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1.
Oxid Med Cell Longev ; 2019: 6470950, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565153

RESUMO

Studies suggest that nitric oxide (NO) may have a possible role in lung carcinogenesis. This study is aimed to evaluate the association of the NO metabolites, namely, nitrite and nitrate, with lung cancer incidence. We conducted a matched case-control study (n = 245 incident lung cancer cases and n = 735 controls) based on the German ESTHER cohort (n = 9,940). Controls were matched to cases on age, sex, smoking status (never/former/current smoking), and pack-years of smoking. The sum of nitrite and nitrate was measured in urine samples using a colorimetric assay and was standardized for renal function by urinary creatinine. Conditional logistic regression models, adjusted for lifestyle factors, asthma prevalence, and family history of lung cancer, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). Among incident lung cancer cases, high nitrite/nitrate levels were statistically significantly associated with current smoking, a low BMI, and the oxidative stress biomarker 8-isoprostane levels. Nitrite/nitrate levels in the top quintile were statistically significantly associated with lung cancer incidence: the OR (95% CI) was 1.37 (1.04-1.82) for comparison with the bottom quintile. This association was unaltered after additional adjustment for 8-isoprostane levels and C-reactive protein (CRP). In conclusion, this large cohort study suggested that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer and this association was independent of smoking, CRP, 8-isoprostane levels, and other established lung cancer risk factors. Further studies are needed to validate these findings and to confirm the hypothesis that pathologically high levels of NO are involved in lung cancer development.

2.
Dis Colon Rectum ; 62(11): 1294-1304, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31567919

RESUMO

BACKGROUND: Despite the increasing number of younger individuals diagnosed with colon and rectal cancer, research on the long-term disease-specific health-related quality of life of younger (<50 years) survivors of colon and rectal cancer is scarce. OBJECTIVE: Our study aimed to compare disease-specific functional deficits and symptoms of survivors of colon and rectal cancer 5 to 16 years postdiagnosis, stratified by age at diagnosis and by sex. DESIGN: This is a cross-sectional study. SETTING: We used data from the population-based CAncEr Survivorship-A multi-Regional study in collaboration with 5 population-based German cancer registries. PATIENTS: Survivors of colon and rectal cancer were included in the study. MAIN OUTCOME MEASURES: Respondents completed the disease-specific European Organization for Research and Treatment of Cancer Quality of Life colorectal cancer module. Age at diagnosis categories were <50, 50 to 59, 60 to 69, and ≥70 years. Least square mean health-related quality of life scores, derived from linear regression, were adjusted for sex, education, time since diagnosis, cancer site, cancer stage, and treatment, where appropriate. RESULTS: The sample comprised 697 survivors of colon cancer and 479 survivors of rectal cancer. In general, survivors of colon and rectal cancer diagnosed at <50 years of age reported lower functioning and higher symptom burden in comparison with survivors diagnosed at an older age. When stratified by sex, female survivors of colon cancer tended to report more concerns with hair loss but fewer sexual problems when compared with male survivors of colon cancer of the same age. Female survivors of rectal cancer in all age groups tended to report lower levels of sexual interest than male survivors of rectal cancer of the same age. LIMITATIONS: This was a cross-sectional study with findings that could be biased toward healthier long-term survivors. The generalizability of results is limited to survivors diagnosed before 2005. CONCLUSIONS: Our results suggest that supportive care for survivors of colon and rectal cancer to improve their self-management of symptoms should be adapted according to cancer type, age at diagnosis, and sex. See Video Abstract at http://links.lww.com/DCR/B29. LA EDAD AL DIAGNÓSTICO Y EL GÉNERO ESTÁN ASOCIADOS CON DÉFICITS A LARGO PLAZO EN LA CALIDAD DE VIDA RELACIONADA CON LA SALUD ESPECíFICA DE LA ENFERMEDAD DE LOS SOBREVIVIENTES DE CÁNCER DE COLON Y RECTO: UN ESTUDIO BASADO EN LA POBLACIÓN:: A pesar del creciente número de individuos jóvenes diagnosticados con cáncer de colon y recto, la investigación sobre la calidad de vida relacionada con la salud específica de la enfermedad a largo plazo de los sobrevivientes de cáncer de colon y recto jóvenes (<50 años) es escasa.Nuestro estudio tuvo como objetivo comparar los déficits funcionales específicos de la enfermedad y los síntomas de los sobrevivientes de cáncer de colon y recto 5-16 años después del diagnóstico, estratificados por edad al momento del diagnóstico y por género.Transversal.Utilizamos datos del estudio Supervivencia de CAncEr basada en la población: Un estudio multirregional en colaboración con cinco bases de datos alemanas de cáncer basados en la población.Sobrevivientes de cáncer de colon y recto.Los encuestados respondieron el módulo de calidad de vida específica para la enfermedad en cáncer colorrectal de la Organización Europea para la Investigación y Tratamiento del Cáncer. Las categorías de edad al diagnóstico fueron <50, 50-59, 60-69 y ≥70 años. Los puntajes de CVRS (calidad de vida relacionada a la salud) medios mínimos cuadrados, derivados de la regresión lineal, se ajustaron por género, educación, tiempo desde el diagnóstico, sitio del cáncer, etapa del cáncer y tratamiento, cuando apropiado.La muestra comprendió 697 y 479 sobrevivientes de cáncer de colon y de recto, respectivamente. En general, los sobrevivientes de cáncer de colon y recto diagnosticados con <50 años de edad reportaron una menor funcionalidad y una mayor carga de síntomas en comparación con los sobrevivientes diagnosticados a una edad más avanzada. Cuando se estratificaron por género, las mujeres sobrevivientes de cáncer de colon tendieron a informar más preocupaciones sobre la pérdida de cabello pero menos problemas sexuales en comparación con los hombres sobrevivientes de colon de la misma edad. Las mujeres sobrevivientes de cáncer rectal en todos los grupos de edad tendieron a informar niveles más bajos de interés sexual que los hombres sobrevivientes de cáncer rectal de la misma edad.Estudio transversal con hallazgos que podrían estar sesgados hacia sobrevivientes a largo plazo más saludables. La generalización de los resultados se limitó a los sobrevivientes diagnosticados antes de 2005.Nuestros resultados sugieren que los cuidados de soporte para los sobrevivientes de cáncer de colon y recto para mejorar su automanejo de síntomas deben adaptarse según el tipo de cáncer, la edad en el momento del diagnóstico y el género. Vea el resumen en video en http://links.lww.com/DCR/B29.

