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1.
Gut ; 73(1): 16-46, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-37770126

RESUMO

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Gastroenterologia , Humanos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos
2.
Surg Endosc ; 37(3): 1749-1755, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36217058

RESUMO

BACKGROUND: Endoscopic ultrasound guided gastrojejunostomy (EUS-GJ) with lumen apposing metal stents has recently emerged as a viable option, as an alternative to surgical gastrojejunostomy and endoscopic enteral stenting, for managing gastric outlet obstruction (GOO). We aim to perform a retrospective analysis of the efficacy, safety and outcomes of EUS-GJ performed at three tertiary institutions in the United Kingdom. METHODS: Consecutive patients who underwent EUS-GJ between August 2018 and March 2021 were identified from a prospectively maintained database. Data were obtained from interrogation of electronic health records. RESULTS: Twenty five patients (15 males) with a median age of 63 years old (range 29-80) were included for analysis. 88% (22/25) of patients had GOO due to underlying malignant disease. All patients were deemed surgically inoperable or at high surgical risk. Both technical and clinical success were achieved in 92% (23/25) of patients. There was an improvement in the mean Gastric Outlet Obstruction Scoring System scores following a technically successful EUS-GJ (2.52 vs 0.68, p < 0.01). Adverse events occurred in 2/25 patients (8%), both due to stent maldeployment necessitating endoscopic closure of the gastric defect with clips. Long-term follow-up data were available for 21 of 23 patients and the re-intervention rate was 4.8% (1/21) over a median follow-up period of 162 (range 5-474) days. CONCLUSION: EUS-GJ in carefully selected patients is an effective and safe procedure when performed by experienced endoscopists.


Assuntos
Derivação Gástrica , Obstrução da Saída Gástrica , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Derivação Gástrica/efeitos adversos , Derivação Gástrica/métodos , Resultado do Tratamento , Estudos Retrospectivos , Obstrução da Saída Gástrica/etiologia , Obstrução da Saída Gástrica/cirurgia , Stents , Reino Unido , Ultrassonografia de Intervenção
3.
Gut ; 71(8): 1669-1683, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35580963

RESUMO

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Inteligência Artificial , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores , Biomarcadores Tumorais , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patologia , Humanos
4.
Pancreatology ; 22(7): 994-1002, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36089484

RESUMO

BACKGROUND: Although emerging data evidences that EUS-guided needle-based confocal laser endomicroscopy (nCLE) accurately diagnoses pancreatic cystic lesions (PCLs), there are a lack of interobserver agreement (IOA) studies utilizing reference histopathological diagnosis and for specific PCL subtypes. Hence, we sought to assess the IOA, intra-observer reliability (IOR), and diagnostic performance of EUS-nCLE using a large cohort of patients with histopathological diagnosis amongst a broad panel of international observers. METHODS: EUS-nCLE videos (n = 76) of subjects with PCLs [intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystadenoma (SCA), pseudocyst, and cystic-neuroendocrine tumors/solid pseudopapillary neoplasm (cystic-NET/SPN)], simulating clinical prevalence rates were obtained from 3 prospective studies. An international panel of 13 endosonographers with nCLE experience, blinded to all PCL data, evaluated the video library twice with a two-week washout for PCL differentiation (mucinous vs. non-mucinous) and subtype diagnosis. RESULTS: The IOA (κ = 0.82, 95% CI 0.77-0.87) and IOR (κ = 0.82, 95% CI 0.78-0.85) were "almost perfect" to differentiate mucinous vs. non-mucinous PCLs. For PCL subtype, IOA was highest for SCA (almost perfect; κ = 0.85), followed by IPMN (substantial, κ = 0.72), and cystic-NET/SPN (substantial, κ = 0.73). The IOA was moderate for MCN (κ = 0.47), and pseudocyst (κ = 0.57). Compared to histopathology, observers differentiated mucinous vs. non-mucinous PCLs with high accuracy (94.8%, 95% CI 93.3-96.1). For detecting specific PCLs subtypes, EUS-nCLE was highly accurate in diagnosing non-mucinous cysts (SCA: 98%; cystic-NET/SPN: 96%; pseudocyst: 96%) and slightly less accurate for mucinous lesions (IPMN: 86%; MCN: 84%). CONCLUSION: Diagnosis of PCLs by EUS-nCLE guided virtual biopsy is very accurate and reliable for the most prevalent pancreatic cysts in clinical practice.


