Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 15 de 15
Filter
1.
Hepatology ; 65(5): 1693-1707, 2017 May.
Article in English | MEDLINE | ID: mdl-28100019

ABSTRACT

Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute ß-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). CONCLUSION: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using ß-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707).


Subject(s)
Adrenergic beta-Antagonists/administration & dosage , Gastrointestinal Hemorrhage/prevention & control , Hypertension, Portal/drug therapy , Liver Cirrhosis/complications , Portal Pressure , Aged , Drug Therapy, Combination , Endoscopy, Gastrointestinal , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/mortality , Humans , Hypertension, Portal/complications , Isosorbide Dinitrate/administration & dosage , Isosorbide Dinitrate/analogs & derivatives , Liver Cirrhosis/mortality , Male , Middle Aged , Recurrence , Spain/epidemiology
2.
PLoS One ; 11(11): e0166741, 2016.
Article in English | MEDLINE | ID: mdl-27893763

ABSTRACT

BACKGROUND: Helicobacter pylory (HP) infection has been associated to an increased rate of type 2 diabetes (T2D) and liver disease through its effect on insulin resistance and systemic inflammation. However, results are inconstant and no studies exist in morbidly obese patients, in which both insulin resistance and inflammation coexist. MATERIAL AND METHODS: Cross-sectional study to evaluate the relationship between HP infection and alterations in carbohydrate metabolism, lipid profile, inflammation markers, and liver disease in patients awaiting for bariatric surgery. HP infection was histologically assessed in gastric antrum biopsy from 416 subjects. Liver biopsy was also available in 93 subjects. RESULTS: Both impaired fasting glucose and T2D were similar when comparing subjects with and without HP infection (24.2% vs. 22%, p = 0.290 and 29.4% vs. 29.1%, p = 0.916, respectively), with no differences between groups in the HOMA-IR, lipid profile neither inflammatory parameters. However, HP infection was higher among subjects with a BMI ≥ 40.0 kg/m2 in comparison with lower degrees of obesity (71.7% vs. 60.0%, p = 0.041). In addition, subjects without HP infection showed higher degrees of steatosis (44.1±26.4% vs. 32.0±20.7%, p = 0.038), as well as a lower prevalence of non-alcoholic steatohepatitis (9.3% vs. 30.7%, p = 0.023). CONCLUSIONS: In patients with morbid obesity, HP infection does not seem to be associated with abnormal carbohydrate metabolism. In addition, less advanced degrees of non-alcoholic fatty disease were observed. We suggest that low-grade inflammation that accompanies obesity mitigates the diabetogenic effect of HP, so the presence of obesity should be considered in studies that evaluate the HP metabolic effects.


Subject(s)
Diabetes Mellitus, Type 2/microbiology , Helicobacter Infections/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Obesity, Morbid/metabolism , Adult , Blood Glucose/metabolism , Carbohydrate Metabolism , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Female , Helicobacter Infections/epidemiology , Helicobacter Infections/physiopathology , Helicobacter pylori/pathogenicity , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Obesity, Morbid/epidemiology , Obesity, Morbid/microbiology
3.
Med. clín (Ed. impr.) ; 141(11): 484-486, dic. 2013.
Article in Spanish | IBECS | ID: ibc-117599

ABSTRACT

Fundamento y objetivo: Describir las características clínicas, el tratamiento más efectivo y la supervivencia de pacientes cirróticos con hidrotórax hepático (HH). Pacientes y método: Estudio descriptivo y retrospectivo de una cohorte de pacientes consecutivos con HH sometidos a una toracocentesis diagnóstica. Entre otros parámetros, se evaluaron las características bioquímicas y radiológicas del derrame pleural, el control del mismo con los tratamientos instaurados y los factores que condicionaron la supervivencia. Resultados: Se incluyeron 77 pacientes con HH. El 14% no tenía ascitis. El HH fue derecho en el 77% de los casos y ocupó la mitad o más del hemitórax en el 68%. El 81% de los líquidos pleurales eran trasudados. El HH refractario a diuréticos (27%) se pudo controlar con trasplante hepático, derivación portosistémica percutánea intrahepática (DPPI) o catéter pleural tunelizado. En cambio, la pleurodesis fracasó en la mayoría de las ocasiones. La mediana de supervivencia fue de 9,1 meses, y solo se vio influida favorablemente por el trasplante hepático. Conclusiones: El HH tiene una supervivencia limitada, solo modificable con el trasplante hepático. En los casos refractarios al tratamiento diurético se debe considerar la DPPI o el catéter pleural tunelizado (AU)


