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1.
Gut Microbes ; 13(1): 1-14, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33874856

RESUMO

Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC.The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.

2.
BMC Med ; 19(1): 1, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33390155

RESUMO

BACKGROUND: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. METHODS: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992-2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. RESULTS: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell's C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264-0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084-0.575)). CONCLUSIONS: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level.

3.
An. pediatr. (2003. Ed. impr.) ; 93(6): 380-395, dic. 2020. tab, graf
Artigo em Espanhol | IBECS-Express | IBECS | ID: ibc-ET5-2331

RESUMO

OBJETIVO: Elaborar un listado de medicamentos altamente tóxicos en la infancia (MAT), comercializados en España, diferenciando aquellos que alcanzan la dosis letal para un niño de 10 Kg con la ingesta de 1-3 unidades. MÉTODO: Se definió MAT como aquellos capaces de producir intoxicaciones graves o letales en niños menores de 8 años. Se consideró toxicidad grave la correspondiente al grado 3 en la clasificación Poisoning Severity Score y la categoría «major effects» en las publicaciones de la American Association of Poison Control Centers. Se realizó una revisión bibliográfica de los informes anuales de la American Association of Poison Control Centers y de PubMed entre enero 2000 y febrero 2019 (palabras clave: «severe», «fatal», «life-threatening», «poisoning», «child», «pediatric», «toxicological emergency»). Además, se realizó un estudio observacional retrospectivo de menores de 8 años que consultaron en un servicio de urgencias pediátrico por sospecha de intoxicación farmacológica entre julio 2012 y junio 2018. Se seleccionaron los principios activos responsables comercializados en España y se determinó la dosis letal o la dosis altamente tóxica. Se calculó el número de unidades necesarias para alcanzarla en niños de 10 kg. RESULTADOS: Se identificaron 7 grupos de MAT: analgésicos; psicofármacos y medicamentos neuromusculares; anticatarrales descongestivos-antitusígenos-antihistamínicos-antiasmáticos; medicamentos cardiovasculares; antimicrobianos; preparados tópicos y otros medicamentos. En 29 principios activos, la ingesta de una única unidad podría causar la muerte en un lactante de 10 kg de peso, en 13 podría causarla la ingesta de 2 unidades y en 10 la ingesta de 3 unidades. CONCLUSIÓN: Existen numerosos MAT comercializados en España, algunos de ellos disponibles en presentaciones potencialmente letales con pocas unidades


OBJECTIVE: To prepare a list of highly toxic drugs in infants (HTDs) marketed in Spain, comparing those that reach the lethal dose in a child of 10kg with the ingestion of 1 to 3 units. METHOD: HTDs are defined as those capable of causing severe or lethal poisoning in children less than 8-year-old. Severe poisoning is considered as that corresponding to Grade 3 in the Poisoning Severity Score classification and to the "major effects" category in publications in the American Association of Poison Control Centers. A literature review was carried out on the annual reports of the American Association of Poison Control Centers, as well as in PubMed, between January 2000 and February 2019 (Keywords "severe", "fatal", "life-threatening", "poisoning", "child", "paediatric", "toxicological emergency"). An observational, retrospective study was also conducted on infants less than 8-year-old that were seen in a Paediatric Emergency Department due to suspected drug poisoning between July 2012 and June 2018. The active ingredients responsible marketed in Spain were selected, and the lethal or highly toxic doses were determined. The number of units (pills) necessary to reach this dose in children of 10kg was calculated. RESULTS: A total of 7 HTD groups were identified: analgesics; psychotropics and other medication used in neurological disorders; catarrh decongestants - cough -antihistamine - asthma drugs; cardiovascular drugs; antibiotics, topical preparations, and other drugs. In 29 active ingredients, the ingestion of a single pill could cause death in 10kg infant, in another 13, the ingestion of 2 pills could cause death, as well as the ingestion of 3 pills in 10 cases. CONCLUSION: There are numerous HTDs marketed in Spain, some of which are available in potentially fatal presentations with few pills

4.
Diabetes Care ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203707

RESUMO

OBJECTIVE: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS: We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10-8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

5.
Cancer Manag Res ; 12: 10251-10260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116879

RESUMO

Background: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA. Methods: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS. Results: Median OS was 16.4 months (range 12.4-20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir <2.4ng/mL, time to PSA nadir >140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. Conclusion: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.

6.
Sci Rep ; 10(1): 13814, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796953

RESUMO

Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.