Assuntos
Cistadenoma Seroso , Tumores Neuroendócrinos , Cisto Pancreático , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Humanos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Estudos Prospectivos , Reprodutibilidade dos Testes , Microscopia Confocal , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/patologia , Cistadenoma Seroso/diagnóstico por imagem , Cistadenoma Seroso/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia
5.
Gastrointest Endosc ; 94(2): 321-328, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33545136

RESUMO

BACKGROUND AND AIMS: Biliary drainage with ERCP is successful in only 80% to 90% of cases of extrahepatic cholangiocarcinoma and pancreatic cancer. We present the results of a multicenter prospective study assessing the safety, feasibility, and quality of life of patients after EUS-guided biliary drainage (EUS-BD) with lumen-apposing metal stents after failed ERCP. METHODS: All consecutive adults with a dilated common bile duct (CBD) ≥14 mm secondary to inoperable malignant distal CBD stricture and failed ERCP biliary drainage were screened and recruited from 3 tertiary UK centers. Technical success of EUS-BD using lumen-apposing metal stents was the primary endpoint. Improvement in serum bilirubin level, 30-day mortality, procedure-related adverse events, and quality of life were secondary endpoints. Improvement in quality of life was measured using a validated questionnaire (EORTC QLQ-BIL21). RESULTS: Twenty patients were included in the analysis. EUS-BD was technically successful in all patients and the clinical success rate was 95% (19 of 20) at day 7 (>50% reduction in bilirubin level) and 92.3% (12 of 13) at day 30 (bilirubin <50 µmol/L). There were significant improvements in overall quality of life score (49 vs 42, P = .03) at day 30. All-cause 30-day mortality was 20% and the moderate adverse event rate was 10% (1 cholangitis and 1 stent migration). CONCLUSION: EUS-BD has acceptable technical success and safety as a second-line palliative treatment for inoperable malignant distal CBD strictures. Randomized controlled studies comparing EUS-BD with percutaneous transhepatic biliary drainage are needed to determine their effectiveness in clinical practice. (ISCRTN registration number: ISRCTN13196704.).


Assuntos
Colestase , Cuidados Paliativos , Adulto , Colangiopancreatografia Retrógrada Endoscópica , Colestase/etiologia , Colestase/cirurgia , Drenagem , Endossonografia , Estudos de Viabilidade , Humanos , Estudos Prospectivos , Qualidade de Vida , Stents
6.
Gastrointest Endosc ; 94(1): 179-186, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33647286

RESUMO

BACKGROUND AND AIMS: Locally advanced pancreatic cancer (LAPC) often causes obstruction. Verteporfin photodynamic therapy (PDT) can feasibly "debulk" the tumor more safely than noncurative surgery and has multiple advantages over older PDT agents. We aimed to assess the feasibility of EUS-guided verteporfin PDT in ablating nonresectable LAPC. METHODS: Adults with LAPC with adequate biliary drainage were prospectively enrolled. Exclusion criteria were significant metastatic disease burden, disease involving >50% duodenal or major artery circumference, and recent treatment with curative intent. CT was obtained between days -28 to 0. On day 0, verteporfin .4 mg/kg was infused 60 to 90 minutes before EUS, during which a diffuser was positioned in the tumor and delivered light at 50 J/cm for 333 seconds. CT was obtained on day 2, with adverse event monitoring occurring on days 1, 2, and 14. The primary outcome was presence of necrosis. RESULTS: Of 8 patients (62.5% men, mean age 65 ± 7.9 years) included in the study, 5 were staged at T3, 2 at T2, and 1 at T1. Most (n = 4) had primary lesions in the pancreatic head. Mean pretrial tumor diameter was 33.3 ± 13.4 mm. On day 2 CT, 5 lesions demonstrated a zone of necrosis measuring a mean diameter of 15.7 ± 5.5 mm; 3 cases did not develop necrosis. No adverse events were noted during the procedure or postprocedure observation period (days 1-3), and no changes in patient-reported outcomes were noted. CONCLUSIONS: In this pilot study, EUS-guided verteporfin PDT is feasible and shows promise as a minimally invasive ablative therapy for LAPC in select patients. Tumor necrosis is visible within 48 hours after treatment. Patient enrollment and data collection are ongoing. (Clinical trial registration number: NCT03033225.).


