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1.
Am Heart J ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33129989

RESUMO

Current clinical practice guidelines for anemia management in non-dialysis dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises two global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N=1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N=1725) had hemoglobin between 8-11 g/dL (US) or 9-12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include 1) correction/conversion (weeks 0-23); 2) maintenance (weeks 24-52); 3) long-term treatment (week 53 to end of treatment); and 4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics were similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.

2.
Cancer Res ; 80(20): 4578-4590, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816852

RESUMO

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

3.
Clin Biochem ; 83: 21-27, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32450078

RESUMO

OBJECTIVES: Measuring blood urea at the same time as serum creatinine in stable ambulatory patients in family practice is largely unnecessary. The objective was to assess the relative impact of changing the laboratory requisition versus audit and feedback and academic detailing on the volume of orders for blood urea. DESIGN AND METHODS: A natural experiment was observed over the period April 2015 to March 2018 in the Canadian province of Newfoundland where three health regions had different approaches to trying to reduce such urea testing. The Eastern and Western regions removed urea from the standard laboratory requisition but the test could still be ordered by writing it on the requisition. Central region requisitions continued to list urea. Audit and feedback was undertaken with family doctors in Eastern region after the requisition change and that was followed by academic detailing. A nephrologist gave presentations to groups of family doctors on one occasion in Central region. RESULTS: The volume of serum creatinine testing was largely unchanged over time in each region. The volume of urea testing reduced by 73%, 48% and 28% in Eastern, Western and central regions. Interrupted time series analysis showed significant changes in test volume after requisition change in Eastern and Western regions as well as after audit and feedback in Eastern and the presentations in Central region. The incremental impact of academic detailing was not statistically significant. CONCLUSION: We conclude that removing urea from standard test order menus was the most effective in reducing test volumes, but combination with audit and feedback augmented the impact.

4.
Heart Rhythm ; 17(7): 1159-1166, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32120009

RESUMO

BACKGROUND: High-level exercise has been associated with a malignant phenotype in desmosomal and genotype-negative forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first study to examine this issue with ARVC secondary to the TMEM43 p.S358L mutation. OBJECTIVE: The purpose of this study was to evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ARVC. METHODS: Individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry who had received a primary prevention implantable cardioverter-defibrillator (ICD) were invited to complete the modified Paffenbarger Physical Activity Questionnaire to assess their physical activity in the year before their ICD implantation. Time-to-event analyses using unadjusted and adjusted Cox proportional hazards models evaluated associations between physical activity and first appropriate ICD discharge secondary to malignant ventricular arrhythmia or cardiac death. RESULTS: In 80 subjects with the TMEM43 p.S358L mutation, exercise ≥9.0 metabolic equivalent of task (MET)-hours/day (high level) in the year before ICD implantation was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge (there were no deaths) relative to physical activity <9.0 MET-hours/day (moderate level) (95% confidence interval [CI] 3.3-24.6 MET-hours/day; P < .001). The median age from birth to first appropriate ICD discharge was 58.5 years (95% CI 56.5-60.5 years) vs 35.8 years (95% CI 28.2-43.4 years) (P < .001) in subjects in moderate- and high-level exercise groups, respectively. CONCLUSION: Exercise ≥9.0 MET-hours/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ARVC. Extrapolating these data, we suggest molecular testing be offered in early childhood to inform exercise choices reflective of the genotype.

5.
Int J Cancer ; 146(3): 861-873, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.


Assuntos
Neoplasias Colorretais/etiologia , Etanol/efeitos adversos , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
7.
BMC Cancer ; 19(1): 133, 2019 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-30738427

