139 results found
Vithayathil M, Bridgewater J, Khan SA, 2021, Medical therapies for intra-hepatic cholangiocarcinoma, JOURNAL OF HEPATOLOGY, Vol: 75, Pages: 981-983, ISSN: 0168-8278
Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes.
Pericleous M, Khan SA, 2021, Epidemiology of HPB malignancy in the elderly, EJSO, Vol: 47, Pages: 503-513, ISSN: 0748-7983
Selvadurai S, Mann K, Mithra S, et al., 2021, Cholangiocarcinoma miscoding in hepatobiliary centres, EJSO, Vol: 47, Pages: 635-639, ISSN: 0748-7983
Abeles R, Foxton M, Khan S, et al., 2020, Androgenic Anabolic Steroid induced liver injury: 2 cases reports assessed for causality by the updated Roussel Uclaf Causality Assessment Method (RUCAM) score and a comprehensive review of the literature, BMJ Open Gastroenterology, Vol: 7, ISSN: 2054-4774
Background Anabolic androgenic steroids (AAS) usage is widespread and increasing. AAS drug-induced liver injury (DILI) is recognised but its clinical course and management is poorly described. We report 2 cases of AAS DILI with associated renal dysfunction, managed successfully with oral corticosteroids.Methods A comprehensive review identified 50 further cases to characterise the clinical and biochemical course. Causality grading was calculated using the updated Roussel Uclaf Causality Assessment Method (RUCAM) score. Data are presented as median values.Results The most common AAS taken was methyldrostanolone. Patients commonly present with jaundice and pruritus but may exhibit other constitutional symptoms. Patients presented 56 days after starting, and bilirubin peaked 28 days after stopping, AAS. Causality assessment was ‘unlikely’ in 1 (2%), ‘possible’ in 31 (60%) and ‘probable’ in 20 (38%). Peak values were: bilirubin 705 μmol/L, alanine transaminase 125 U/L, aspartate transaminase 71 U/L, alkaline phosphatase 262 U/L, gamma-glutamyl transferase 52 U/L, international normalised ratio 1.1. Liver biopsies showed ‘bland’ canalicular cholestasis. 43% of patients developed kidney injury (peak creatinine 225 μmol/L). Therapies included antipruritics, ursodeoxycholic acid and corticosteroids. No patients died or required liver transplantation.Conclusions Physicians are likely to encounter AAS DILI. Causality assessment using the updated RUCAM should be performed but defining indications and proving efficacy for therapies remains challenging.
Banales JM, Marin JJG, Lamarca A, et al., 2020, Cholangiocarcinoma 2020: the next horizon in mechanisms and management, NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, Vol: 17, Pages: 557-588, ISSN: 1759-5045
Khan SA, Clements O, Kim JU, et al., 2020, Reply to: 'Letter regarding [Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis]', JOURNAL OF HEPATOLOGY, Vol: 72, Pages: 1217-1217, ISSN: 0168-8278
Dumenci O, U AMR, Khan S, et al., 2020, Exploring metabolic consequences of CPS1 and CAD dysregulation in hepatocellular carcinoma by network reconstruction, Journal of Hepatocellular Carcinoma, Vol: 7, Pages: 1-9, ISSN: 2253-5969
Purpose: Hepatocellular carcinoma (HCC) is the fourth commonest cause of cancer-related mortality; it is associated with various genetic alterations, some involved in metabolic reprogramming. This study aimed to explore the potential metabolic impact of Carbamoyl Phosphate Synthase I (CPS1) and carbamoyl phosphate synthetase/aspartate transcarbamoylase/dihydroorotase (CAD) dysregulation through the reconstruction of a network that integrates information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, Human Metabolome Database (HMDB) and Human Protein Atlas (HPA). Methods and Results: Existing literature was used to determine the roles of CPS1 and CAD in HCC. CPS1 downregulation is thought to play a role in hepatocarcinogenesis through an increased glutamine availability for de novo pyrimidine biosynthesis, which CAD catalyzes the first three steps for. KEGG, HMDB and HPA were used to reconstruct a network of relevant pathways, demonstrating the relationships between genes and metabolites using the MetaboSignal package in R. The network was filtered to exclude any duplicates, and those greater than three steps away from CPS1 or CAD. Consequently, a network of 18 metabolites, 28 metabolic genes and 1 signaling gene was obtained, which indicated expression profiles and prognostic information of each gene in the network.Conclusion: Information from different databases was collated to form an informative network that integrated different ‘-omics’ approaches, demonstrating the relationships between genetic and metabolic components of urea cycle and the de novo pyrimidine biosynthesis pathway. This study paves the way for further research by acting as a template to investigate the relationships between genes and metabolites, explore their potential roles in various diseases and aid the development of new screening and treatment methods through network reconstruction.