Assuntos
Neoplasias Pancreáticas , Fotoquimioterapia , Porfirinas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Projetos Piloto , Porfirinas/uso terapêutico , Verteporfina/uso terapêutico
7.
PLoS Med ; 17(12): e1003489, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33301466

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. METHODS AND FINDINGS: Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. CONCLUSIONS: We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.


Assuntos
Biomarcadores Tumorais/urina , Carcinoma Ductal Pancreático/diagnóstico , Detecção Precoce de Câncer , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/urina , Europa (Continente) , Feminino , Humanos , Litostatina/urina , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/urina , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fator Trefoil-1/urina , Urinálise , Proteínas de Transporte Vesicular/urina , Adulto Jovem
8.
Endoscopy ; 52(4): 293-304, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32052404

RESUMO

In Europe at present, but also in 2040, 1 in 3 cancer-related deaths are expected to be caused by digestive cancers. Endoscopic technologies enable diagnosis, with relatively low invasiveness, of precancerous conditions and early cancers, thereby improving patient survival. Overall, endoscopy capacity must be adjusted to facilitate both effective screening programs and rigorous control of the quality assurance and surveillance systems required. 1 : For average-risk populations, ESGE recommends the implementation of organized population-based screening programs FOR COLORECTAL CANCER: , based on fecal immunochemical testing (FIT), targeting individuals, irrespective of gender, aged between 50 and 75 years. Depending on local factors, namely the adherence of the target population and availability of endoscopy services, primary screening by colonoscopy or sigmoidoscopy may also be recommendable. 2 : In high-risk populations, endoscopic screening FOR GASTRIC CANCER: should be considered for individuals aged more than 40 years. Its use in countries/regions with intermediate risk may be considered on the basis of local settings and availability of endoscopic resources. 3 : For esophageal and pancreatic cancer, endoscopic screening may be considered only in high-risk individuals:- FOR SQUAMOUS CELL CARCINOMA: , in those with a personal history of head/neck cancer, achalasia, or previous caustic injury; - FOR BARRETT'S ESOPHAGUS (BE)-ASSOCIATED ADENOCARCINOMA: , in those with long-standing gastroesophageal reflux disease symptoms (i. e., > 5 years) and multiple risk factors (age ≥ 50 years, white race, male sex, obesity, first-degree relative with BE or esophageal adenocarcinoma [EAC]). - FOR PANCREATIC CANCER SCREENING: , endoscopic ultrasound may be used in selected high-risk patients such as those with a strong family history and/or genetic susceptibility.


Assuntos
Esôfago de Barrett , Neoplasias Esofágicas , Idoso , Detecção Precoce de Câncer , Endoscopia Gastrointestinal , Neoplasias Esofágicas/diagnóstico por imagem , Europa (Continente) , Humanos , Masculino , Pessoa de Meia-Idade
9.
Gut ; 68(8): 1356-1378, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31154395

RESUMO

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.


Assuntos
Neoplasias do Sistema Biliar , Colangite Esclerosante , Técnicas de Diagnóstico do Sistema Digestório , Doença Relacionada a Imunoglobulina G4/diagnóstico , Administração dos Cuidados ao Paciente/métodos , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/etiologia , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/etiologia , Diagnóstico Diferencial , Humanos , Prognóstico , Reino Unido
10.
Gastroenterology ; 155(3): 752-759.e5, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29803836

RESUMO

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917.