RESUMO

BACKGROUND: Differentiating between cancer patients who will experience metastasis within a short time and who will be long-term survivors without metastasis is a critical aim in healthcare. The microsatellite instability (MSI)-high tumor phenotype is such a differentiator in colorectal cancer, as patients with these tumors are unlikely to experience metastasis. Our aim in this study was to determine if germline genetic variations could further differentiate colorectal cancer patients based on the long-term risk and timing of metastasis. METHODS: The patient cohort consisted of 379 stage I-III Caucasian colorectal cancer patients with microsatellite stable or MSI-low tumors. We performed univariable analysis on 810,622 common single nucleotide polymorphisms (SNPs) under different genetic models. Depending on the long-term metastasis-free survival probability estimates, we applied a mixture cure model, Cox proportional hazards regression model, or log-rank test. For SNPs reaching Bonferroni-corrected significance (p < 6.2 × 10- 8) having valid genetic models, multivariable analysis adjusting for significant baseline characteristics was conducted. RESULTS: After adjusting for significant baseline characteristics, specific genotypes of ten polymorphisms were significantly associated with time-to-metastasis. These polymorphisms are three intergenic SNPs, rs5749032 (p = 1.28 × 10- 10), rs2327990 (p = 9.59 × 10- 10), rs1145724 (p = 3 × 10- 8), and seven SNPs within the non-coding sequences of three genes: FHIT (p = 2.59 × 10- 9), EPHB1 (p = 8.23 × 10- 9), and MIR7515 (p = 4.87 × 10- 8). CONCLUSIONS: Our results suggest novel associations of specific genotypes of SNPs with early metastasis in Caucasian colorectal cancer patients. These associations, once replicated in other patient cohorts, could assist in the development of personalized treatment strategies for colorectal cancer patients.

8.
Mol Genet Genomic Med ; 6(6): 1021-1030, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30300963

RESUMO

BACKGROUND: Hereditary Non-Polyposis Colorectal cancer is caused by Lynch Syndrome (LS; an autosomal dominant condition) or by Familial Colorectal Cancer Type-X (FCCTX; a condition of high family risk that fulfills Amsterdam criteria). The lifetime risk of developing colorectal cancer (CRC) in FCCTX family members is high and CRC occurs later than in LS. METHODS: To determine the impact of primary prevention colonoscopic screening in asymptomatic first-degree relatives of incident CRC cases in 20 families with FCCTX, we compared cancer incidence and survival in 79 males and 83 females, assumed to be at 50% risk of inheriting a genetic CRC susceptibility factor, who entered screening to an unscreened control group from the families, matched for age at entry into screening and for sex. RESULTS: In males, median age at entry into screening was 44.8 years, median follow-up 12.4 years, 12% developed CRC, and 46% died after 30 years of follow-up. Compared to the unscreened group, relative risk of CRC was 0.27 (95% confidence intervals (CI) 0.10-0.71). In screened females, comparable results were 44.5 years at entry, 11.2 years of follow-up, 7.1% developed CRC, and 7.2% died after 30 years of follow-up. The relative risk of CRC compared to the unscreened group was 0.19 (95% CI 0.07-0.48). CONCLUSION: Primary prevention screening colonoscopy in asymptomatic family members significantly decreased the risk of CRC in FCCTX.


Assuntos
Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
9.
Kidney Int ; 94(4): 661-662, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30243312

RESUMO

Use of calcimimetics will be influenced not only by assessment of benefits and harms in individual patients but also by cost and by national guidelines. The Japanese Society for Dialysis Therapy has a lower PTH threshold for PTH control than other countries. The current RCT, despite its limitations, provides a rationale for use of evocalcet in the management of secondary hyperPTH.


Assuntos
Cinacalcete , Hiperparatireoidismo Secundário , Calcimiméticos , Humanos , Diálise Renal
10.
Biomark Res ; 6: 17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29942513

RESUMO

Background: Colorectal cancer has significant impact on individuals and healthcare systems. Many genes have been identified to influence its pathogenesis. However, the genetic basis of mucinous tumor histology, an aggressive subtype of colorectal cancer, is currently not well-known. This study aimed to identify common and rare genetic variations that are associated with the mucinous tumor phenotype. Methods: Genome-wide single nucleotide polymorphism (SNP) data was investigated in a colorectal cancer patient cohort (n = 505). Association analyses were performed for 729,373 common SNPs and 275,645 rare SNPs. Common SNP association analysis was performed using univariable and multivariable logistic regression under different genetic models. Rare-variant association analysis was performed using a multi-marker test. Results: No associations reached the traditional genome-wide significance. However, promising genetic associations were identified. The identified common SNPs significantly improved the discriminatory accuracy of the model for mucinous tumor phenotype. Specifically, the area under the receiver operating characteristic curve increased from 0.703 (95% CI: 0.634-0.773) to 0.916 (95% CI: 0.873-0.960) when considering the most significant SNPs. Additionally, the rare variant analysis identified a number of genetic regions that potentially contain causal rare variants associated with the mucinous tumor phenotype. Conclusions: This is the first study applying both common and rare variant analyses to identify genetic associations with mucinous tumor phenotype using a genome-wide genotype data. Our results suggested novel associations with mucinous tumors. Once confirmed, these results will not only help us understand the biological basis of mucinous histology, but may also help develop targeted treatment options for mucinous tumors.