3.
J Natl Compr Canc Netw ; 17(9): 1089-1099, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31487678

RESUMO

BACKGROUND: Chemotherapy underuse in elderly patients (aged ≥75 years) with colon cancer has been reported in previous studies. However, these studies were mostly registry-based and limited in their potential to consider underlying reasons of such undertreatment. This study aimed to evaluate patient and hospital determinants of chemotherapeutic treatment in patients with stage III colon cancer, with a particular focus on age and underlying reasons for nontreatment of elderly patients. METHODS: A total of 629 patients with stage III colon cancer who were diagnosed in 2003 through 2012 and recruited into a population-based study in the Rhine-Neckar region of Germany were included. Information on sociodemographic and lifestyle factors, comorbidities, and treatment was collected from patient interviews and physicians. Patient (with an emphasis on age) and hospital factors were evaluated for their associations with administration of adjuvant chemotherapy overall and of oxaliplatin specifically using multivariable logistic regression. RESULTS: Administration of chemotherapy decreased from 94% in patients aged 30 to 64 years to 51% in those aged ≥75 years. A very strong decline in chemotherapy use with age persisted even after comprehensive adjustment for multiple patient factors-including comorbidities-and hospital factors and was also seen among patients without any major comorbidities. Between 2005 and 2008, and 2009 and 2012, chemotherapy administration in patients aged ≥75 years decreased from 60% to 41%. Among chemotherapy recipients, old age was also strongly associated with higher odds of nonadministration of oxaliplatin. The 2 most commonly reported reasons for chemotherapy nonreceipt among the study population were patient refusal (30%) and old age (24%). CONCLUSIONS: Age was the strongest predictor of chemotherapy underuse, irrespective of comorbidities and even in patients without comorbidities. Such underuse due just to older age in otherwise healthy patients deserves increased attention in clinical practice to ensure that elderly patients also get the best possible care. Patients' refusal as the most frequent reason for chemotherapy nonreceipt also warrants further investigation to exclude misinformation as underlying cause.