Assuntos
Cateterismo/métodos , Colangite Esclerosante/cirurgia , Dilatação/métodos , Stents , Adulto , Sistema Biliar/patologia , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangite Esclerosante/patologia , Constrição Patológica/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do Tratamento , Adulto Jovem
11.
Eur J Clin Invest ; 49(5): e13088, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30762236

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) complicates primary sclerosing cholangitis (PSC) in 10%-20% of cases, but current tools for prediction of a CCA diagnosis are inadequate. Recently, we demonstrated the utility of the enhanced liver fibrosis (ELF) test to stratify prognosis in PSC. We observed that patients with PSC + CCA had significantly higher ELF score than those with PSC alone. In this study, we aimed to investigate further this association in a larger cohort of PSC patients with CCA compared with patients with PSC or CCA alone. MATERIALS AND METHODS: Stored sera from patients with PSC (n = 119), CCA without known chronic liver disease (n = 36) and PSC + CCA (n = 32) were tested for ELF. ELF score, gender, age, age at disease diagnosis, inflammatory bowel disease, PSC duration and severity, and CCA features were compared amongst the three cohorts. Factors related to an elevated ELF score were investigated. RESULTS: Enhanced liver fibrosis score was significantly higher in patients with CCA without underlying chronic liver disease and in patients with PSC + CCA compared to those with PSC alone (P < 0.001). In multivariate analysis, elevated ELF score was associated with the diagnosis of CCA independently of age and PSC status (P < 0.001). CONCLUSIONS: Enhanced liver fibrosis score was elevated in patients with CCA irrespective of the presence of PSC, and independently of liver disease stage. Our results indicate that the association between high ELF score and CCA may be related to the tumour's desmoplastic nature, independent of background liver fibrosis, suggesting that ELF score could be used to risk stratify for CCA in PSC.


Assuntos
Neoplasias dos Ductos Biliares/complicações , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/complicações , Tumor de Klatskin/complicações , Cirrose Hepática/etiologia , Idoso , Biomarcadores/metabolismo , Colangite Esclerosante , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Medição de Risco
12.
BMC Cancer ; 19(1): 185, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819129

RESUMO

BACKGROUND: Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-ß, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION: Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.


Assuntos
Neoplasias dos Ductos Biliares/etiologia , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/etiologia , Colangiocarcinoma/metabolismo , Animais , Neoplasias dos Ductos Biliares/patologia , Biomarcadores , Colangiocarcinoma/patologia , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Risco , Transdução de Sinais
13.
Liver Int ; 39 Suppl 1: 108-122, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30843325

RESUMO

The high mortality rate of cholangiocarcinoma (CCA) is due, in part, to the lack of non-invasive approaches able to accurately detect this silent tumour at early stages, when therapeutic options can be potentially curative or may at least increase the overall survival of patients. The fact that the majority of CCA tumours are not linked to any known aetiological factor highly compromises the monitoring of patients at risk for tumour development and also their early diagnosis. Combination of clinical/biochemical features, imaging techniques and analysis of non-specific tumour biomarkers in serum are commonly used to help in the diagnosis of CCA, but tumour biopsy is usually required to confirm the diagnosis. Moreover, no prognostic biomarkers are currently used in the clinical setting, deserving more innovative research, and international validation and consensus. Important efforts have been made in the last few years to identify accurate non-invasive biomarkers, by using innovative techniques and high-throughput omics technologies. This review summarizes and discusses the advances in the investigation of novel diagnostic and prognostic biomarkers in CCA and envisions the future directions in this field of research.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Biomarcadores Tumorais/análise , Colangiocarcinoma/diagnóstico , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Biópsia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Diagnóstico Precoce , Humanos , Prognóstico , Proteômica
14.
Gut ; 67(9): 1568-1594, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29593060

RESUMO

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Colagogos e Coleréticos/uso terapêutico , Colangite/diagnóstico , Colangite/terapia , Gastroenterologia , Ácido Ursodesoxicólico/uso terapêutico , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Autoanticorpos/sangue , Bilirrubina/sangue , Biomarcadores/sangue , Ácido Quenodesoxicólico/uso terapêutico , Colangite/sangue , Progressão da Doença , Humanos , Cirrose Hepática Biliar , Mitocôndrias/imunologia , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Sociedades Médicas , Resultado do Tratamento , Reino Unido
15.
Gastroenterology ; 152(8): 1975-1984.e8, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28274849

RESUMO

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.