11.
Nutr J ; 17(1): 55, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29793493

RESUMO

BACKGROUND: Dietary patterns are commonly used in epidemiological research, yet there have been few studies assessing if and how research results may vary across dietary patterns. This study aimed to estimate the risk of mortality/recurrence/metastasis using different dietary patterns and comparison amongst the patterns. METHODS: Dietary patterns were identified by Cluster Analysis (CA), Principal Component Analysis (PCA), Alternate Mediterranean Diet score (altMED), Recommended Food Score (RFS) and Dietary Inflammatory Index (DII) scores using a 169-item food frequency questionnaire. Five hundred thirty-two colorectal cancer patients diagnosed between 1999 and 2003 in Newfoundland were followed-up until 2010. Overall Mortality (OM) and combined Mortality, Recurrence or Metastasis (cMRM) were identified. Comparisons were made with adjusted Cox proportional Hazards Ratios (HRs), correlation coefficients and the distributions of individuals in defined clusters by quartiles of factor and index scores. RESULTS: One hundred and seventy cases died from all causes and 29 had a cancer recurrence/metastasis during follow-up. Processed meats as classified by PCA (HR 1.82; 95% confidence interval (CI) 1.07-3.09), clusters characterized by meat and dairy products (HR 2.19; 95% CI 1.03-4.67) and total grains, sugar, soft drinks (HR 1.95; 95% CI 1.13-3.37) were associated with a higher risk of cMRM. Poor adherence to AltMED increased the risk of all-cause OM (HR 1.62; 95% CI 1.04-2.56). Prudent vegetable, high sugar pattern, RFS and DII had no significant association with both OM and cMRM. CONCLUSION: Estimation of OM and cMRM varied across dietary patterns which is attributed to the differences in the foundation of each pattern.


Assuntos
Neoplasias Colorretais/mortalidade , Dieta/estatística & dados numéricos , Adulto , Idoso , Análise por Conglomerados , Estudos de Coortes , Registros de Dieta , Dieta Mediterrânea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Terra Nova e Labrador/epidemiologia , Avaliação Nutricional , Modelos de Riscos Proporcionais , Fatores de Risco , Inquéritos e Questionários , Taxa de Sobrevida
12.
PLoS One ; 13(2): e0192316, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29394274

RESUMO

BACKGROUND: Metastasis is a major cause of mortality in cancer. Identifying prognostic factors that distinguish patients who will experience metastasis in the short-term and those that will be free of metastasis in the long-term is of particular interest in current medical research. The objective of this study was to examine if select genetic polymorphisms can differentiate colorectal cancer patients based on timing and long-term risk of metastasis. METHODS: The patient cohort consisted of 402 stage I-III colorectal cancer patients with microsatellite instability (MSI)-low (MSI-L) or microsatellite stable (MSS) tumors. We applied multivariable mixture cure model, which is the proper model when there is a substantial group of patients who remain free of metastasis in the long-term, to 26 polymorphisms. Time-dependent receiver operator characteristic (ROC) curve analysis was performed to determine the change in discriminatory accuracy of the models when the significant SNPs were included. RESULTS: After adjusting for significant baseline characteristics, two polymorphisms were significantly associated with time-to-metastasis: TT and TC genotypes of the XRCC3 Thr241Met (p = 0.042) and the 3R/3R genotype of TYMS 5'-UTR variable number tandem repeat (VNTR) (p = 0.009) were associated with decreased time-to-metastasis. ROC curves showed that the discriminatory accuracy of the model is increased slightly when these polymorphisms were added to the significant baseline characteristics. CONCLUSIONS: Our results indicate XRCC3 Thr241Met and TYMS 5'-UTR VNTR polymorphisms are associated with time-to-metastasis, and may have potential biological roles in expediting the metastatic process. Once replicated, these associations could contribute to the development of precision medicine for colorectal cancer patients.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Metionina/genética , Metástase Neoplásica , Treonina/genética , Timidilato Sintase/genética , Neoplasias Colorretais/patologia , Humanos , Polimorfismo de Nucleotídeo Único
13.
BMC Cancer ; 18(1): 155, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409465