Background and objective: To describe the clinical characteristics, the Most Effective treatment and survival of cirrhotic patients with hepatic hydrothorax (HH ). Patients and method: Descriptive and retrospective analysis of a cohort of consecutive patients with HH Undergoing a diagnostic thoracentesis. The biochemical and radiological features of the pleural effusion , its Control With Different therapies and the factors affecting, survival Were EVALUATED, Among other parameters. Results: Seventy -seven patients with HH Were included, of Whom 14% did not have ascites. HH was right -sided in 77 % of the cases, and occupied half or more of the hemithorax in 68 %. Were transudative pleural fluids in 81 % of the cases you. Diuretic -resistant HH (27 % ) Could be managed with liver transplantation, transjugular intrahepatic portosystemic shunt (TIPS ) or indwelling pleural catheters. However, in Most patients failed pleurodesis. Median survival was 9.1 months , and it was only by liver transplantation Affected favorably. Conclusions: HH has a limited survival, Influenced by liver transplantation only. In diuretic -resistant cases, indwelling pleural catheters or TIPS Should be Considered as a management option (AU)


Subject(s)
Humans , Hydrothorax/etiology , Liver Cirrhosis/complications , Portasystemic Shunt, Transjugular Intrahepatic , Retrospective Studies , Drainage , Survival Analysis , Liver Transplantation , Pleurodesis , Pleural Effusion/surgery
4.
Med Clin (Barc) ; 141(11): 484-6, 2013 Dec 07.
Article in Spanish | MEDLINE | ID: mdl-24018252

ABSTRACT

BACKGROUND AND OBJECTIVE: To describe the clinical characteristics, the most effective treatment and survival of cirrhotic patients with hepatic hydrothorax (HH). PATIENTS AND METHOD: Descriptive and retrospective analysis of a cohort of consecutive patients with HH undergoing a diagnostic thoracentesis. The biochemical and radiological features of the pleural effusion, its control with different therapies and the factors affecting survival were evaluated, among other parameters. RESULTS: Seventy-seven patients with HH were included, of whom 14% did not have ascites. HH was right-sided in 77% of the cases, and occupied half or more of the hemithorax in 68%. Pleural fluids were transudative in 81% of the cases. Diuretic-resistant HH (27%) could be managed with liver transplantation, transjugular intrahepatic portosystemic shunt (TIPS) or indwelling pleural catheters. However, pleurodesis failed in most patients. Median survival was 9.1 months, and it was only favorably affected by liver transplantation. CONCLUSIONS: HH has a limited survival, only influenced by liver transplantation. In diuretic-resistant cases, TIPS or pleural indwelling catheters should be considered as a management option.


Subject(s)
Hydrothorax/etiology , Hydrothorax/therapy , Liver Cirrhosis/complications , Aged , Catheters, Indwelling , Combined Modality Therapy , Diuretics/therapeutic use , Female , Humans , Hydrothorax/diagnosis , Hydrothorax/mortality , Kaplan-Meier Estimate , Liver Transplantation , Male , Middle Aged , Pleurodesis , Portasystemic Shunt, Transjugular Intrahepatic , Retrospective Studies , Treatment Outcome
5.
Carcinogenesis ; 34(10): 2286-91, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23712746

ABSTRACT

Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.


Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Genetic Variation , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Genotype , Humans , Male , Middle Aged , Neoplasm Staging , Polymorphism, Single Nucleotide , Population Surveillance , Prognosis
6.
Gastroenterology ; 144(5): 926-932.e1; quiz e13-4, 2013 May.
Article in English | MEDLINE | ID: mdl-23354017

ABSTRACT

BACKGROUND & AIMS: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. METHODS: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. RESULTS: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P < .001). CONCLUSIONS: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , DNA, Neoplasm/genetics , Nuclear Proteins/genetics , Population Surveillance , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair , DNA Repair , Female , Germ-Line Mutation , Humans , Immunohistochemistry , Incidence , Male , Microsatellite Instability , Middle Aged , MutL Protein Homolog 1 , Nuclear Proteins/metabolism , Risk Factors , Spain/epidemiology
7.
Gastroenterology ; 140(4): 1174-81, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21185836

