taken for reasons other than AF could more easily be avoided (AU)

[Medication-related negative outcomes in patients with permanent atrial fibrillation attended in a hospital emergency department]. / Resultados negativos asociados a la medicación en los pacientes con fibrilación auricular permanente atendidos en un servicio de urgencias hospitalario.

OBJECTIVES: To detect the frequency of negative outcomes associated with medication in patients with permanent atrial fibrillation (AF) who are attended in a hospital emergency department, and to assess type and severity of such outcomes related to AF medications as well as the rate of preventable negative outcomes. MATERIAL AND METHODS: Descriptive, observational cross-sectional study in patients with permanent AF who were attended in the emergency department of a tertiary care hospital during a 3-month period. A pharmacist interviewed the patients to record demographic characteristics, health problems, degree of functional impairment, and current drug treatments. An emergency physician and a pharmacist reviewed the patients' questionnaires and medical histories and evaluated them using the Dader method of pharmacotherapeutic follow-up. RESULTS: Of the 210 patients assessed, 198 entered the final analysis. They had a mean (SD) age of 80.5 (7.3) years, and 114 (57.5%) were women. One handred and thirty-four (67.7%) patients had medication-related negative outcomes; 61 (45.5%) of the outcomes were related to treatment for permanent AF. Twenty-four of these 61 patients (39.3%) had problems affecting safety; 36 (59%) of the problems were caused by drugs to control heart rate. Of the 73 patients with negative outcomes unrelated to AF medication, 34 (46.6%) were related to necessary medications and 38 (52.1%) were taking antibiotics. The frequencies of avoidable negative outcomes were significantly different between the group of patients with problems related to drug therapy for AF (where 55.7% were due to medications considered unnecessary) and those with problems unrelated to AF medications (where 78.1% were from avoidable medications) (P=.010). However, the level of seriousness was similar. CONCLUSION: Nearly two-thirds of patients with permanent AF who come to the emergency department have a medication- related negative outcome that may or may not be related to AF treatment. Problems from drugs taken for reasons other than AF could more easily be avoided.

OBJETIVO: Detectar la frecuencia de resultados negativos asociados a la medicación (RNM) en los pacientes con fibrilación auricular permanente (FAP) atendidos en un servicio de urgencias hospitalario (SUH), y evaluar su tipología, evitabilidad y gravedad en función de su relación con la terapia farmacológica para la fibrilación auricular (FA). METODO: Estudio observacional descriptivo de una serie de casos con análisis transversal que incluyó a los pacientes atendidos con FAP en un servicio de urgencias (SU) de un hospital de tercer nivel durante 3 meses. Un farmacéutico entrevistó a los pacientes recogiendo datos demográficos, problemas de salud, grado de dependencia y terapia farmacológica. Un grupo evaluador, formado por un urgenciólogo y un farmacéutico, revisaron los cuestionarios y las historias clínicas para la evaluación de los RNM según el método Dáder. RESULTADOS: Del total de 210 pacientes evaluados se incluyeron finalmente 198 pacientes con una edad media de 80,5 (DE 7,3) años, de los cuales 114 (57,5%) fueron mujeres. Ciento treinta y cuatro (67,7%) pacientes sufrieron un RNM, de los cuales 61 (45,5%) estaban relacionadas con el tratamiento de la FA (RNM-RTFA). De los 61 pacientes con RNM-RTFA, 24 (39,3%) fueron RNM de seguridad y 36 (59%) estaban causados por los fármacos para el control de la frecuencia. De los 73 pacientes con RNM no relacionadas con el tratamiento de la FA (RNM-NRTFA), 34 (46,6%) fueron RNM de necesidad y 38 (52,1%) eran por antibióticos. Entre los dos grupos, hubo diferencias estadísticamente significativas en cuanto a la evitabilidad (RNM-RTFA 55,7% vs RNM-NRTFA 78,1%; p = 0,010), pero no para la gravedad (p = 0,265). CONCLUSIONES: Casi dos tercios de los pacientes con FAP que acuden a un SUH sufren un RNM relacionado o no con la medicación específica para la FA, siendo más evitables los RNM del grupo de fármacos no relacionados con el tratamiento de esta enfermedad.

