RESUMEN
The aim of this study was to understand experiences of wait time among patients awaiting scheduled orthopaedic or cardiac surgery. Using a qualitative approach, 32 patients completed two interviews each regarding their wait time experiences, including effects of waiting. Patient experiences of wait time varied regardless of actual wait time and included reports of restriction, uncertainty, resignation, coping and opportunity. Participants' waiting experiences indicate a complex relationship between greater symptom severity and less tolerance for wait time. We suggest healthcare resources focus on alleviating the deleterious effects of waiting for certain patients rather than reducing absolute wait times.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos/psicología , Procedimientos Ortopédicos/psicología , Periodo Preoperatorio , Listas de Espera , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Investigación Cualitativa , Factores de TiempoRESUMEN
BACKGROUND: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. METHODS: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). RESULTS: Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. CONCLUSION: Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Neoplasias Esofágicas/genética , Receptor alfa de Estrógeno/genética , Polimorfismo de Nucleótido Simple , Receptores de Oxitocina/genética , ADP-Ribosil Ciclasa 1/genética , Adenocarcinoma/epidemiología , Aromatasa/genética , Esófago de Barrett/epidemiología , Neoplasias Esofágicas/epidemiología , Receptor beta de Estrógeno/genética , Femenino , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Glicoproteínas de Membrana/genética , Oxitocina/genética , Factores SexualesRESUMEN
Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
Asunto(s)
Adenocarcinoma/diagnóstico , Esófago de Barrett/diagnóstico , Neoplasias Esofágicas/diagnóstico , Esófago/metabolismo , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Adenocarcinoma/etnología , Adenocarcinoma/genética , Adenocarcinoma/patología , Anciano , Esófago de Barrett/etnología , Esófago de Barrett/genética , Esófago de Barrett/patología , Estudios de Casos y Controles , Neoplasias Esofágicas/etnología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Esófago/patología , Femenino , Reflujo Gastroesofágico/genética , Reflujo Gastroesofágico/patología , Regulación de la Expresión Génica , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/genética , Obesidad/patología , Factores de Riesgo , Factores Sexuales , Fumar/genética , Fumar/patología , Población BlancaRESUMEN
Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Esofágicas/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma/patología , Anciano , Esófago de Barrett/patología , Estudios de Casos y Controles , Progresión de la Enfermedad , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. METHODS: We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
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Adenocarcinoma/genética , Esófago de Barrett/genética , Índice de Masa Corporal , Neoplasias Esofágicas/genética , Análisis de la Aleatorización Mendeliana , Obesidad/genética , Polimorfismo de Nucleótido Simple , Lesiones Precancerosas/genética , Adenocarcinoma/epidemiología , Adulto , Anciano , Esófago de Barrett/complicaciones , Esófago de Barrett/epidemiología , Neoplasias Esofágicas/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/epidemiología , Lesiones Precancerosas/epidemiología , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de RiesgoRESUMEN
Research on patients' experiences of wait time for scheduled surgery has centered predominantly on the relative tolerability of perceived wait time and impacts on quality of life. We explored patients' experiences of time while waiting for three types of surgery with varied wait times--hip or knee replacement, shoulder surgery, and cardiac surgery. Thirty-two patients were recruited by their surgeons. We asked participants about their perceptions of time while waiting in two separate interviews. Using interpretative phenomenological analysis (IPA), we discovered connections between participant suffering, meaningfulness of time, and agency over the waiting period and the lived duration of time experience. Our findings reveal that chronological duration is not necessarily the most relevant consideration in determining the quality of waiting experience. Those findings helped us create a conceptual framework for lived wait time. We suggest that clinicians and policy makers consider the complexity of wait time experience to enhance preoperative patient care.