ABSTRACT

BACKGROUND & AIMS: 5-Fluorouracil (5-FU)-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy. METHODS: We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated. RESULTS: Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II-III (n = 196), 32.7% were CIMP positive. Among patients with stages II-III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5-0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3-2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1-3.8). CONCLUSIONS: Patients with CIMP-positive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Colorectal Neoplasms , CpG Islands/physiology , DNA Methylation , Fluorouracil/administration & dosage , Aged , Aged, 80 and over , Chemotherapy, Adjuvant/methods , Cohort Studies , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Disease-Free Survival , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Phenotype , Predictive Value of Tests , Prognosis , Proportional Hazards Models
8.
Gastroenterology ; 139(3): 788-96, 796.e1-6, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20638935

ABSTRACT

BACKGROUND & AIMS: Ten common low-penetrant genetic variants have been consistently associated with colorectal cancer (CRC) risk; little is known about the correlation between these variants and CRC phenotype. Characterization of such a correlation would improve CRC management and prevention programs. We assessed the association between these genetic variants and CRC phenotype in patients and modeled pairwise combinations to detect epistasis. METHODS: The validation population corresponded to a prospective, multicenter, population-based cohort (EPICOLON I) of 1096 patients with newly diagnosed CRC. The replication set was an independent, prospective, multicenter Spanish cohort (EPICOLON II) of 895 patients with newly diagnosed CRC. For individual single nucleotide polymorphism (SNP) association analyses, a multivariate method using logistic regression was applied in EPICOLON I and subsequently prospectively validated in EPICOLON II. Interactions between SNPs were assessed using the likelihood ratio test. RESULTS: Validated results confirmed that the C allele on 8q23.3 (rs16892766) was significantly associated with advanced-stage tumors (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.15-1.90; P value = 4.9 x 10(-3)). The G allele on 8q24.21 (rs6983267) was more common in patients with a familial history of CRC (OR, 2.02; 95% CI, 1.35-3.03; P value = 3.9 x 10(-4)). The combination of rs6983267 on 8q24.21 and rs9929218 on 16q22.2 was associated with a history of colorectal adenoma (carriers of GG and AA, respectively; OR, 2.28; 95% CI, 1.32-3.93; P = 5.0 x 10(-4)). CONCLUSIONS: CRC susceptibility variants at 8q23.3, 8q24.21, and 16q22.2 appear to be associated with cancer phenotype. These findings might be used to develop screening and surveillance strategies.


Subject(s)
Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 8 , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Cell Differentiation , Colorectal Neoplasms/pathology , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Logistic Models , Male , Middle Aged , Neoplasm Staging , Odds Ratio , Pedigree , Phenotype , Prospective Studies , Reproducibility of Results , Risk Assessment , Risk Factors , Spain
9.
Gastroenterol. hepatol. (Ed. impr.) ; 33(4): 288-296, Abr. 2010. ilus, tab
Article in English | IBECS | ID: ibc-84017

ABSTRACT

BackgroundInflammatory bowel disease is a premalignant condition for developing colorectal cancer. Since a correlation has been suggested between telomere length, chromosomal instability and neoplastic transformation in this setting, we sought to investigate whether telomerase expression in colorectal mucosa may constitute a biomarker for malignant transformation in patients with inflammatory bowel disease.Patients and methodsForty-seven patients with inflammatory bowel disease with and without cancer or dysplasia were evaluated for human telomerase reverse transcriptase hTERT immunostaining in paraffin-embedded, formalin-fixed colorectal tissues. In addition, hTERT mRNA expression was assessed in fresh frozen specimens from a second set of 35 patients with inflammatory bowel disease at high or low risk for neoplastic transformation.ResultsFive out of 10 patients (50%) with colorectal cancer or high-grade dysplasia exhibited hTERT immunochemical detection in adjacent, non-transformed colonic mucosa. However, this phenomenon was also observed in non-affected mucosa of patients with either long-standing (13 out of 19 patients; 68%) or short duration (13 out of 18 patients; 72%) disease without cancer or dysplasia. On the other hand, hTERT mRNA expression in non-affected colorectal mucosa from patients at high risk for neoplastic transformation due to long-standing disease was higher than in those at low risk (7.42±6.43 vs. 2.87±1.47, respectively; p=0.006).ConclusionsWhereas hTERT immunostaining provides equivocal results, the observation that patients at high risk for colorectal cancer because of long-standing inflammatory bowel disease overexpress hTERT mRNA in non-affected colorectal mucosa suggests its potential usefulness as a biomarker of the risk of malignant transformation(AU)