PTEN and PI3K/AKT in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. In the last years, the identification of activating EGFR mutations, conferring increased sensitivity and disease response to tyrosine kinase inhibitors, has changed the prospect of NSCLC patients. The PTEN/PI3K/AKT pathway regulates multiple cellular functions, including cell growth, differentiation, proliferation, survival, motility, invasion and intracellular trafficking. Alterations in this pathway, mainly PTEN inactivation, have been associated with resistance to EGFR-tyrosine kinase inhibitor therapy and lower survival in NSCLC patients. In this review, we will briefly discuss the main PTEN/PI3K/AKT pathway alterations found in NSCLC, as well as the cell processes regulated by PTEN/PI3K/AKT leading to tumorigenesis.

Estudio LIFAC: evaluación de la utilidad de un libro de incidencias en farmacia comunitaria / LIFAC study: assessment of the usefulness of an incident book in community pharmacy

Objetivo: El farmacéutico comunitario se ve obligado en numerosas ocasiones a atender las necesidades que los pacientes le plantean en demanda de soluciones, mediante actuaciones que la estricta observación de la legalidad vigente le impide realizar pero que su preparación profesional y su cercanía al paciente, avalan. El registro escrito de este tipo de situaciones y la decisión adoptada por el farmacéutico es el objeto de este estudio, con el fin de evaluar su utilidad, categorizar e inventariar las incidencias que se presentan, servir de respaldo de su actuación y mejorar la calidad asistencial al paciente. Métodos: Diseño multicéntrico, nacional y prospectivo. Se ofreció la participación a socios de SEFAC que registraron en formato electrónico (Libro de Incidencias) las incidencias producidas en el quehacer profesional diario según una plantilla de tipos predefinidos acordada por la Comisión de Bioética de SEFAC. Resultados: 170 farmacéuticos comunitarios registraron 1.565 incidencias. 64,7% dispensaciones excepcionales resueltas en un 29,7% mediante la ficha de paciente y un 14,5% tras entrevista farmacéutico-paciente. El 35,3% correspondieron a otros tipos de incidencias: no dispensación por razones clínicas (21,5%) y prescripción incorrecta (14,5%). El grupo terapéutico más implicado fue el de los antiinfecciosos (20,1%) y relacionados con el SNC (18,7%). Conclusiones: El estudio LIFAC pone de manifiesto que el farmacéutico comunitario resuelve situaciones en las que de una u otra manera la salud de los pacientes se ve comprometida. Los participantes perciben que el registro de las incidencias es de gran ayuda para la justificación de su actuación profesional en situaciones complejas o comprometidas (AU)

Aim: The community pharmacist is often obliged to deal with patient needs put to them in terms of demanding solutions, by means of actions that strict observation of prevailing legality prevents carrying out but which comes guaranteed by their professional training and proximity to the patient. Strict record of this kind of situation and the decision taken by the pharmacist is the object of this study, with the purpose of assessing its usefulness, categorizing and making an inventory of the incidents that present, serving as a support for their action and improving the quality of patient care. Methods: Multicenter, national and prospective design. SEFAC (Spanish Society for Community Pharmacy) members were given the opportunity to take part; they made an electronic record (Incident Book) of the incidences that occurred in daily professional work according to a preset template agreed by the SEFAC Bioethics Committee. Results: A total of 170 community pharmacists recorded 1565 incidences; 64.7% cases of exceptional dispensing were resolved in 29.7% and 14.5% by means of the patient record and after a pharmacist-patient meeting, respectively. A total of 35.3% corresponded to other kinds of incident: no dispensing for clinical reasons (21.5%) and incorrect prescription (14.5%). The therapeutic group most involved was anti-infectious drugs (20.1%) and related to the CNS (18.7%). Conclusions: The LIFAC study highlights that the community pharmacist resolves situations in which patient health is in some way seen as compromised. Participants perceive that the record of incidents is of major help to justify their professional work in complex or compromised situations (AU)

MET: a new promising biomarker in non-small-cell lung carcinoma.