7.
Int J Cancer ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32734650

RESUMO

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

8.
An Pediatr (Barc) ; 93(6): 380-395, 2020 Dec.
Artigo em Espanhol | MEDLINE | ID: mdl-32284232

RESUMO

OBJECTIVE: To prepare a list of highly toxic drugs in infants (HTDs) marketed in Spain, comparing those that reach the lethal dose in a child of 10kg with the ingestion of 1 to 3 units. METHOD: HTDs are defined as those capable of causing severe or lethal poisoning in children less than 8-year-old. Severe poisoning is considered as that corresponding to Grade 3 in the Poisoning Severity Score classification and to the "major effects" category in publications in the American Association of Poison Control Centers. A literature review was carried out on the annual reports of the American Association of Poison Control Centers, as well as in PubMed, between January 2000 and February 2019 (Keywords "severe", "fatal", "life-threatening", "poisoning", "child", "paediatric", "toxicological emergency"). An observational, retrospective study was also conducted on infants less than 8-year-old that were seen in a Paediatric Emergency Department due to suspected drug poisoning between July 2012 and June 2018. The active ingredients responsible marketed in Spain were selected, and the lethal or highly toxic doses were determined. The number of units (pills) necessary to reach this dose in children of 10kg was calculated. RESULTS: A total of 7 HTD groups were identified: analgesics; psychotropics and other medication used in neurological disorders; catarrh decongestants - cough -antihistamine - asthma drugs; cardiovascular drugs; antibiotics, topical preparations, and other drugs. In 29 active ingredients, the ingestion of a single pill could cause death in 10kg infant, in another 13, the ingestion of 2 pills could cause death, as well as the ingestion of 3 pills in 10 cases. CONCLUSION: There are numerous HTDs marketed in Spain, some of which are available in potentially fatal presentations with few pills.

9.
Sex., salud soc. (Rio J.) ; (33): 59-78, set.-dez. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1059093

RESUMO

Resumen Este artículo se propone describir algunas de las características de la Ginecología Natural, a partir de la consideración de su desarrollo como expresión sociocultural emergente en la última década en América Latina. Siguiendo los criterios de la teoría fundamentada, se describen dos de las categorías más comunes en una serie de textos escritos y circulados de manera independiente a lo largo del territorio en los últimos cuatro años. Por un lado, el principio informativo y pedagógico, que traza una trama de saberes recuperados y compartidos entre pares. Por el otro, un cuestionamiento constante de la deriva patologizadora y biomedicalizante de la medicina. Los resultados obtenidos permiten esbozar un ideario compartido, pero en constante transformación.


Resumo Este artigo pretende descrever algumas das características da Ginecologia Natural, com base em seu desenvolvimento como expressão sociocultural emergente na América Latina desta última década. Seguindo critérios da teoria fundamentada, são descritas duas das categorias comuns em textos escritos e circulados de maneira independente nesse território, nos últimos quatro anos. Por um lado, o princípio informativo e pedagógico, que mostra um entrelaçamento de saberes recuperados e compartilhados entre pares. Por outro, um questionamento constante da tendência patologizadora e biomedicalizante da medicina. Os resultados obtidos permitem delinear um conjunto de ideias compartilhado e, não obstante, em constante transformação.


Abstract This article tries to describe some of the characteristics of Natural Gynecology, considering its development as a sociocultural expression that emerged in the last decade in Latin America. Following the criteria of the Grounded theory, two of the most common categories in a series of texts written and distributed independently in the last four years are described. On the one hand, the informative and pedagogic principle, combining information brought from ancient knowledge and from the knowledge that is shared among pairs. On the other hand, a constant questioning of the pathologizing and biomedicalizing drift of medicine. The results obtained allow us to sketch a shared ideology, but in permanent transformation.


Assuntos
Humanos , Feminino , Saúde da Mulher , Saúde Sexual e Reprodutiva , Ginecologia , Medicina Tradicional , Feminismo , Fatores Culturais , Fatores Sociológicos , América Latina
10.
Nutrients ; 11(8)2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434255

RESUMO

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor ß (TGFß) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.