AntecedentesLa enfermedad intestinal inflamatoria es una condición premaligna para el desarrollo de cáncer colorrectal. Puesto que se ha propuesto la existencia de una correlación entre la longitud de telomero, la inestabilidad cromosómica y la transformación neoplásica en este contexto, nos propusimos investigar si la expresión de la telomerasa en la mucosa colorrectal puede constituir un marcador biológico de transformación neoplásica en pacientes con enfermedad intestinal inflamatoria.Pacientes y métodosSe evaluaron 47 pacientes con enfermedad intestinal inflamatoria, con y sin cáncer o displasia, para inmunotinción de hTERT (transcriptasa inversa de telomerasa humana) en tejidos colorrectales preservados en parafina y fijados con formol. Además, se evaluó la expresión de la ARNm de la hTERT en muestras congeladas procedentes de un segundo grupo de 35 pacientes con enfermedad intestinal inflamatoria clasificados de alto o bajo riesgo de transformación neoplásica.ResultadosCinco de 10 pacientes (50%) con cáncer colorrectal o un grado elevado de displasia presentaban detección inmunoquímica de la hTERT en la mucosa colónica adyacente sin transformación maligna. Sin embargo, este fenómeno también se observó en mucosa no afecta de pacientes que presentaban enfermedad de larga duración (13 de 19 pacientes; 68%) y de corta duración (13 de 18 pacientes; 72%), sin presencia de cáncer ni displasia. Por otro lado, la expresión del ARN de la hTERT en mucosa colorrectal no afecta de pacientes con alto riesgo de transformación neoplásica, debido a enfermedad prolongada, fue mayor que en aquellos con bajo riesgo (7,42±6,43 frente a 2,87±1,47, respectivamente; p=0,006).(..) (AU)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Cell Transformation, Neoplastic/genetics , Inflammatory Bowel Diseases/enzymology , Intestinal Mucosa/enzymology , RNA, Messenger/biosynthesis , Telomerase/genetics , Biomarkers/analysis , Colonoscopy , Colorectal Neoplasms/prevention & control , Immunoenzyme Techniques , Inflammatory Bowel Diseases/genetics , Risk , RNA, Messenger/analysis , Time Factors
10.
Gastroenterol Hepatol ; 33(4): 288-96, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20334955

ABSTRACT

BACKGROUND: Inflammatory bowel disease is a premalignant condition for developing colorectal cancer. Since a correlation has been suggested between telomere length, chromosomal instability and neoplastic transformation in this setting, we sought to investigate whether telomerase expression in colorectal mucosa may constitute a biomarker for malignant transformation in patients with inflammatory bowel disease. PATIENTS AND METHODS: Forty-seven patients with inflammatory bowel disease with and without cancer or dysplasia were evaluated for human telomerase reverse transcriptase hTERT immunostaining in paraffin-embedded, formalin-fixed colorectal tissues. In addition, hTERT mRNA expression was assessed in fresh frozen specimens from a second set of 35 patients with inflammatory bowel disease at high or low risk for neoplastic transformation. RESULTS: Five out of 10 patients (50%) with colorectal cancer or high-grade dysplasia exhibited hTERT immunochemical detection in adjacent, non-transformed colonic mucosa. However, this phenomenon was also observed in non-affected mucosa of patients with either long-standing (13 out of 19 patients; 68%) or short duration (13 out of 18 patients; 72%) disease without cancer or dysplasia. On the other hand, hTERT mRNA expression in non-affected colorectal mucosa from patients at high risk for neoplastic transformation due to long-standing disease was higher than in those at low risk (7.42+/-6.43 vs. 2.87+/-1.47, respectively; p=0.006). CONCLUSIONS: Whereas hTERT immunostaining provides equivocal results, the observation that patients at high risk for colorectal cancer because of long-standing inflammatory bowel disease overexpress hTERT mRNA in non-affected colorectal mucosa suggests its potential usefulness as a biomarker of the risk of malignant transformation.