Assuntos
Colangite Esclerosante/epidemiologia , Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Adulto , Distribuição por Idade , Austrália/epidemiologia , Distribuição de Qui-Quadrado , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/mortalidade , Colangite Esclerosante/cirurgia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/mortalidade , Colite Ulcerativa/cirurgia , Doença de Crohn/diagnóstico , Doença de Crohn/mortalidade , Doença de Crohn/cirurgia , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Análise Multivariada , América do Norte/epidemiologia , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Distribuição por Sexo , Fatores de Tempo , Adulto Jovem
16.
Pancreatology ; 18(2): 170-175, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29338919

RESUMO

BACKGROUND/OBJECTIVES: To evaluate the agreement between the imaging modalities MRI-MRCP and EUS in cystic lesions of the pancreas which were thought to be a BD-IPMN. METHODS: Multicenter retrospective study included all patients between 2010 and 2015 with a suspected BD-IPMN who underwent an EUS and MRI-MRCP within 6 months or less of each other. Location, number, size, worrisome features and high-risk stigmata were evaluated. Interobserver agreement was evaluated by Kappa score. RESULTS: 173 patients were included (97 UHSC, 76 UCLH-RFH), mean age 65 (range 25-87 years), 66 males. When comparing both modalities there was good agreement for the location of the cyst. The median lesion size was larger by MRI-MRCP than EUS although it was not significant. With regards to worrisome features, there was moderate agreement for main PD of 5-9 mm and abrupt change (k = 0.45 and 0.52). Fair agreement was seen for the cyst wall thickening (k = 0.25). No agreement was seen between the presence of non-enhanced mural nodules or lymphadenopathy (k < 0). With regards to high-risk stigmata, poor agreement was obtained for the detection of an enhanced solid component (k = 0.12). No agreement was observed for main PD > 10 mm (k < 0). CONCLUSIONS: In this multicentre study of patients with a BD-IPMN under active surveillance, most disagreement between these modalities was seen in the proximal pancreas. There was generally only minimal concordance between the imaging findings of EUS and MRI-MRCP for the detection of high-risk stigmata and worrisome features.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico por imagem , Carcinoma Ductal Pancreático/diagnóstico por imagem , Colangiopancreatografia por Ressonância Magnética , Endossonografia , Pâncreas/diagnóstico por imagem , Ductos Pancreáticos/diagnóstico por imagem , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Ductos Pancreáticos/patologia , Estudos Retrospectivos
17.
BMC Pediatr ; 18(1): 42, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29426291

RESUMO

BACKGROUND: In adults ERCP and endoscopic ultrasound (EUS) are standard methods of evaluating and treating many hepatopancreaticobiliary (HPB) conditions. HPB disease is being diagnosed with increasing frequency in children but information about role of ERCP and EUS and their outcomes in this population remain limited. Therefore the aims of this study were to describe the paediatric ERCP and EUS experience from a large tertiary referral HPB centre, and to systematically compare outcomes with those of other published series. METHODS: All patients <18 years undergoing an ERCP or EUS between January 1992-December 2014 were included. Indications for the procedure, rates of technical success, procedural adverse events and reinterventions were recorded in all cases. RESULTS: Ninety children underwent 111 procedures (87 ERCPs and 24 EUS). 53% (48) were female with a median age of 14 years (range: 3 months - 17 years). Procedures were performed under general anaesthesia (n = 48) or conscious sedation (n = 63). Common indications for ERCP included chronic or recurrent pancreatitis and biliary obstruction. Patients frequently had multiple comorbidities, with a median ASA grade of 2 (range 1-4). Therapeutic procedures performed included biliary or pancreatic sphincterotomy, common bile duct or pancreatic duct stone removal, biliary or pancreatic stent insertion, EUS-guided fine needle aspiration and endoscopic transmural drainage of pancreatic fluid collections. No adverse events were reported following ERCP but there was one complication requiring surgery following EUS guided cystenterostomy. CONCLUSION: ERCP and EUS in children and adolescents have high technical success rates and low rates of adverse events when performed in high volume HPB centres.