Non-small-cell lung cancer (NSCLC) leads cancer-related deaths worldwide. Mutations in the kinase domain of the EGFR gene provide sensitivity to tyrosine kinase inhibitors (TKI) drugs. TKI show initial response rates over 75% in mutant EGFR-NSCLC patients, although most of these patients acquire resistance to EGFR inhibitors after therapy. EGFR-TKI resistance mechanisms include amplification in MET and its ligand, and also MET mutations. MET signaling dysregulation has been involved in tumor cell growth, survival, migration and invasion, angiogenesis and activation of several pathways, therefore representing an attractive target for anticancer drug development. In this review, we will discuss MET-related mechanisms of EGFR-TKI resistance in NSCLC, as well as the main drugs targeted to inhibit MET pathway.

Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis.

Abstract Rheumatoid arthritis (RA) is a common illness of global significance for public health. Methotrexate (MTX) is the most broadly used disease-modifying antirheumatic drug for the treatment of RA, but it displays marked person-to-person variation in its propensity for toxicity. Several studies have suggested that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC1) G80A, and ABCB1 C3435T, could be related to methotrexate toxicity. This prospective study examined the different frequencies of MTHFR, RFC1, and ABCB1 pharmacogenetic variations between patients who have RA and those without RA. We also sought to assess the association between these polymorphisms and MTX toxicity. Four single-nucleotide polymorphisms (SNPs) were genotyped: C677T and A1298C from MTHFR, G80A from RFC1, and C3435T from ABCB1. The efficacy and toxicity of MTX were evaluated through clinical follow-up during 1 year of treatment. RA patients showed a higher frequency of the T allele at MTHFR C677T than patients without RA (p=0.049). There was a significant association between the presence of both the T allele at MTHFR C677T (p=0.006), and the C allele at ABCB1 C3435T (p=0.046), with toxicity development after 12 months of MTX treatment. However, there was no correlation between MTX toxicity and either the A allele at MTHFR A1298C or the G allele at RFC1 A80G. These data suggest that the presence of the MTHFR C677T and ABCB1 C3435T SNPs contribute to MTX toxicity in patients with RA. These observations contribute to a rapidly-growing knowledge base on the pharmacogenetics of RA and personalized medicine.

Efecto de la actuación farmacéutica en la adherencia del tratamiento farmacológico de pacientes ambulatorios con riesgo cardiovascular (Estudio EMDADER-CV-INCUMPLIMIENTO) / Effect of pharmacist involvement in adherence to medications in patients with high to moderate cardiovascular risk (Study EMDADER-CV-INCUMPLIMIENTO)

Objetivo: Evaluar el efecto de la actuación del farmacéutico, mediante seguimiento farmacoterapéutico(SFT) en la mejora de la adherencia y de objetivos terapéuticos.Diseño: Estudio clínico experimental controlado, aleatorizado, comparativo de un programade SFT con el proceso habitual en farmacias comunitarias españolas mejorado con educaciónsanitaria, durante 8 meses.Emplazamiento: Nueve farmacias comunitarias españolas.Participantes: Pacientes entre 25-74 años con riesgo cardiovascular (RCV) alto-moderado, queacudieron con una receta, a su nombre, de medicamentos para al menos un factor de RCV.Intervenciones: Los pacientes se asignaron aleatoriamente al grupo intervención (GI), querecibió SFT y educación sanitaria, o al grupo control (GC), que recibió solamente educación sanitaria. Mediciones principales: Adherencia al tratamiento y cifras de presión arterial (PA) y colesteroltotal (CT), al inicio y final estudio.Resultados: De los 87 pacientes reclutados, 85 acabaron el estudio: 41 del GC y 44 del GI.Ambos grupos aumentaron la adherencia al final del estudio [GC: 26,9%; IC95%:12,7 a 41; GI:27,3%; IC95%:13,6 a 41]. Aunque el GI mostró mejores resultados en la variación de las cifrasde PA y CT, las diferencias en relación al GC no fueron estadísticamente significativas.Conclusiones: El SFT y la educación sanitaria mejoran la adherencia al tratamiento. Ademásser paciente cumplidor al final del estudio se relaciona con la mejora de los objetivos de lapresión arterial y de presión arterial/colesterol total(AU)