Assuntos
Neoplasias Colorretais/epidemiologia , Vitamina D/sangue , Vitamina D/genética , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenômenos Fisiológicos da Nutrição , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Fatores de Risco , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Vitamina D/análogos & derivados
11.
Mol Genet Genomic Med ; 7(8): e832, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31273931

RESUMO

BACKGROUND: MicroRNAs are small regulatory RNAs with important roles in carcinogenesis. Genetic variants in these regulatory molecules may contribute to disease. We aim to identify allelic variants in microRNAs as susceptibility factors to gastric cancer using association studies and functional approaches. METHODS: Twenty-one single nucleotide variants potentially functional, because of their location in either the seed, mature or precursor region of 22 microRNAs, were selected for association studies. Genetic association with gastric cancer in 365 cases and 1,284 matched controls (European Prospective Investigation into Cancer and Nutrition Cohort) was analysed using logistic regression. MicroRNA overexpression, transcriptome analysis, and target gene validation experiments were performed for functional studies. RESULTS: rs3746444:T>C, in the seed of MIR499A and mature MIR499B, associated with the cardia adenocarcinoma location; rs12416605:C>T, in the seed of MIR938, associated with the diffuse subtype; and rs2114358:T>C, in the precursor MIR1206, associated with the noncardia phenotype. In all cases, the association was inverse, indicating a protective affect against gastric cancer of the three minor allelic variants. MIR499 rs3746444:T>C and MIR1206 rs2114358:T>C are reported to affect the expression of these miRNAs, but the effect of MIR938 rs12416605:C>T is unknown yet. Functional approaches showed that the expression of MIR938 is affected by rs12416605:C>T and revealed that MIR938 could regulate a subset of cancer-related genes in an allele-specific fashion. Furthermore, we demonstrated that CXCL12, a chemokine participating in gastric cancer metastasis, is specifically regulated by only one of the rs12416605:C>T alleles. CONCLUSION: rs12416605 appears to be involved in gastric cancer by affecting the regulatory function of MIR938 on genes related to this cancer type, particularly on CXCL12 posttranscriptional regulation.


Assuntos
Quimiocina CXCL12/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , MicroRNAs/genética , Neoplasias Gástricas/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estômago/patologia , Neoplasias Gástricas/patologia
14.
Int J Cancer ; 143(11): 2777-2786, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171605

RESUMO

Gastric carcinogenesis proceeds through a series of gastric cancer precursor lesions (GCPLs) leading to gastric cancer (GC) development. Although Helicobacter pylori infection initiates this process, genetic factors also play a role. We previously reported that genetic variability in MUC2 is associated with the evolution of GCPLs. In order to replicate previous results in an independent sample series and to explore whether genetic variability in other candidate genes plays a role in the evolution of GCPL, genomic DNA from 559 patients with GCPLs, recruited from 9 Spanish hospitals and followed for a mean of 12 years, was genotyped for 141 SNPs in 29 genes. After follow-up, 45.5% of the lesions remained stable, 37% regressed and 17.5% progressed to a more severe lesion. Genetic association with the evolution of the lesions (progression or regression) was analyzed by multinomial and binomial logistic regression. After correction for multiple comparisons, the results obtained confirmed the inverse association between MUC2 variants and the regression of the lesions. A significant association was also observed between NFKB1 and CD14 variants and the evolution of the lesions; interestingly, this association was with both progression and regression in the same direction, which could reflect the dual role of inflammation in cancer. Stratified analyses according to H. pylori virulence factors indicated some significant and differential effects but none of them passed the FDR test. These results confirm that genetic variability in MUC2, NFKB1 and CD14 may have a role in the evolution of the GCPLs along time and in gastric carcinogenesis.


Assuntos
Predisposição Genética para Doença/genética , Receptores de Lipopolissacarídeos/genética , Mucina-2/genética , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único/genética , Lesões Pré-Cancerosas/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Progressão da Doença , Seguimentos , Genótipo , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia
15.
Lancet Oncol ; 19(7): 975-986, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880291

RESUMO

BACKGROUND: Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. METHODS: We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. FINDINGS: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8-20·4) with olaparib and abiraterone and 8·2 months (5·5-9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44-0·97, p=0·034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. INTERPRETATION: Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer. FUNDING: AstraZeneca.


Assuntos
Androstenos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Fatores Etários , Idoso , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias de Próstata Resistentes à Castração/patologia , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento
16.
Cancer Med ; 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29766673

RESUMO

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined  = 5.66 × 10-5 ; ORcombined  = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined  = 1.02 × 10-4 ; ORcombined  = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p < 0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p = 0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.

17.
Target Oncol ; 13(3): 309-331, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29569164

RESUMO

Metastatic renal cell carcinoma (mRCC) is an incurable malignancy, characterized by its resistance to traditional chemotherapy, radiation, and hormonal therapy. Treatment perspectives and prognosis of patients with mRCC have been significantly improved by advances in the understanding of its molecular pathogenesis, which have led to the development of targeted therapeutics. Different molecular factors derived from the tumor or the host detected in both tissue or serum could be predictive of therapeutic benefit. Some of them suggest a rational selection of patients to be treated with certain therapies, though none have been validated for routine use. This article provides an overview of both clinical and molecular factors associated with predictive or prognostic value in mRCC and emphasizes that both should be considered in parallel to provide the most appropriate, individualized treatment and achieve the best outcomes in clinical practice.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Prognóstico
18.
Diabetes ; 67(6): 1200-1205, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29523632

RESUMO

Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 µg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.