Assuntos
Doenças Biliares , Colangiopancreatografia Retrógrada Endoscópica , Endossonografia , Pancreatopatias , Adolescente , Doenças Biliares/diagnóstico por imagem , Doenças Biliares/terapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/terapia , Estudos Retrospectivos , Resultado do Tratamento
18.
Br J Cancer ; 116(3): 349-355, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28081547

RESUMO

BACKGROUND: Biliary brush cytology is the standard method of evaluating biliary strictures, but is insensitive at detecting malignancy. In pancreaticobiliary cancer minichromosome maintenance replication proteins (MCM 2-7) are dysregulated in the biliary epithelium and MCM5 levels are elevated in bile samples. This study aimed to validate an immunocolorimetric ELISA assay for MCM5 as a pancreaticobiliary cancer biomarker in biliary brush samples. METHODS: Biliary brush specimens were collected prospectively at ERCP from patients with a biliary stricture. Collected samples were frozen at -80 °C. The supernatant was washed and lysed cells incubated with HRP-labelled anti-MCM5 mouse monoclonal antibody. Test positivity was determined by optical density absorbance. Patients underwent biliary brush cytology or additional investigations as per clinical routine. RESULTS: Ninety-seven patients were included in the study; 50 had malignant strictures. Median age was 65 years (range 21-94) and 51 were male. Compared with final diagnosis the MCM5 assay had a sensitivity for malignancy of 65.4% compared with 25.0% for cytology. In the 72 patients with paired MCM5 assay and biliary brush cytology, MCM5 demonstrated an improved sensitivity (55.6% vs 25.0%; P=0.0002) for the detection of malignancy. CONCLUSIONS: Minichromosome maintenance replication protein5 is a more sensitive indicator of pancreaticobiliary malignancy than standard biliary brush cytology.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares/patologia , Proteínas de Ciclo Celular/análise , Citodiagnóstico/métodos , Microvilosidades/patologia , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/metabolismo , Ductos Biliares/ultraestrutura , Proteínas de Ciclo Celular/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Microvilosidades/metabolismo , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Adulto Jovem
19.
Endoscopy ; 49(6): 588-608, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28420030

RESUMO

1 ESGE/EASL recommend that, as the primary diagnostic modality for PSC, magnetic resonance cholangiography (MRC) should be preferred over endoscopic retrograde cholangiopancreatography (ERCP).Moderate quality evidence, strong recommendation. 2 ESGE/EASL suggest that ERCP can be considered if MRC plus liver biopsy is equivocal or contraindicated in patients with persisting clinical suspicion of PSC. The risks of ERCP have to be weighed against the potential benefit with regard to surveillance and treatment recommendations.Low quality evidence, weak recommendation. 6 ESGE/EASL suggest that, in patients with an established diagnosis of PSC, MRC should be considered before therapeutic ERCP.Weak recommendation, low quality evidence. 7 ESGE/EASL suggest performing endoscopic treatment with concomitant ductal sampling (brush cytology, endobiliary biopsies) of suspected significant strictures identified at MRC in PSC patients who present with symptoms likely to improve following endoscopic treatment.Strong recommendation, low quality evidence. 9 ESGE/EASL recommend weighing the anticipated benefits of biliary papillotomy/sphincterotomy against its risks on a case-by-case basis.Strong recommendation, moderate quality evidence.Biliary papillotomy/sphincterotomy should be considered especially after difficult cannulation.Strong recommendation, low quality evidence. 16 ESGE/EASL suggest routine administration of prophylactic antibiotics before ERCP in patients with PSC.Strong recommendation, low quality evidence. 17 EASL/ESGE recommend that cholangiocarcinoma (CCA) should be suspected in any patient with worsening cholestasis, weight loss, raised serum CA19-9, and/or new or progressive dominant stricture, particularly with an associated enhancing mass lesion.Strong recommendation, moderate quality evidence. 19 ESGE/EASL recommend ductal sampling (brush cytology, endobiliary biopsies) as part of the initial investigation for the diagnosis and staging of suspected CCA in patients with PSC.Strong recommendation, high quality evidence.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Colangiocarcinoma/diagnóstico , Colangiografia/normas , Colangiopancreatografia Retrógrada Endoscópica/normas , Colangite Esclerosante/diagnóstico por imagem , Colangite Esclerosante/terapia , Imageamento por Ressonância Magnética/normas , Biópsia/normas , Colangite Esclerosante/patologia , Humanos , Esfinterotomia Endoscópica/normas
20.
Cochrane Database Syst Rev ; 4: CD012645, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28431197