4.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

6.
Int J Cancer ; 2019 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-31495913

RESUMO

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.

7.
Gastroenterology ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31472152

RESUMO

BACKGROUND & AIMS: Quantitative fecal immunochemical tests (FITs) for hemoglobin are commonly used for colorectal cancer (CRC) screening. We aimed to quantify the change in CRC and advanced adenoma detection and number of positive test results at different positivity thresholds and by sex and age. METHODS: We searched MEDLINE and EMBASE, selecting articles of FIT for CRC detection in asymptomatic adults undergoing screening. We calculated sensitivity and specificity, as well as detected number of cancers, advanced adenomas, and positive test results at positivity thresholds ≤10 µg hemoglobin/g feces, 10 to ≤20 µg/g, 20 to ≤30 µg/g, and >30 µg/g. We also analyzed results from stratified by patient sex, age, and reference standard. RESULTS: Our meta-analysis comprised 46 studies with 2.4 million participants and 6478 detected cancers. Sensitivity for detection of CRC increased from 69% (95% CI, 63%-75%) at thresholds >10 µg/g and ≤20 µg/g to 80% (95% CI, 76%-83%) at thresholds ≤10 µg/g. At these threshold values, sensitivity for detection of advanced adenomas increased from 21% (95% CI, 18%-2%5) to 31% (95% CI, 27%-35%), whereas specificity decreased from 94% (95% CI, 93%-96%) to 91% (95% CI, 89%-93%). In 3 studies stratified by sex, sensitivity of CRC detection was 77% in men (95% CI, 75%-79%) and 81% in women (95% CI, 60%-100%) (P=.68). In 3 studies stratified by age groups, sensitivity of CRC detection was 85% for ages 50-59 years (95% CI, 71%-99%) and 73% for ages 60-69 years (95% CI, 71%-75%) (P=.10). All studies with colonoscopy follow up had similar sensitivity levels for detection of CRC to studies that analyzed 2-year registry follow-up data (74%; 95% CI, 68%-78% vs 75%; 95% CI, 73%-77%). CONCLUSIONS: In a meta-analysis of studies that analyzed detection of CRC and advanced adenomas at different FIT positivity thresholds, we found the sensitivity and specificity of detection to vary with positive cut-off value. It might be possible to decrease positive threshold values for centers with sufficient follow-up colonoscopy resources. More research is needed to precisely establish FIT thresholds for each sex and age subgroup.

8.
Int J Cancer ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31483856

RESUMO

We critically examined existing approaches for the estimation of the excess familial risk of cancer which can be attributed to identified common genetic risk variants and propose an alternative, more straightforward approach for calculating this proportion using well-established epidemiological methodology. We applied the underlying equations of the traditional approaches and the new epidemiological approach for colorectal cancer (CRC) in a large population-based case-control study in Germany with 4,447 cases and 3,480 controls, who were recruited from 2003 to 2016 and for whom interview, medical and genomic data were available. Having a family history of CRC (FH) was associated with a 1.77-fold risk increase in our study population (95% CI 1.52-2.07). Traditional approaches yielded estimates of the FH-associated risk explained by 97 common genetics variants from 9.6% to 23.1%, depending on various assumptions. Our alternative approach resulted in smaller and more consistent estimates of this proportion, ranging from 5.4% to 14.3%. Commonly employed methods may lead to strongly divergent and possibly exaggerated estimates of excess familial risk of cancer explained by associated known common genetic variants. Our results suggest that familial risk and risk associated with known common genetic variants might reflect two complementary major sources of risk. This article is protected by copyright. All rights reserved.