RESUMO

BACKGROUND: The rs2282679 A>C polymorphism in the vitamin D binding protein gene is associated with lower circulating levels of vitamin D. We investigated associations of this SNP with colorectal cancer (CRC) risk and survival and whether the associations vary by dietary vitamin D intake and tumor molecular phenotype. METHODS: A population-based case-control study identified 637 incident CRC cases (including 489 participants with follow-up data on mortality end-points) and 489 matched controls. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom® myDesign™ Array in controls. Logistic regression examined the association between the rs2282679 polymorphism and CRC risk with inclusion of potential confounders. Kaplan-Meier curves and multivariable Cox models assessed the polymorphism relative to overall survival (OS) and disease-free survival (DFS). RESULTS: The rs2282679 polymorphism was not associated with overall CRC risk; there was evidence, however, of effect modification by total vitamin D intake (Pinteraction = 0.019). Survival analyses showed that the C allele was correlated with poor DFS (per-allele HR, 1.36; 95%CI, 1.05-1.77). The association of rs2282679 on DFS was limited to BRAF wild-type tumors (HR, 1.58; 95%CI, 1.12-2.23). For OS, the C allele was associated with higher all-cause mortality among patients with higher levels of dietary vitamin D (HR, 2.11; 95%CI, 1.29-3.74), calcium (HR, 1.93; 95%CI, 1.08-3.46), milk (HR, 2.36; 95%CI, 1.26-4.44), and total dairy product intakes (HR, 2.03; 95%CI, 1.11-3.72). CONCLUSION: The rs2282679 SNP was not associated with overall CRC risk, but may be associated with survival after cancer diagnosis. The association of this SNP on survival among CRC patients may differ according to dietary vitamin D and calcium intakes and according to tumor BRAF mutation status.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteína de Ligação a Vitamina D/genética , Idoso , Estudos de Casos e Controles , Dieta , Feminino , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem
14.
Nutrition ; 42: 69-74, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28870481

RESUMO

OBJECTIVE: Chronic inflammation is implicated in causing cancer. Diet plays an important role in regulating chronic inflammation by altering circulating levels of inflammatory biomarkers. Effect of single food or nutrient on cancer often is inconclusive; perhaps due to dietary interactions and multicolinearity. The aim of this study was to determine prediagnostic inflammatory potential of overall diet in relation to risk for colorectal cancer (CRC). METHODS: In all, 547 patients with CRC from Newfoundland Familial Colorectal Cancer Registry and 685 controls from the general population were identified. Data on sociodemographic, medical history, lifestyle, and a 169-item food frequency questionnaire were collected retrospectively from both groups. Energy-adjusted Dietary Inflammatory Index (DII) score was calculated and used as both categorical and continuous variables for analysis. Odds ratio was estimated using multivariable logistic regression after adjusting potential confounders. A linear test for trend was performed using the median value in each quartile. RESULTS: Overall energy-adjusted mean DII score was -0.81 (range -5.19 to 6.93). Cases (-0.73 ± 1.5) had slightly higher DII scores than controls (-0.89 ± 1.6; P = 0.04). After adjusting the potential confounders, a statistically significant association was found between DII score and CRC risk. Using DII as a continuous variable (odds ratio [OR]continuous 1.10, 95% confidence interval [CI] 1.01-1.20) and categorical variable (ORquartile 1 versus 4 1.65, 95% CI 1.13-2.42; Ptrend = 0.02). CONCLUSION: Our findings indicate that proinflammatory diets are associated with an increased risk for CRC in the Newfoundland population.