Subject(s)
Cell Transformation, Neoplastic/genetics , Inflammatory Bowel Diseases/enzymology , Intestinal Mucosa/enzymology , RNA, Messenger/biosynthesis , Telomerase/genetics , Adult , Aged , Aged, 80 and over , Biomarkers/analysis , Colonoscopy , Colorectal Neoplasms/prevention & control , Disease Progression , Enzyme Induction , Female , Humans , Immunoenzyme Techniques , Inflammatory Bowel Diseases/genetics , Male , Middle Aged , RNA, Messenger/analysis , Risk , Single-Blind Method , Time Factors
11.
Clin Genet ; 78(2): 186-90, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20095990

ABSTRACT

Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. The novel MSH2 c.[2635-3T>C; 2635-5C>T] mutation was identified in 4 Lynch families, cosegregating with the disease. This mutation, located in intron 15, was predicted to alter the correct mRNA processing by in silico analysis. Our aim was to perform the c.[2635-3T>C; 2635-5C>T] mutation screening in high risk CRC cases and control populations, to evaluate the founder effect in our population by haplotype analysis and to confirm the pathogenic effect of the mutation by MSH2 expression studies. Mutation screening was performed by SSCP and CSCE in genomic DNA from 323 high risk CRC cases and 289 controls. Haplotyping was performed analysing 4 MSH2 extragenic microsatellite markers (D2S288, D2S2227, D2S1247 and D2S1248) in 50 controls and mutation carriers by using the PHASE program. We analysed the effect of the mutation in mRNA processing by RT-PCR and in MSH2 expression by qRT-PCR using RNA from 5 mutation carriers and 18 controls. None of the remaining high risk CRC cases or controls analysed harboured the mutation. We identified a common telomeric haplotype and two centromeric haplotypes, both rare in our population. Although we were not able to identify any abnormal transcript by RT-PCR with the design used, we observed a significant reduction of mRNA MSH2 expression in carriers when compared with controls. Haplotype analyses suggest a founder effect of the c.[2635-3T>C; 2635-5C>T] MSH2 mutation and expression studies support a pathogenic role of this mutation.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Founder Effect , MutS Homolog 2 Protein/genetics , Alternative Splicing/genetics , Exons/genetics , Family , Female , Haplotypes/genetics , Humans , Male , Pedigree , Spain
12.
Eur J Cancer ; 45(3): 365-73, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18722765

ABSTRACT

AIMS: The aim of this study is to evaluate if mismatch repair (MMR) defective colorectal cancer has a different response to adjuvant 5-fluorouracil (5-FU) chemotherapy in a cohort of patients prospectively followed during 5 years. METHODS: The cohort included 754 surgically treated patients with colorectal cancer. MMR status was diagnosed by MLH1 and MSH2 immunohistochemistry and microsatellite instability analysis. Median follow-up was 49.2 months (range 1-73). At inclusion, 505 patients were diagnosed as TNM II or III stage, analysis of the efficacy of adjuvant chemotherapy was made on this population. Adjuvant chemotherapy was applied to 248 patients (98.2% 5-FU based). RESULTS: MMR deficiency was found in 76 patients (10.1%). No differences were found in overall survival (log-rank p=0.3) or disease-free survival (log-rank p=0.3) regarding MMR status. Adjuvant chemotherapy improves survival in patients in the II or III stage, but this improvement is only evident in patients with MMR-competent tumours (log-rank p=0.00001). Survival of patients with MMR-defective tumours does not improve with adjuvant chemotherapy (log-rank p=0.7). A multivariate analysis showed an independent effect of the interaction between MMR status and adjuvant chemotherapy (Hazard ratio 2.04; 95% confidence interval: 1.42-2.93). CONCLUSION: In a cohort of colorectal cancer patients, those with MMR-deficient tumours seem not to benefit from 5-FU-based chemotherapy.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Colorectal Neoplasms/drug therapy , DNA Mismatch Repair/drug effects , Fluorouracil/therapeutic use , Microsatellite Instability/drug effects , Aged , Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant/methods , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , DNA Mismatch Repair/genetics , Female , Humans , Male , Neoplasm Staging , Prospective Studies
13.
J Steroid Biochem Mol Biol ; 111(1-2): 87-90, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18583126