Assuntos
Diabetes Mellitus Tipo 2/sangue , alfa-2-Glicoproteína-HS/análise , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Ensaio de Imunoadsorção Enzimática , Europa (Continente)/epidemiologia , Feminino , Estudos de Associação Genética , Alemanha/epidemiologia , Humanos , Imunoturbidimetria , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Reprodutibilidade dos Testes , Risco , alfa-2-Glicoproteína-HS/genética
19.
PLoS One ; 12(9): e0184737, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28931046

RESUMO

BACKGROUND: Locally advanced esophageal carcinoma (LAEC) represents less than 30% of all diagnosed esophageal carcinoma worldwide. The standard of care for resectable tumours consists of preoperative chemoradiotherapy (CRT) followed by surgery. Despite the curative intent, the prognosis is still poor mainly due to relapse. A multidisciplinary approach is required in order to optimize the therapeutic strategy and follow-up. Differences in outcomes between the two main histological subtypes, adenocarcinoma (ADC) and squamous cell carcinoma (SCC), have been reported. Nevertheless, the heterogeneity in trials design and data available have hampered the achievement of clear conclusions. The purpose of this study is to report the outcomes from a cohort of patients with LAEC treated with a multidisciplinary approach and to remark the differences observed between the two main histologic subtypes and their clinical implications. METHODS: We retrospectively reviewed 100 patients diagnosed with LAEC that were treated with preoperative CRT at our institution and integrated centres. Histopathological characteristics and toxicities during treatment were recorded. Patterns of recurrence at the first relapse were analysed. Survival curves were plotted using the Kaplan Meier method and multivariate Cox proportional hazards models were used. RESULTS: Among the patients who received preoperative CRT, 83% underwent surgery. The median overall survival (mOS) was 31.7 months, 26.9 months for ADC and 45.5 for SCC (p-value = 0.33). In the multivariate Cox regression analysis, ypN+ was the only factor that negatively influenced in OS (OR = 4.1, p-value = 0.022). Patterns of recurrence differed according to histologic subtype. Distant relapse was more frequent in ADC (62%), whereas locoregional relapse was higher in SCC (50%) (p-value = 0.027). Second line therapeutic strategies could be offered to 50% of those patients who relapsed. CONCLUSIONS: Differences in outcomes and recurrence pattern could be observed between the two main histologic subtypes of LAEC. A better molecular characterization, adapted therapeutic regimens and follow up strategies should be adopted in order to improve survival of these patients.


Assuntos
Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias Esofágicas/terapia , Recidiva Local de Neoplasia/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia , Taxa de Sobrevida
20.
Carcinogenesis ; 38(7): 691-698, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28535209

RESUMO

Epidemiologic evidence linking environmental exposure to polycyclic aromatic hydrocarbons (PAH) with breast cancer is limited. Measurement of DNA adducts formed by aromatic compounds, including PAH, has been carried in breast tissue samples and white blood cells from women with breast cancer and different kinds of controls. However, these studies provide inconsistent results and bias cannot be ruled out. During the 7-year follow-up period, 305 women were diagnosed with first primary breast cancer in the EPIC-Spain cohort, and were compared with a sample of 149 women without breast cancer at recruitment, using a case-cohort approach. Aromatic adducts to DNA from leukocytes collected at recruitment were measured by means of the 32P-post-labelling technique. The relative risk and 95% confidence interval (CI), adjusted by relevant confounders, were estimated by a modified version of Cox proportional hazards model. There was a significant increased risk for developing breast cancer when DNA adduct concentrations were doubled, with adjusted RR of 1.61 (95% CI 1.29-2.01). The increase in breast cancer risk was observed both for pre- and post-menopausal women. There was a significant interaction with tobacco smoking and body mass index, with higher effect of DNA adducts on breast cancer risk among smokers and women with normal weight. The results from our study support the hypothesis that factors leading to higher levels of aromatic DNA adducts in white blood cells may be involved in development of breast cancer.


Assuntos
Neoplasias da Mama/genética , Adutos de DNA/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Adulto , Idoso , Índice de Massa Corporal , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Estudos de Coortes , Adutos de DNA/genética , Exposição Ambiental , Feminino , Humanos , Leucócitos , Pessoa de Meia-Idade , Fatores de Risco , Fumar/efeitos adversos , Espanha
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