Asunto(s)
Pacientes/psicología , Procedimientos Quirúrgicos Operativos , Tiempo , Listas de Espera , Femenino , Humanos , Entrevistas como Asunto , Masculino , Calidad de Vida , Estrés PsicológicoRESUMEN
BACKGROUND: Previous studies have evidenced an association between gastroesophageal reflux and esophageal adenocarcinoma (EA). It is unknown to what extent these associations vary by population, age, sex, body mass index, and cigarette smoking, or whether duration and frequency of symptoms interact in predicting risk. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) allowed an in-depth assessment of these issues. METHODS: Detailed information on heartburn and regurgitation symptoms and covariates were available from five BEACON case-control studies of EA and esophagogastric junction adenocarcinoma (EGJA). We conducted single-study multivariable logistic regressions followed by random-effects meta-analysis. Stratified analyses, meta-regressions, and sensitivity analyses were also conducted. RESULTS: Five studies provided 1,128 EA cases, 1,229 EGJA cases, and 4,057 controls for analysis. All summary estimates indicated positive, significant associations between heartburn/regurgitation symptoms and EA. Increasing heartburn duration was associated with increasing EA risk; odds ratios were 2.80, 3.85, and 6.24 for symptom durations of <10 years, 10 to <20 years, and ≥20 years. Associations with EGJA were slighter weaker, but still statistically significant for those with the highest exposure. Both frequency and duration of heartburn/regurgitation symptoms were independently associated with higher risk. We observed similar strengths of associations when stratified by age, sex, cigarette smoking, and body mass index. CONCLUSIONS: This analysis indicates that the association between heartburn/regurgitation symptoms and EA is strong, increases with increased duration and/or frequency, and is consistent across major risk factors. Weaker associations for EGJA suggest that this cancer site has a dissimilar pathogenesis or represents a mixed population of patients.
Asunto(s)
Adenocarcinoma/etiología , Neoplasias Esofágicas/etiología , Reflujo Gastroesofágico/epidemiología , Factores de Edad , Anciano , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Reflujo Gastroesofágico/complicaciones , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , FumarRESUMEN
BACKGROUND: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas. METHODS: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and ß-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability. RESULTS: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-ß-catenin complex, markedly depleted ß-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin™ exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage. CONCLUSIONS: A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.
Asunto(s)
Neoplasias Esofágicas/enzimología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Mutación Missense , Proteínas de Neoplasias/biosíntesis , Telomerasa/biosíntesis , Homeostasis del Telómero , Sustitución de Aminoácidos , Animales , Línea Celular Tumoral , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , ARN/biosíntesis , ARN/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Telomerasa/genética , Telómero/enzimología , Telómero/genéticaRESUMEN
BACKGROUND & AIMS: Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). METHODS: We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett's and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable. RESULTS: Height was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62-0.79 for men and OR, 0.57; 95% CI 0.40-0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62-0.77 for men and OR, 0.61; 95% CI, 0.48-0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis. CONCLUSIONS: Height is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.
Asunto(s)
Adenocarcinoma/epidemiología , Estatura , Neoplasias Esofágicas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/epidemiología , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used. RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
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Adenocarcinoma/genética , Esófago de Barrett/genética , Trastornos de los Cromosomas/genética , Neoplasias Esofágicas/genética , Reflujo Gastroesofágico/genética , Mutación de Línea Germinal , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Programas Informáticos , Estudios en Gemelos como AsuntoRESUMEN
Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Neoplasias Esofágicas/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Adenocarcinoma/epidemiología , Esófago de Barrett/epidemiología , Esófago de Barrett/patología , Estudios de Casos y Controles , Neoplasias Esofágicas/epidemiología , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms. METHODS: Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m(2)) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender. RESULTS: The association of OA and OGJA increased directly with increasing BMI (P for trend <0.001). Compared with individuals with a BMI <25, BMI ≥40 was associated with both OA (OR 4.76, 95% CI 2.96-7.66) and OGJA (OR 3.07, 95% CI 1.89-4.99). These associations were similar when stratified by gender and GERD symptoms. There was evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk. CONCLUSIONS: These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA.