RESUMO

BACKGROUND: The treatment of people with pancreatic necrosis differs from that of people with oedematous pancreatitis. It is important to know the diagnostic accuracy of serum C-reactive protein (CRP), serum procalcitonin, and serum lactate dehydrogenase (LDH) as a triage test for the detection of pancreatic necrosis in people with acute pancreatitis, so that an informed decision can be made as to whether the person with pancreatic necrosis needs further investigations such as computed tomography (CT) scan or magnetic resonance imaging (MRI) scan and treatment for pancreatic necrosis started. There is currently no standard clinical practice, although CRP, particularly an increasing trend of CRP, is often used as a triage test to determine whether the person requires further imaging. There is also currently no systematic review of the diagnostic test accuracy of CRP, procalcitonin, and LDH for the diagnosis of pancreatic necrosis in people with acute pancreatitis. OBJECTIVES: To compare the diagnostic accuracy of CRP, procalcitonin, or LDH (index test), either alone or in combination, in the diagnosis of necrotising pancreatitis in people with acute pancreatitis and without organ failure. SEARCH METHODS: We searched MEDLINE, Embase, Science Citation Index Expanded, National Institute for Health Research (NIHR HTA and DARE), and other databases until March 2017. We searched the references of the included studies to identify additional studies. We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. We also performed a 'related search' and 'citing reference' search in MEDLINE and Embase. SELECTION CRITERIA: We included all studies that evaluated the diagnostic test accuracy of CRP, procalcitonin, and LDH for the diagnosis of pancreatic necrosis in people with acute pancreatitis using the following reference standards, either alone or in combination: radiological features of pancreatic necrosis (contrast-enhanced CT or MRI), surgeon's judgement of pancreatic necrosis during surgery, or histological confirmation of pancreatic necrosis. Had we found case-control studies, we planned to exclude them because they are prone to bias; however, we did not locate any. Two review authors independently identified the relevant studies from the retrieved references. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, including methodological quality assessment, from the included studies. As the included studies reported CRP, procalcitonin, and LDH on different days of admission and measured at different cut-off levels, it was not possible to perform a meta-analysis using the bivariate model as planned. We have reported the sensitivity, specificity, post-test probability of a positive and negative index test along with 95% confidence interval (CI) on each of the different days of admission and measured at different cut-off levels. MAIN RESULTS: A total of three studies including 242 participants met the inclusion criteria for this review. One study reported the diagnostic performance of CRP for two threshold levels (> 200 mg/L and > 279 mg/L) without stating the day on which the CRP was measured. One study reported the diagnostic performance of procalcitonin on day 1 (1 day after admission) using a threshold level of 0.5 ng/mL. One study reported the diagnostic performance of CRP on day 3 (3 days after admission) using a threshold level of 140 mg/L and LDH on day 5 (5 days after admission) using a threshold level of 290 U/L. The sensitivities and specificities varied: the point estimate of the sensitivities ranged from 0.72 to 0.88, while the point estimate of the specificities ranged from 0.75 to 1.00 for the different index tests on different days of hospital admission. However, the confidence intervals were wide: confidence intervals of sensitivities ranged from 0.51 to 0.97, while those of specificities ranged from 0.18 to 1.00 for the different tests on different days of hospital admission. Overall, none of the tests assessed in this review were sufficiently accurate to suggest that they could be useful in clinical practice. AUTHORS' CONCLUSIONS: The paucity of data and methodological deficiencies in the studies meant that it was not possible to arrive at any conclusions regarding the diagnostic test accuracy of the index test because of the uncertainty of the results. Further well-designed diagnostic test accuracy studies with prespecified index test thresholds of CRP, procalcitonin, LDH; appropriate follow-up (for at least two weeks to ensure that the person does not have pancreatic necrosis, as early scans may not indicate pancreatic necrosis); and clearly defined reference standards (of surgical or radiological confirmation of pancreatic necrosis) are important to reliably determine the diagnostic accuracy of CRP, procalcitonin, and LDH.


Assuntos
Proteína C-Reativa/análise , Calcitonina/sangue , L-Lactato Desidrogenase/sangue , Pancreatite Necrosante Aguda/diagnóstico , Doença Aguda , Biomarcadores/sangue , Intervalos de Confiança , Diagnóstico Diferencial , Humanos , Pancreatite/sangue , Pancreatite/diagnóstico , Pancreatite/enzimologia , Pancreatite Necrosante Aguda/sangue , Pancreatite Necrosante Aguda/enzimologia , Sensibilidade e Especificidade
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