9.
Int J Cancer ; 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31376284

RESUMO

Helicobacter pylori (H. pylori) infection is considered as principal cause of gastric cancer. It is further associated with a reduced risk of esophageal adenocarcinomas. In a large prospective population-based cohort study including 9,949 subjects with average observation time of 13.8 years, we assessed the risk of invasive gastric and esophageal cancer according to H. pylori infection and presence of chronic atrophic gastritis (CAG). Incidence rates and hazard ratios (HR) derived by Cox proportional hazards models and adjusted for relevant confounders were derived by seroprevalence of H. pylori and cytotoxin-associated gene A (CagA) antibodies and presence of CAG based on serological markers at baseline, respectively. During follow-up, 30 cases of noncardia gastric cancer and 33 cases of esophageal cancer were observed. Infection by H. pylori without and with expression of CagA was associated with a 5.2-fold (95% confidence interval 1.00-27.1) and an 18.2-fold (4.3-77.4) increase of noncardia gastric cancer incidence. A 0.65-fold decreased risk of esophageal adenocarcinomas (HR 0.35, 0.12-0.97) was observed among H. pylori-infected individuals. In participants infected with CagA expressed H. pylori, the presence of mild/moderate and severe CAG was associated with a 6.4-fold (1.3-31.0) and an 11.8-fold (3.1-45.4) increase of gastric cancer incidence, respectively. The results of this prospective population-based cohort study may contribute relevant evidence to the ongoing research of H. pylori-related cancers. The results may furthermore enhance the empirical basis for risk stratification among H. pylori-infected people and for recommendations regarding H. pylori screening and treatment among older adults in a Western population.

10.
Am J Gastroenterol ; 114(9): 1520-1530, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31464746

RESUMO

OBJECTIVES: Many risk scores have been proposed to predict presence of advanced colorectal neoplasms, but a comprehensive comparison conducted in the same population is sparse. The aim of this study was to evaluate and directly compare the diagnostic performance of published risk prediction models for advanced colorectal neoplasms. METHODS: Data were drawn from 2 cohorts of subjects undergoing screening colonoscopy in Germany, i.e., KolosSal (n = 16,195) and BliTz (n = 7,444). Absolute risks and relative risks were generated for the presence of at least 1 advanced neoplasm, taking the lowest risk group as the reference group. Performance of risk models was assessed by the area under the receiver operating characteristic curve (AUC) and compared by the net reclassification improvement. RESULTS: The 2 cohorts included 1,917 (11.8%) and 848 (11.4%) participants with advanced neoplasm, respectively. Absolute risks were mostly between 5% and 10% among participants in the lowest risk group and between 15% and 20% among participants in the highest risk group, and relative risks mostly ranged from 2.0 to 4.0 across the risk models in both cohorts. The AUCs ranged from 0.58 to 0.65 in KolosSal and from 0.57 to 0.61 in BliTz for all risk scores. Compared to models with lower AUC, classification was significantly improved in most models with higher AUC. DISCUSSION: Risk models for advanced colorectal neoplasms generally yielded modest discriminatory power, despite some variation in performance between models. Future studies should evaluate the performance of these risk models in racially diverse populations and investigate possible extensions, such as combination with polygenic risk scores.

11.
Sci Rep ; 9(1): 12524, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467304

RESUMO

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

12.
Ann Surg ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31425290

RESUMO

OBJECTIVE: This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. SUMMARY BACKGROUND DATA: ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. METHODS: Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. RESULTS: Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from node-negative to node-positive disease [ORSEER-18=1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR = 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18 = 0.98, 95% CI = 0.98-0.99; HRNCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. CONCLUSIONS: In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31375970

RESUMO

PURPOSE: To investigate the associations of diuretics overall, non-potassium-sparing diuretics in specific, and laxative use with cardiovascular mortality (CVM) in subjects with antihypertensive treatment. METHODS: Analyses included 4253 participants, aged 50 to 75 years, from the German ESTHER cohort and 105,359 participants, aged 50 to 69 years, from the UK Biobank. Cox proportional hazard regression models were applied in both studies, and then results were pooled using random-effects model meta-analyses. RESULTS: During 14 and 7 years of follow-up, 476 and 1616 CVM cases were observed in the ESTHER study and the UK Biobank, respectively. Compared to non-users, a 1.6-fold (hazard ratio [95% confidence interval] 1.57 [1.29; 1.90]), a 1.4-fold (1.39 [1.26; 1.53]), and no statistically significantly increased (1.13 [0.94; 1.36]) CVM were observed in users of diuretics overall, non-potassium-sparing diuretics in specific, and laxatives, respectively. Concurrent use of non-potassium-sparing diuretics and laxatives was associated with a 2-fold increased CVM (2.05 [1.55; 2.71]) when compared to users of neither diuretics nor laxatives. However, a test for interaction slightly missed statistical significance (p = 0.075). CONCLUSIONS: These consistent results from two large cohort studies imply that more research is needed on the safety of diuretics in routine care. Although not statistically significant in this study, a drug-drug interaction of non-potassium-sparing diuretics and laxatives appears plausible. Physicians and pharmacists are advised to clarify additional laxative use in users of non-potassium-sparing diuretics and inform about the risk of concurrent use. Moreover, closer potassium monitoring intervals (e.g., every 3 months) might be indicated in concurrent users to prevent fatal cardiovascular events.