Asunto(s)
Adenocarcinoma/epidemiología , Índice de Masa Corporal , Neoplasias Esofágicas/epidemiología , Reflujo Gastroesofágico/epidemiología , Adulto , Anciano , Unión Esofagogástrica , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Distribución por SexoRESUMEN
OBJECTIVE: Recent studies have suggested that human solid tumors may contain subpopulations of cancer stem cells with the capacity for self-renewal and the potential to initiate and maintain tumor growth. The aim of this study was to use human esophageal cell lines to identify and characterize putative esophageal cancer stem cell populations. METHODS: To enrich stemlike cells, Het-1A (derived from immortalized normal esophageal epithelium), OE33, and JH-EsoAd1 (each derived from primary esophageal adenocarcinomas) were cultured using serum-free media to form spheres. A comprehensive analysis of parent and spheroid cells was performed by flow cytometry, Western blot analysis, immunohistochemistry and polymerase chain reaction array to study cancer stem cell-related genes, colony formation assays to assess clonogenicity, xenotransplantation to assess tumorigenicity, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays to assess chemosensitivity to 5-fluorouracil and cisplatin. RESULTS: For all cell lines, clonogenicity, tumorigenicity, and chemoresistance to 5-fluorouracil and cisplatin were significantly higher than for spheroid cells compared with parent cells. Spheroids exhibited an increased frequency of cells expressing integrin α6(bri)/CD71(dim), and Achaete-scute complex homolog 2 messenger RNA and protein were also significantly overexpressed in spheroid cells compared with parent cells. CONCLUSIONS: The higher clonogenicity, tumorigenicity, and drug resistance exhibited by spheroids derived from Het-1A, OE33, and JH-EsoAd1 reflects an enrichment of stemlike cell populations within each esophageal cell line. Esophageal cells enriched for integrin α6(bri)/CD71(dim) and/or overexpressing Achaete-scute complex homolog 2 would appear to represent at least a subpopulation of stemlike cells in Het-1A, OE33, and JH-EsoAd1.
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Adenocarcinoma/patología , Células Epiteliales/patología , Neoplasias Esofágicas/patología , Células Madre Neoplásicas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animales , Antígenos CD/metabolismo , Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Resistencia a Antineoplásicos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Citometría de Flujo , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Integrina alfa6/metabolismo , Ratones , Ratones Desnudos , Ratones Transgénicos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Transferrina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esferoides Celulares , Factores de Tiempo , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration. METHODS: The authors pooled data from 12 case-control studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1242 (EAC), 1263 (EGJA) and 954 (ESCC) cases and 7053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux. RESULTS: For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P<0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P=0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P<0.01). CONCLUSIONS: Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases.
Asunto(s)
Adenocarcinoma/epidemiología , Consumo de Bebidas Alcohólicas/efectos adversos , Carcinoma de Células Escamosas/epidemiología , Neoplasias Esofágicas/epidemiología , Fumar/efectos adversos , Adenocarcinoma/etiología , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas/epidemiología , Índice de Masa Corporal , Carcinoma de Células Escamosas/etiología , Estudios de Casos y Controles , Neoplasias Esofágicas/etiología , Unión Esofagogástrica/patología , Femenino , Reflujo Gastroesofágico/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Oportunidad Relativa , Factores de Riesgo , Factores Sexuales , Fumar/epidemiología , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported to reduce risks of esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations. METHODS: We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model. RESULTS: Compared with nonusers, individuals who have used NSAIDs had a statistically significant reduced risk of EAC (OR, 0.68; 95% CI, 0.56-0.83); they also appeared to have a reduced risk of EGJA (OR, 0.83; 95% CI, 0.66-1.03). Similar reductions in risk were observed among individuals who took aspirin or nonaspirin NSAIDs. The highest levels of frequency (daily or more frequently) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk of EAC, with ORs of 0.56 (95% CI, 0.43-0.73; P(trend) < .001) and 0.63 (95% CI, 0.45-0.90; P(trend) = .04), respectively. CONCLUSIONS: Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, our pooled analysis suggests a possible role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