Assuntos
Neoplasias Colorretais/epidemiologia , Dieta/métodos , Inflamação/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terra Nova e Labrador/epidemiologia , Fatores de Risco
15.
Br J Cancer ; 117(6): 898-906, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28765616

RESUMO

BACKGROUND: Increased serum levels of vitamin D and calcium have been associated with lower risks of colorectal cancer (CRC) incidence and mortality. These inverse associations may be mediated by the vitamin D receptor (VDR) and the calcium-sensing receptor (CASR). We investigated genetic variants in VDR and CASR for their relevance to CRC prognosis. METHODS: A population-based cohort of 531 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and cancer recurrence until April 2010. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip. Multivariate Cox models assessed 41 tag single-nucleotide polymorphisms and relative haplotypes on VDR and CASR in relation to all-cause mortality (overall survival, OS) and disease-free survival (DFS). RESULTS: Gene-level associations were observed between VDR and the DFS of rectal cancer patients (P=0.037) as well as between CASR and the OS of colon cancer patients (P=0.014). Haplotype analysis within linkage blocks of CASR revealed the G-G-G-G-G-A-C haplotype (rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757) to be associated with a decreased OS of colon cancer (HR, 3.15; 95% CI, 1.66-5.96). Potential interactions were seen among prediagnostic dietary calcium intake with the CASR R990G (Pint=0.040) and the CASR G-T-G-G-G-G-C haplotype for rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757 (Pint=0.017), with decreased OS time associated with these variants limited to patients consuming dietary calcium below the median, although the stratified results were not statistically significant after correction for multiple testing. CONCLUSIONS: Polymorphic variations in VDR and CASR may be associated with survival after a diagnosis of CRC.


Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Variação Genética , Recidiva Local de Neoplasia , Receptores de Calcitriol/genética , Receptores de Detecção de Cálcio/genética , Neoplasias Retais/genética , Neoplasias Retais/mortalidade , Dieta/efeitos adversos , Intervalo Livre de Doença , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Terra Nova e Labrador , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais
16.
Contemp Clin Trials ; 48: 119-24, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27080930

RESUMO

BACKGROUND: Unlike conventional time-to-event analysis of composite endpoints in clinical trials, the "win ratio" method allows for flexibility in prioritizing their components. Here, we compare the EVOLVE trial findings using the win ratio with those from time-to-event analysis. EXPOSURE: Randomization to cinacalcet or placebo. OUTCOME: The primary composite endpoint combining all-cause mortality and non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, and peripheral vascular events. ANALYSIS: In an unadjusted analysis, we paired each participant from the cinacalcet arm with every participant from the placebo arm within randomization strata. Pairs were classified as "winners" or "losers," according to which participant died first during the shared follow-up time, or experienced the next ranked event first. We ranked non-fatal events in two ways: 1) all ranked evenly; and 2) prioritized by their effect on health-related quality of life. The win ratio equaled the total winners divided by total losers. Further analyses were conducted where the win ratio was stratified by, or adjusted for, age. RESULTS: The unadjusted win ratio for the primary composite endpoint was 1.09 (95% CI 0.97 to 1.21), a statistically non-significant result which supports the primary trial result - unadjusted hazard ratio 0.93 (95% CI 0.85 to 1.02). Age-stratified analyses showed a nominally significant benefit of cinacalcet (win ratio 1.14, 95% CI 1.04 to 1.26). Ranking of non-fatal outcomes by their relative effects on quality of life did not materially alter the results. CONCLUSION: The win ratio method corroborated the findings of EVOLVE based on conventional time-to-event analysis. EVOLVE ClinicalTrials.gov number: NCT00345839.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Idoso , Angina Instável/epidemiologia , Causas de Morte , Feminino , Insuficiência Cardíaca/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/epidemiologia , Doenças Vasculares Periféricas/epidemiologia , Modelos de Riscos Proporcionais , Resultado do Tratamento
17.
Artigo em Inglês | MEDLINE | ID: mdl-26966288

RESUMO

BACKGROUND: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. METHODS AND RESULTS: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. CONCLUSIONS: ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.