Objective: To evaluate the effect of pharmacist involvement, by means of PharmacotherapyFollow-Up (PFU) in the improvement of medication adherence and therapeutic outcomes.Design: An experimental, controlled, and randomised clinical study comparing a PFU programwith the routine process in Spanish community pharmacies improved with health educationduring 8 months.Setting: Nine Spanish community pharmacies.Participants: Patients between 25 and 74 years with a moderate-high cardiovascular risk (CVR),who arrived with a prescription, in their name, for drugs for at least one CVR factor.Interventions: The patients were randomly assigned to the intervention group (IG), and receivedPFU and health education, or the control group (CG), who received health educationonly.Main measurements: Adherence to treatment, and blood pressure (BP) and total cholesterol(TC) levels at the beginning and end of the study.Results: Of the 87 patients enrolled, 85 finished the study: 41 from the CG and 44 from the IG.Both groups increased adherence at the end of the [CG: 26.9%; 95% CI: 12.7- 41; IG: 27.3%; 95%CI: 13.6 - 41]. Although the IG showed better results in the variation of BP and TC levels, thedifferences compared to the CG were not statistically significant.Conclusions: PFU and health education improves adherence to treatment. To be a patient whocompletes the study is also associated with improvement in the blood pressure and bloodpressure/total cholesterol objectives(AU)

Adecuación a los códigos de conducta para información biomédica en internet de sitios web útiles para el seguimiento farmacoterapéutico / Objetivos: Evaluar la adecuación de los sitios web destinados a proporcionar información para la realización de seguimiento farmacoterapéutico a 4 códigos de conducta

Objetivos: Evaluar la adecuación de los sitios web destinados a proporcionar información para la realización de seguimiento farmacoterapéutico a 4 códigos de conducta. Métodos: Estudio descriptivo del cumplimiento de los criterios de calidad de 19 sitios web seleccionados por ser los de mayor utilización por los farmacéuticos en un estudio previo. Se realizó un análisis descriptivo y se estimó el coeficiente kappa para valorar la concordancia entre evaluadores (criterios de Fleiss) . Resultados y conclusiones: Fisterra fue la página mejor valorada en los 4 códigos, y la fuente de acceso a guías clínicas mejor calificada. La Cochrane Library y Pubmed las mejor valoradas en revisiones y fuentes secundarias. JAMA y British Medical Journal fueron las revistas mejor calificadas seguidas de Atención Primaria y Medicina Clínica. Entre los vademécums, el BOT y el Martindale obtuvieron las mejores calificaciones y el Boletín Terapéutico Andaluz y el Butlletí Groc recibieron altas calificaciones de entre los boletines de medicamentos. La Organización Mundial de la Salud fue la agencia mejor calificada. Los sitios con menor calificación fueron Pharmaceutical Care, Seguimiento Farmacoterapéutico y el Vademécum Internacional España MediMedia-Medicom. La concordancia entre evaluadores fue aceptable para los 4 códigos. Conclusiones: La calidad de los sitios web que utilizan los farmacéuticos es muy variable, aunque la mayoría superan los 60 puntos (sobre 100) en los 4 códigos de conducta usados en la evaluación

Objectives: To assess adherence to four codes of conduct in websites providing information useful for pharmacotherapy follow-up. Methods: We performed a descriptive study of adherence to quality criteria in 19 websites. These sites had been identified in a previous study as being those most frequently used by pharmacists. A descriptive analysis was performed and the kappa coefficient was calculated to evaluate interrater concordance (Fleiss' criteria for evaluation of the kappa index). Results: The most highly rated source of clinical practice guidelines and that which adhered most closely to the 4 codes of conduct was Fisterra. The websites most highly rated in reviews and secondary sources were the Cochrane Library and PubMed. The most highly rated journals were JAMA and the BMJ, followed by Atención Primaria and Medicina Clínica. Among drug information guides, the highest scores were obtained by BOT and Martindale's. The highest rated drug bulletins were the Boletín Terapéutico Andaluz and Butlletí Groc. The most highly rated agency was the World Health Organization. The journals with the lowest scores were Pharmaceutical Care and Seguimiento Farmacoterapéutico followed by the Spanish Internacional Vademecum MediMedia-Medicom. According to Fleiss's criteria, interrater concordance was acceptable for the 4 codes. Conclusions: The quality of the web sites evaluated varied widely, although most received scores of more than 60 points (out of 100) in the 4 codes of conduct used for evaluation