Asunto(s)
Adenocarcinoma/prevención & control , Antiinflamatorios no Esteroideos/uso terapéutico , Anticarcinógenos/uso terapéutico , Neoplasias Esofágicas/prevención & control , Unión Esofagogástrica/efectos de los fármacos , Neoplasias Gástricas/prevención & control , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Canadá/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Medición de Riesgo , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patología , Factores de Tiempo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Alcohol intake is a strong and well established risk factor for oesophageal squamous cell carcinoma (OSCC), but the association with oesophageal adenocarcinoma (OA) or adjacent tumours of the oesophagogastric junction (OGJA), remains unclear. Therefore, the association of alcohol intake with OSCC, OA, and OGJA was determined in nine case-control studies and two cohort studies of the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON). MATERIALS AND METHODS: Information was collected on alcohol intake, age, sex, education, body mass index, gastro-oesophageal reflux, and tobacco smoking from each study. Along with 10,854 controls, 1821 OA, and 1837 OGJA, seven studies also collected OSCC cases (n=1016). Study specific ORs and 95% CIs were calculated from multivariate adjusted logistic regression models for alcohol intake in categories compared to non-drinkers. Summary risk estimates were obtained by random effects models. Results No increase was observed in the risk of OA or OGJA for increasing levels of any of the alcohol intake measures examined. ORs for the highest frequency category (≥ 7 drinks per day) were 0.97 (95% CI 0.68 to 1.36) for OA and 0.77 (95% CI = 0.54 to 1.10) for OGJA. Suggestive findings linked moderate intake (eg, 0.5 to <1 drink per day) to decreased risk of OA (OR 0.63, 95% CI 0.41 to 0.99) and OGJA (OR 0.78, 95% CI 0.62 to 0.99). In contrast, alcohol intake was strongly associated with increased risk of OSCC (OR for ≥ 7 drinks per day 9.62, 95% CI 4.26 to 21.71). CONCLUSIONS: In contrast to OSCC, higher alcohol consumption was not associated with increased risk of either OA or OGJA. The apparent inverse association observed with moderate alcohol intake should be evaluated in future prospective studies.
Asunto(s)
Adenocarcinoma/etiología , Consumo de Bebidas Alcohólicas/efectos adversos , Neoplasias Esofágicas/etiología , Medición de Riesgo/métodos , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Adulto JovenRESUMEN
This study examined the frequency of loss of imprinting (LOI) and expression of the insulin-like growth factor 2 (IGF2) gene, and their relationship to selected clinical and pathological factors, in a well defined series of 90 Chinese patients with gastric cancer (GC) and 90 matched patients (controls) diagnosed with nonmalignant conditions. Using peripheral blood and gastric tissue samples, polymerase chain reaction-based assays and restriction endonuclease (Apa I) digestion revealed 33 GC patients and 21 controls to be Apa I informative. LOI of IGF2 was positive in 48.5% (16/33) of primary GC tumor tissues, in 21.2% (7/33) of histologically normal adjacent gastric mucosa (AM) and in 12.1% (4/33) of distant gastric mucosa (DM), and in 15.2% (5/33) of peripheral blood lymphocytes (PBLs). The prevalence of IGF2 LOI in PBL was not statistically different between GC patients (5/33, 15.2%) and control subjects (2/21, 9.5%), P = 0.69. Although patients who were found to have LOI of IGF2 were more likely to have advanced stage gastric tumors (P = 0.04), no statistically significant differences in survival were found based on imprinting status. IGF2 LOI was associated with an increased expression of IGF2 level in both tumors (P < 0.01) and blood (P < 0.01). The results of this study implicate IGF2 LOI in the molecular pathogenesis of GC, most likely through increased IGF2 expression. Although the precise molecular mechanisms by which LOI of IGF2 increases GC risk require further study, LOI of IGF2 may be a potentially important clinical epigenetic marker to identify individuals at increased risk for gastric malignancy.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Impresión Genómica , Factor II del Crecimiento Similar a la Insulina/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Inmunohistoquímica , Factor II del Crecimiento Similar a la Insulina/metabolismo , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/sangre , Neoplasias Gástricas/metabolismoRESUMEN
