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1.
Gastroenterology ; 2020 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-31926173

RESUMEN

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 y was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P<.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 y (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P=.001 and P=.003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P=.015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P=.002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

2.
Genet Med ; 22(1): 15-25, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31337882

RESUMEN

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

3.
Z Gastroenterol ; 57(11): 1309-1320, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-31739377

RESUMEN

INTRODUCTION: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. METHODS: The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. RESULTS: A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. CONCLUSION: LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN , Endoscopía del Sistema Digestivo/métodos , Guías de Práctica Clínica como Asunto , Conducta de Reducción del Riesgo , Neoplasias Colorrectales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Alemania , Humanos , Vigilancia de la Población , Factores de Tiempo
4.
Artículo en Inglés | MEDLINE | ID: mdl-30858900

RESUMEN

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

5.
Cancer Cell ; 35(2): 256-266.e5, 2019 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-30753826

RESUMEN

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Desoxirribonucleasa (Dímero de Pirimidina)/genética , Perfilación de la Expresión Génica , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genética , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor/deficiencia , Reparación del ADN/genética , Desoxirribonucleasa (Dímero de Pirimidina)/deficiencia , Europa (Continente) , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Herencia , Humanos , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Linaje , Fenotipo , Medición de Riesgo , Factores de Riesgo , Adulto Joven
6.
Gastroenterology ; 155(5): 1400-1409.e2, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30063918

RESUMEN

BACKGROUND & AIMS: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). METHODS: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). RESULTS: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy. CONCLUSIONS: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.


Asunto(s)
Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales/diagnóstico , Adulto , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales
7.
Artículo en Inglés | MEDLINE | ID: mdl-29213343

RESUMEN

Background: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified. Methods: To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing. Results: The BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected. Conclusions: Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS.

8.
PLoS Pathog ; 13(5): e1006373, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28505204

RESUMEN

Innate lymphocyte cells (ILCs), a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV)-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(-) individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI) tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+)ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+) patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+) and HIV(-) individuals.


Asunto(s)
Infecciones por VIH/inmunología , Intestinos/inmunología , Linfocitos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Inmunidad Innata , Interleucina-7/genética , Interleucina-7/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Intestinos/virología , Linfocitos/virología , Especificidad de Órganos
9.
J Hepatol ; 66(5): 888-896, 2017 05.
Artículo en Albanés, Inglés | MEDLINE | ID: mdl-28040549

RESUMEN

BACKGROUND & AIMS: CD4+ regulatory T cells (Tregs) expand during chronic hepatitis C virus (HCV) infection, inhibit antiviral immunity and promote fibrosis. Direct-acting antiviral agents (DAA) have revolutionized HCV therapy. However, it is unclear if Tregs are normalized after DAA-induced HCV elimination. METHODS: We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3+ CD25+ CD4+ T cells were studied by multi-color flow cytometry and co-culture inhibition assays. RESULTS: Frequencies and activation status of Foxp3+ CD25+ CD4+ T cells remained elevated above those of normal controls in both treatment groups even long-term after HCV elimination. Co-culture assays indicated a dose-response relationship for functional inhibition of autologous CD4+ effector T cells and confirmed that activation of Tregs remained largely unchanged over the observation period. Unlike IFN-free regimens, SOF plus IFN/ribavirin induced a transiently increased frequency of Foxp3+ CD25+ CD4+ T cells at EOT (5.0% at baseline to 6.1% at EOT; p=0.001). These Foxp3+ CD25+ CD4+ T cells co-expressed the activation markers glycoprotein A repetitions predominant (GARP; p=0.012) and tumor necrosis factor receptor superfamily, member 4 (OX-40; p=0.001) but showed unchanged in vitro inhibitory activity. CONCLUSION: Although IFN-based DAA therapy induced transient expansion of activated Foxp3+ CD25+ CD4+ T cells, neither IFN-based nor IFN-free DAA regimens normalized frequencies and activation status of Tregs one year after viral elimination. Persistence of immunosuppressive Tregs may thus contribute to complications of liver disease even long-term after HCV cure. LAY SUMMARY: In chronic hepatitis C virus (HCV) infection, CD4+ regulatory T cells (Tregs) can reduce antiviral immune responses, promote liver fibrosis and may increase the risk for liver cancer, because they gradually expand during disease. Modern direct-acting antiviral agents (DAA) can "cure" hepatitis C in almost all treated patients. However, our study shows that DAA do not normalize the increased frequency and activation status of Tregs even long-term after HCV elimination. Tregs may persistently modulate functions of the immune system even after "cure" of hepatitis C.


Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Femenino , Factores de Transcripción Forkhead/análisis , Galectinas/sangre , Hepatitis C Crónica/inmunología , Humanos , Masculino , Persona de Mediana Edad
10.
Endosc Int Open ; 4(12): E1305-E1310, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27995193

RESUMEN

Background and study aims: Hereditary diffuse gastric cancer (HGGC), an autosomal dominant tumor-syndrome, accounts for 1 % to 3 % of gastric cancers worldwide. Presumably 30 % to 40 % of all patients fulfilling the clinical guidelines for HDGC are carriers of a pathogenic mutation in the CDH1 gene. Patients often show multiple foci of signet ring cell carcinoma at early age and are advised to undergo prophylactic total gastrectomy (PTG). Our aim was to improve the endoscopic detection of HDGC by using an enhanced endoscopic protocol. Patient and methods: Patients with a proven CDH1 germline mutation identified in our institute were prospectively included. Patients were advised to undergo PTG and offered a baseline endoscopic examination prior surgery. Examination was performed by using high-resolution white-light endoscopy and pan-gastric chromoendoscopy with indigo carmine as dye combined with targeted and multiple random biopsies assessed by an expert histopathologist. Postoperative histopathology was compared with results from endoscopic biopsies. Results: Between September 2012 and November 2014 8 patients with a proven CDH1 germline mutation were included. We conducted 44 targeted (6.3/patient) and 225 random (32.1/patient) biopsies in 7 patients. We detected 1 gastric cancer by random biopsy (14 %). All other examinations showed no signs of cancer. Histopathology of gastrectomy specimen revealed multiple foci of gastric carcinoma in 6 patients (86 %) with a total number of 27 cancer foci. Conclusions: Examination with targeted and random biopsies combined with chromoendoscopy is not able to detect small foci of gastric cancer in CDH1 mutation carriers. Therefore PTG is advocated in these patients.

11.
Int J Colorectal Dis ; 31(12): 1825-1833, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27682646

RESUMEN

PURPOSE: Germline mutations in several genes confer a relevant lifetime risk of gastric cancer. In this context, an increasing involvement of a surgeon can be seen, mainly with the question of performing a prophylactic operation. METHODS: Patients with hereditary tumor syndromes predisposing for gastric cancer who received care leading to prophylactic total gastrectomy in our Center for Hereditary Tumor Syndromes were analyzed. For each patient, the multidisciplinary decision-making process, the perioperative course, and the histopathologic findings were assessed. Short-term morbidity was evaluated based on the medical reports. RESULTS: The analysis includes nine patients (six female, three male) with a median age of 41.6 (range 23-60) years. Indication for prophylactic total gastrectomy was based on family history and genetic analysis (eight patients with a germline mutation of the CDH1 gene and one patient with a SMAD4 mutation). Removal of the entire gastric mucosa was documented intraoperatively by fresh frozen section examination. Extended (DII) lymphadenectomy was performed in four patients. Histopathologic examination of gastrectomy specimens revealed six patients (6/9, 67 %) with multifocal signet ring cell carcinomas. In our series, prophylactic total gastrectomy was a safe procedure without mortality and low morbidity. CONCLUSIONS: Patients with hereditary syndromes predisposing for gastric cancer should be evaluated for this curative procedure in a specialized center. Further research is necessary, and the implementation of nationwide registers including patients with prophylactic gastrointestinal operations due to hereditary tumor syndrome is advisable.


Asunto(s)
Gastrectomía , Predisposición Genética a la Enfermedad , Neoplasias Gástricas/prevención & control , Neoplasias Gástricas/cirugía , Adulto , Femenino , Humanos , Masculino , Factores de Riesgo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adulto Joven
12.
Endosc Int Open ; 4(2): E164-9, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26878043

RESUMEN

BACKGROUND AND STUDY AIMS: Colorectal cancer (CRC) is one of the most common cancers worldwide, and several efforts have been made to reduce its occurrence or severity. Although colonoscopy is considered the gold standard in CRC prevention, it has its disadvantages: missed lesions, bleeding, and perforation. Furthermore, a high number of patients undergo this procedure even though no polyps are detected. Therefore, an initial screening examination may be warranted. Our aim was to compare the adenoma detection rate of magnetic resonance colonography (MRC) with that of optical colonoscopy. PATIENTS AND METHODS: A total of 25 patients with an intermediate risk for CRC (17 men, 8 women; mean age 57.6, standard deviation 11) underwent MRC with a 3.0-tesla magnet, followed by colonoscopy. The endoscopist was initially blinded to the results of MRC and unblinded immediately after examining the distal rectum. Following endoscopic excision, the size, anatomical localization, and appearance of all polyps were described according to the Paris classification. RESULTS: A total of 93 lesions were detected during colonoscopy. These included a malignant infiltration of the transverse colon due to gastric cancer in 1 patient, 28 adenomas in 10 patients, 19 hyperplastic polyps in 9 patients, and 45 non-neoplastic lesions. In 5 patients, no lesion was detected. MRC detected significantly fewer lesions: 1 adenoma (P = 0.001) and 1 hyperplastic polyp (P = 0.004). The malignant infiltration was seen with both modalities. Of the 28 adenomas, 23 (82 %) were 5 mm or smaller; only 4 adenomas 10 mm or larger (14 %) were detected. CONCLUSION: MRC does not detect adenomas sufficiently independently of the location of the lesion. Even advanced lesions were missed. Therefore, colonoscopy should still be considered the current gold standard, even for diagnostic purposes.