14.
Nutrients ; 11(8)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412610

RESUMO

The objective of the study was to investigate the potential association of human milk leptin concentrations with child body mass index (BMI) and BMI trajectory patterns up to two years of age among children in the Ulm SPATZ Health Study. Leptin concentration was measured in skimmed human milk by ELISA (R&D System). Child BMI was determined at two to three days, three to four weeks, four to five months, one year, and two years of age. In SPATZ, leptin concentration at six weeks was inversely associated with child BMI at four to five weeks [beta -0.13, 95%CI -0.21;-0.05)] and at three to four months -0.12 -0.21;-0.03)]. Among infants of average BMI shortly after delivery, six week leptin was positively associated with greater increase in BMI from four to five weeks up to two years of age [0.16 (0.04;0.27)]. No associations were observed for six month leptin. Direction of association was the same in the Ulm Birth Cohort Study (UBCS), but statistically insignificant as the point estimate included the null effect value. Our results from SPATZ suggest human milk leptin may play a role in early infant growth. However, it is plausible that the lack of associations in UBCS suggest that these differences of human milk leptin composition between populations could have an impact in infant growth and development in a given population.

15.
Clin Epigenetics ; 11(1): 109, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340858

RESUMO

BACKGROUND: Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival. RESULTS: Patients with CRC followed up for a median of 5.2 years were divided into a study cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip and restricted to 43 genes used to define CIMP status in previous studies. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, and BRAF mutation status. In the study cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score of the lowest methylation level showed poorer disease-specific survival compared with patients with the highest methylation level in both the study cohort and the validation cohort (HR = 3.11 and 95% CI = 1.97-4.91, and HR = 3.06 and 95% CI = 1.71-5.45, respectively). CONCLUSIONS: A CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP. Further studies are required to confirm these findings.

16.
Int J Cancer ; 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291471

RESUMO

In October 2002, screening colonoscopy was added to the German colorectal cancer (CRC) screening program as an alternative to fecal occult blood test (FOBT). We aimed to evaluate the change in CRC screening use after introduction of the dual screening offer and to assess determinants of screening use. Data were drawn from a population-based cohort study initiated during 2000-2002 in Germany (n = 5,845, age range at recruitment: 50-75 years). We conducted both cross-sectional and longitudinal analyses to obtain uptake rates of CRC screening based on four waves of data. Age-group specific proportions of participants having had FOBT within 2 years remained essentially unchanged at 61-67% between 2000 and 2002 (1st wave) and 2005-2007 (3rd wave). The proportions of participants having undergone screening colonoscopy within 10 years increased from 23-29% to 46-57%, leading to a substantial overall increase in being up-to-date with CRC screening from 66-68% to 77-80%. In 2008-2010 (4th wave), FOBT use declined and colonoscopy use continued to increase. Obesity was significantly associated with lower prevalence of being up-to-date with FOBT (odds ratio [OR] at 8-year follow-up 0.68; 95% confidence interval [CI], 0.58-0.80) and screening colonoscopy (OR, 0.73; 95% CI, 0.62-0.86). Also, smokers were less likely to have ever used FOBT (OR, 0.54; 95% CI, 0.40-0.75) or colonoscopy (OR, 0.75; 95% CI, 0.63-0.90) compared to nonsmokers. After the introduction of dual screening offer, the overall adherence to CRC screening steeply increased, mainly due to an increase in screening colonoscopy uptake. Screening tests kept being underused by obese people and smokers who are at elevated CRC risk.