PURPOSE: Esophageal cancer is one of the most aggressive and deadly forms of cancer; highlighting the need to identify biomarkers for early detection and prognostic classification. Our recent studies have identified inflammatory gene and microRNA signatures derived from tumor and nontumor tissues as prognostic biomarkers of hepatocellular, lung, and colorectal adenocarcinoma. Here, we examine the relationship between expression of these inflammatory genes and micro RNA (miRNA) expression in esophageal adenocarcinoma and patient survival. EXPERIMENTAL DESIGN: We measured the expression of 23 inflammation-associated genes in tumors and adjacent normal tissues from 93 patients (58 Barrett's and 35 Sporadic adenocarcinomas) by quantitative reverse transcription-polymerase chain reaction. These data were used to build an inflammatory risk model, based on multivariate Cox regression, to predict survival in a training cohort (n = 47). We then determined whether this model could predict survival in a cohort of 46 patients. Expression data for miRNA-375 were available for these patients and was combined with inflammatory gene expression. RESULTS: IFN-γ, IL-1α, IL-8, IL-21, IL-23, and proteoglycan expression in tumor and nontumor samples were each associated with poor prognosis based on Cox regression [(Z-score)>1.5] and therefore were used to generate an inflammatory risk score (IRS). Patients with a high IRS had poor prognosis compared with those with a low IRS in the training (P = 0.002) and test (P = 0.012) cohorts. This association was stronger in the group with Barrett's history. When combining with miRNA-375, the combined IRS/miR signature was an improved prognostic classifier than either one alone. CONCLUSION: Transcriptional profiling of inflammation-associated genes and miRNA expression in resected esophageal Barrett's-associated adenocarcinoma tissues may have clinical utility as predictors of prognosis.
Asunto(s)
Adenocarcinoma/diagnóstico , Esófago de Barrett/diagnóstico , Neoplasias Esofágicas/diagnóstico , Inflamación/genética , MicroARNs/genética , Adenocarcinoma/clasificación , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Esófago de Barrett/clasificación , Esófago de Barrett/genética , Esófago de Barrett/patología , Neoplasias Esofágicas/clasificación , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Inflamación/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND: Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose-response, and duration of cigarette smoking cessation. METHODS: We used primary data from 10 population-based case-control studies and two cohort studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided. RESULTS: The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose-response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and > or =10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar. CONCLUSIONS: Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.
Asunto(s)
Adenocarcinoma/etiología , Neoplasias Esofágicas/etiología , Unión Esofagogástrica , Cese del Hábito de Fumar , Fumar/efectos adversos , Neoplasias Gástricas/etiología , Adenocarcinoma/epidemiología , Relación Dosis-Respuesta a Droga , Neoplasias Esofágicas/epidemiología , Femenino , Humanos , Incidencia , Masculino , Proyectos de Investigación , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Factores de TiempoRESUMEN
OBJECTIVE: To study the impact of obesity on postoperative morbidity and outcome following surgical resection of primary oesophageal adenocarcinoma (EADC). METHODS: From a prospective database, we compared clinicopathological findings (age, gender, surgical approach, tumour differentiation and stage), postoperative mortality, morbidity, length of hospitalisation, disease-free survival (DFS) and overall survival (OS) between 56 obese (body mass index (BMI)≥30 mgkg(-2)) and 86 non-obese (BMI<30 mgkg(-2)) patients with EADC. RESULTS: In this consecutive series, there were 118 male and 24 female patients with a median age of 63 years (range, 36-85 years). For all patients, the 5-year OS was 26.9%, with a median survival of 20 months. No significant differences (P>0.05) were found between obese and non-obese patients, with respect to age, gender, surgical approach (transthoracic vs transhiatal), pT-stage, duration of hospital stay, postoperative mortality or morbidity. However, compared with non-obese patients, obese patients had a higher frequency of postoperative respiratory complications (odds ratio (OR), 3.05; 95% confidence intervals (CIs), 1.29-7.17). DFS and OS at 5 years were increased for patients who were obese at the time of oesophageal resection (P=0.008). CONCLUSIONS: Obesity is not associated with increased postoperative complication rates or adverse outcome following oesophageal resection, and should therefore not be considered a relative contraindication to the surgical management of EADC. The improved survival of obese patients who underwent oesophageal resection for EADC suggests that further investigation of the association between obesity and oesophageal malignancy is now warranted.