13.
Eur J Gastroenterol Hepatol ; 28(6): 689-95, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26882171

RESUMEN

BACKGROUND AND AIM: Although an eight-residue insertion in HLA-DQß1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS: We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQß1 insertion carriers and noncarriers. RESULTS: Our data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren's syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQß1 insertion carriers (P=0.031). CONCLUSION: Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQß1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.


Asunto(s)
Enfermedades Autoinmunes/epidemiología , Acalasia del Esófago/epidemiología , Cadenas beta de HLA-DQ/genética , Hipersensibilidad/epidemiología , Complicaciones del Embarazo/epidemiología , Virosis/epidemiología , Adulto , Alelos , Estudios de Casos y Controles , Varicela/epidemiología , Comorbilidad , Acalasia del Esófago/genética , Europa (Continente)/epidemiología , Grupo de Ascendencia Continental Europea/genética , Familia , Femenino , Genotipo , Herpes Zóster/epidemiología , Herpesvirus Humano 3 , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Embarazo , Complicaciones del Embarazo/genética , Psoriasis/epidemiología , Síndrome de Sjögren/epidemiología
14.
J Hepatol ; 59(2): 229-35, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23624000

RESUMEN

BACKGROUND & AIMS: Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. METHODS: Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. RESULTS: We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. CONCLUSIONS: Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.


Asunto(s)
Hepatitis C Crónica/inmunología , Hepatitis C Crónica/patología , Interleucina-8/biosíntesis , Linfocitos T Reguladores/inmunología , Inmunidad Adaptativa , Adulto , Anciano , Biomarcadores/metabolismo , Progresión de la Enfermedad , Femenino , Fibrosis , Factores de Transcripción Forkhead/metabolismo , Células Estrelladas Hepáticas/inmunología , Células Estrelladas Hepáticas/metabolismo , Humanos , Hígado/inmunología , Hígado/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/clasificación , Linfocitos T Reguladores/metabolismo , Regulación hacia Arriba , Adulto Joven
15.
Eur J Gastroenterol Hepatol ; 25(3): 368-72, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23114792

RESUMEN

BACKGROUND/AIMS: The noninvasive measurement of liver stiffness using transient elastography (TE) is increasingly being used alongside liver biopsy. However, several conditions may lead to higher liver stiffness values without reflecting more fibrosis. Such conditions (e.g. hepatitis, cholestasis, heart failure, mechanical ventilation) limit the interpretation of liver stiffness measurements. The influence of hemodialysis on the measurement of liver stiffness has not been investigated to date. Here, we analyzed liver stiffness assessed by fibroscan in 17 patients directly before and after a hemodialysis session. PATIENTS AND METHODS: Measurement of hepatic stiffness by TE was carried out using the Fibroscan device with the 'M probe' directly before and directly after one session of hemodialysis. Each measurement consisted of at least 10 individual and valid measurements, with a success rate of at least 60%, and an interquartile range of less than 25%. All measurements were carried out by one investigator not involved in patient management. RESULTS: Before dialysis, the median TE was 5.1 kPa (2.8-17 kPa). Ten patients had values below the threshold of 7.1 kPa and seven patients had TE>7.1 kPa. The median net fluid withdrawal by hemodialysis was 2.5 l (0.4-3.1 l) and did not differ between patients. After dialysis, the TE median was 7.4 kPa (3.5-12.5 kPa) and had changed in all patients except one. Liver stiffness increased significantly when the initial TE was lower than 7.1 kPa (P=0.05), but not when the initial TE was higher than 7.1 kPa. Furthermore, the magnitude of the change in TE after hemodialysis correlated inversely with the liver stiffness before hemodialysis (P=0.03) and with spleen length measured by ultrasound (P=0.03). CONCLUSION: This study is the first to report on the influence of hemodialysis on liver stiffness measurement. In contrast to previous reports, liver stiffness might increase after fluid withdrawal if patients do not show significant fibrosis. We conclude that before dialysis, TE possibly better differentiates between patients with or without significant fibrosis.


Asunto(s)
Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática/diagnóstico por imagen , Hígado/diagnóstico por imagen , Diálisis Renal , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Elasticidad , Femenino , Alemania , Humanos , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Diálisis Renal/efectos adversos , Bazo/diagnóstico por imagen , Resultado del Tratamiento
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