ABSTRACT

A high expression of vitamin D receptor (VDR) in colorectal cancer (CRC) tumoral tissue has been related to a good prognosis and it has been proposed that it could be a good biological marker of CRC progression. Nevertheless, there are no previous studies that compare the VDR expression in tumoral towards normal tissue of the same CRC patient in relation to VDR BsmI genotype. We collected normal and tumoral tissue samples, as well as blood samples, from CRC patients (n=170) and controls (n=122). VDR genotyping was performed and BsmI homozygous patients were selected (CRC=50, Cont=32). VDR mRNA and protein levels were analyzed. We also measured 25-Hydroxyvitamin D serum levels. We found no differences in the polymorphism distribution in tumoral versus normal tissue (control: BB=15.7%, bb=41.3%, Bb=43%; CRC: BB=14.2%, bb=41.9%, Bb=43.9%). Furthermore, VDR levels decreased in colonic cancer tissue (mean: 3.03) versus normal mucosa (11.62) from the same patient (p<0.001), but this decrease was similar in both genotypes. There were differences in 25-Hydroxyvitamin D(3) levels between the CRC and the control group (CRC=8.65 ng/ml, Cont=18.15 ng/ml). In conclusion, we found a decrease in VDR levels in tumoral compared with normal mucosa from the same patient. This difference is independent of the BsmI polymorphism.


Subject(s)
Colorectal Neoplasms/genetics , Polymorphism, Genetic , Receptors, Calcitriol/genetics , Receptors, Calcitriol/metabolism , Case-Control Studies , Genotype , Homozygote , Humans , Retrospective Studies
14.
Dis Colon Rectum ; 50(7): 971-80, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17468913

ABSTRACT

PURPOSE: Patients with colorectal cancer have a high risk of developing metachronous neoplasms. Identification of predictive factors associated with such conditions would allow individualized follow-up strategies in these patients. This study was designed to identify individual and familial factors associated with the development of metachronous colorectal neoplasms in patients with colorectal cancer. METHODS: In the context of a prospective, multicenter, general population-based study-the EPICOLON project-all patients with colorectal cancer attended in ten Spanish hospitals during a one-year period were included. Patients with familial adenomatous polyposis or inflammatory bowel disease were excluded. All patients were monitored by colonoscopy within two years of the diagnoses. Demographic, clinical, pathologic, molecular (microsatellite instability status and immunohistochemistry for MSH2 and MLH1), and familial characteristics (fulfillment of Amsterdam I or II criteria, and revised Bethesda guidelines) were analyzed. RESULTS: A total of 353 patients were included in the study. At two years of follow-up, colonoscopy revealed the presence of adenomas in 89 (25 percent) patients and colorectal cancer in 14 (3.9 percent) patients, in 7 cases restricted to anastomosis. Univariate analysis demonstrated that development of metachronous neoplasm (adenoma or colorectal cancer) was associated with personal history of previous colorectal cancer (odds ratio, 5.58; 95 percent confidence interval, 1.01-31.01), and presence of previous or synchronous adenomas (odds ratio, 1.77; 95 percent confidence interval, 1.21-3.17). Although nonstatistical significance was achieved, metachronisms were associated with gender (P<0.09) and differentiation degree (P<0.08). Multivariate analysis identified previous or synchronous adenomas (odds ratio, 1.98; 95 percent confidence interval, 1.16-3.38) as independent predictive factor. Neither presence of tumor DNA microsatellite instability nor family history correlated with the presence of metachronous neoplasms. CONCLUSIONS: Patients with previous or synchronous colorectal adenoma have an increased risk of developing metachronous colorectal neoplasms. Accordingly, this subgroup of patients may benefit from specific surveillance strategies.


Subject(s)
Colorectal Neoplasms/diagnosis , Neoplasms, Second Primary/diagnosis , Adaptor Proteins, Signal Transducing/genetics , Aged , Colonoscopy , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Confidence Intervals , DNA Repair , DNA, Neoplasm/genetics , Female , Follow-Up Studies , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Incidence , Male , Microsatellite Instability , MutL Protein Homolog 1 , MutS Homolog 2 Protein/genetics , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/genetics , Nuclear Proteins/genetics , Odds Ratio , Prognosis , Prospective Studies , Spain/epidemiology , Time Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...