Assuntos
Displasia Arritmogênica Ventricular Direita/terapia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Proteínas de Membrana/genética , Mutação , Prevenção Primária/instrumentação , Prevenção Secundária/instrumentação , Taquicardia Ventricular/terapia , Fibrilação Ventricular/terapia , Adulto , Fatores Etários , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/mortalidade , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Análise Mutacional de DNA , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Linhagem , Fenótipo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/genética , Fibrilação Ventricular/mortalidade , Fibrilação Ventricular/fisiopatologia
18.
Med Decis Making ; 36(8): 965-72, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26987347

RESUMO

BACKGROUND: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) clinical trial evaluated the effects of cinacalcet on clinical events in patients with secondary hyperparathyroidism (sHPT) who were on hemodialysis. Health-related quality of life (HRQoL) was assessed by a generic, preference-based health outcome measure (EQ-5D) at scheduled visits and after a study event. Here, we report the HRQoL analysis from EVOLVE. METHODS: We assessed changes in HRQoL from baseline to scheduled visits, and estimated the acute (3 mo) and chronic (beyond 3 mo) effects of sHPT-related events on HRQoL using generalized estimating equation analysis controlling for baseline HRQoL and randomized assignment. RESULTS: Data on HRQoL were available for 3547 of 3883 subjects, with 1650 events in the placebo and 1502 in the cinacalcet arm. At the study end, no difference in change from baseline HRQoL was observed in the direct comparison of EQ-5D by treatment arms. The regression analysis showed significant effects of events on HRQoL and a modest positive effect of cinacalcet. Estimated quality-adjusted life-year gains were of similar magnitude based on the observed data or the predictions from the model, with only a small gain in precision from the predicted analysis. CONCLUSIONS: By contrast with a conventional comparison, a regression analysis demonstrated large decrements in HRQoL after events and a modest improvement in HRQoL with cinacalcet. As randomized controlled trials are rarely powered to detect differences in HRQoL, a prespecified regression analysis may be acceptable to improve precision of the effects and understand their origin.


Assuntos
Calcimiméticos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Calcimiméticos/administração & dosagem , Cinacalcete/administração & dosagem , Análise Custo-Benefício , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Análise de Regressão , Diálise Renal , Projetos de Pesquisa
19.
BMC Cancer ; 16: 113, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26884349

RESUMO

BACKGROUND: Aberrant Wnt signaling activation occurs commonly in colorectal carcinogenesis, leading to upregulation of many target genes. APC (adenomatous polyposis coli) is an important component of the ß-catenin destruction complex, which regulates Wnt signaling, and is often mutated in colorectal cancer (CRC). In addition to mutational events, epigenetic changes arise frequently in CRC, specifically, promoter hypermethylation which silences tumor suppressor genes. APC and the Wnt signaling target gene ITF2 (immunoglobulin transcription factor 2) incur hypermethylation in various cancers, however, methylation-dependent regulation of these genes in CRC has not been studied in large, well-characterized patient cohorts. The microsatellite instability (MSI) subtype of CRC, featuring DNA mismatch repair deficiency and often promoter hypermethylation of MutL homolog 1 (MLH1), has a favorable outcome and is characterized by different chemotherapeutic responses than microsatellite stable (MSS) tumors. Other epigenetic events distinguishing these subtypes have not yet been fully elucidated. METHODS: Here, we quantify promoter methylation of ITF2 and APC by MethyLight in two case-case studies nested in population-based CRC cohorts from the Ontario Familial Colorectal Cancer Registry (n = 330) and the Newfoundland Familial Colorectal Cancer Registry (n = 102) comparing MSI status groups. RESULTS: ITF2 and APC methylation are significantly associated with tumor versus normal state (both P < 1.0 × 10(-6)). ITF2 is methylated in 45.8% of MSI cases and 26.9% of MSS cases and is significantly associated with MSI in Ontario (P = 0.002) and Newfoundland (P = 0.005) as well as the MSI-associated feature of MLH1 promoter hypermethylation (P = 6.72 × 10(-4)). APC methylation, although tumor-specific, does not show a significant association with tumor subtype, age, gender, or stage, indicating it is a general tumor-specific CRC biomarker. CONCLUSIONS: This study demonstrates, for the first time, MSI-associated ITF2 methylation, and further reveals the subtype-specific epigenetic events modulating Wnt signaling in CRC.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Neoplasias Colorretais/genética , Metilação de DNA/genética , Instabilidade de Microssatélites , Fatores de Transcrição/genética , Estudos de Coortes , Colo/química , Neoplasias Colorretais/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Fator de Transcrição 4 , Via de Sinalização Wnt
20.
Hemodial Int ; 20(3): 421-31, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26564024

RESUMO

Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.


Assuntos
Doenças Cardiovasculares/terapia , Cinacalcete/uso terapêutico , Soluções para Diálise/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos
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