17.
Environ Sci Technol ; 53(16): 9876-9883, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31310111

RESUMO

A positive association between Bisphenol A (BPA) exposure and coronary heart disease has been shown, but not in patients with type 2 diabetes (T2D). During the treatment of drinking water, chlorination leads to the formation of chlorinated derivatives of Bisphenol A (ClxBPA), that have higher estrogenic activity than BPA. No evidence exists for a relationship between exposure to ClxBPA and myocardial infarction in patients with T2D. The objective of this study was to evaluate the relationship between exposure to BPA, ClxBPA and the occurrence of myocardial infarction (MI) in patients with T2D. Two nested case-control studies in two independent European cohorts were performed. Each case with incident MI during follow-up was matched to one control on age, sex, and personal cardiovascular history in the same cohort. Association between baseline urine concentrations of BPA and of ClxBPA and incident MI was determined. Exposure to BPA was 31% in the ESTHER cohort and 18% in the SURDIAGENE cohort. In a meta-analysis of the two studies, occurrence of MI was significantly associated with urine BPA detection: adjusted OR = 1.97 (1.05-3.70), p = 0.04. Exposure to ClxBPA significantly differed in the SURDIAGENE and ESTHER studies: 24% and 8%, respectively (p = 0.0003). It was very strongly associated with MI in the SURDIAGENE cohort with an adjusted odds ratio (OR) of 14.15 (2.77-72.40) but this association was not replicated in the ESTHER study: adjusted OR: 0.17 (0.02-1.23). Whether these results may be explained by different water chlorination processes in France and Germany, resulting in different ClxBPA exposure levels, requires further investigation.

18.
BMC Cancer ; 19(1): 681, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296182

RESUMO

BACKGROUND: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients. METHODS: CRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies. RESULTS: We observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations). CONCLUSIONS: External validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice.

19.
Cancer Prev Res (Phila) ; 12(9): 617-630, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289028

RESUMO

Monitoring population-level colonoscopy and sigmoidoscopy use is crucial to estimate the future burden of colorectal cancer and guide screening efforts. We conducted a systematic literature search on colonoscopy and sigmoidoscopy use, published between November 2016 and December 2018 in the databases PubMed and Web of Science to update previous reviews and analyze time trends for various countries. In addition, we used data from the German and European Health Interview Surveys and the National Health Interview Survey to explore recent time trends for Germany and the US, respectively. The literature search yielded 23 new articles: fourteen from the US and nine from Australia, Canada, England, Germany, Saudi Arabia, and South Korea. Colonoscopy use within 10 years was highest and, apart from the youngest age groups eligible for colorectal cancer screening, kept increasing to levels close to 60% in the US and Germany. A recent steep increase was also observed for South Korea. Limited data were available on sigmoidoscopy use; regional studies from the US suggest that sigmoidoscopy has become rarely used. Despite high uptake and ongoing increase in the US, Germany, and South Korea, use of colonoscopy and sigmoidoscopy has either remained low or essentially unknown for the majority of countries.

20.
J Occup Environ Med ; 61(5): 397-404, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31268937

RESUMO

OBJECTIVE: To investigate the associations between head and neck cancer (HNC) risk and occupations. METHODS: We harmonized data on occupations in a pooled analysis of 8839 HNC cases and 13,730 controls in International Head and Neck Cancer Epidemiology (INHANCE) consortium. Logistic regression was used to estimate odds ratios (ORs) for associations of occupations and HNC risk. Population attributable fraction (PAF) for occupations was calculated using the formula PEC × (OR - 1)/OR. RESULTS: Trend of increasing HNC risk was found with increasing duration of employment for many occupations, including cooks (OR = 1.36; 95% confidence interval [CI] 1.09 to 1.68), cleaners (OR = 1.38; 95% CI 1.13 to 1.69), painters (OR = 1.82; 95% CI 1.42 to 2.35). The PAF for a priori occupations was 14.5% (95% CI 7.1% to 21.9%) for HNC. CONCLUSIONS: We found associations between certain occupations and HNC risks, including for subsites, with a duration-response relationship.

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