Clements O, Eliahoo J, Kim JU, et al., 2020, Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis, Journal of Hepatology, Vol: 72, Pages: 95-103, ISSN: 0168-8278
Background & AimsCholangiocarcinoma (CCA) carries a poor prognosis, is increasing in incidence and its causes are poorly understood. Although some risk factors are known, they vary globally and collectively account for a minority of cases. The aim of this study was to perform a comprehensive meta-analysis of risk factors for intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), from Eastern and Western world studies.MethodsA literature search of case-control studies was performed to identify potential risk factors for iCCA and eCCA. Pooled odds ratios (ORs) with 95% CIs and heterogeneity were calculated. Funnel plots were used to assess publication bias, and meta-regression was used to select risk factors for comparison between Eastern and Western studies.ResultsA total of 13 risk factors were selected from 25 case-control studies in 7 geographically diverse countries. The strongest risk factors for both iCCA and eCCA were biliary cysts and stones, cirrhosis, hepatitis B and hepatitis C. Choledochal cysts conferred the greatest risk of both iCCA and eCCA with pooled ORs of 26.71 (95% CI 15.80–45.16) and 34.94 (24.36–50.12), respectively. No significant associations were found between hypertension and obesity for either iCCA or eCCA. Comparing Eastern and Western populations, there was a difference for the association of hepatitis B with iCCA (coefficient = −0.15195; 95% CI −0.278 to −0.025; p = 0.022).ConclusionThis is the most comprehensive meta-analysis of CCA risk factors to date. Some risk factors, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of this cancer.
Khan SA, Genus T, Morement H, et al., 2019, Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma, JOURNAL OF HEPATOLOGY, Vol: 71, Pages: 1261-1262, ISSN: 0168-8278
Youssaf A, Kim J, Eliahoo J, et al., 2019, Ablative therapy for unresectable intrahepatic cholangiocarcinoma: A systematic review and meta-analysis, Journal of Clinical and Experimental Hepatology, Vol: 9, Pages: 740-748, ISSN: 0973-6883
Background: Intrahepatic cholangiocarcinoma (iCCA) is usually a fatal malignancy with rising incidence globally. Surgical resection currently remains the only curative treatment. However, as only a minority of iCCA are amenable to resection, new therapeutic modalities are needed. Aims: Our aims were to systematically review and perform a meta-analysis on the existing literature regarding the use of ablative therapies in iCCA; and to assess their efficacy as a treatment modality by calculating pooled survival results and investigate associations between prognostic factors and survival. Methods: A comprehensive search of the PubMed database for relevant articles was performed. Studies assessing survival in patients with iCCA undergoing ablation were included. Data were extracted on patient, tumour and treatment characteristics and survival. Random effects meta-analysis was used to pool the data. Galbraith plots were used to investigate heterogeneity; bubble plots were formulated using regression-based meta-analysis. Results: 10 studies were included in the final analysis, yielding an aggregate of 206 patients (69.5% male, median age 51.2-72.5) and 320 tumours. 70.4% of patients were recurrent cases of iCCA and 29.6% primary iCCA. Median overall survival ranged from 8.7 to 52.4 months. Pooled survival rates for 1, 3 and 5-year survival were 76% (95% CI: 68-83%), 33% (21-44%) and 16% (7-26%), respectively. No significant association was found between the median age, number of tumours or median tumour size and 1-year survival. Conclusion: Ablative therapies display promising potential as treatment modalities for iCCA. However, further research is necessary to validate these findings.
Howell J, Atkinson SR, Pinato DJ, et al., 2019, Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma, European Journal of Cancer, Vol: 116, Pages: 56-66, ISSN: 0959-8049
BACKGROUND: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.
Khan SA, Tavolari S, Brandi G, 2019, Cholangiocarcinoma: Epidemiology and risk factors, LIVER INTERNATIONAL, Vol: 39, Pages: 19-31, ISSN: 1478-3223
Toledano M, Mukherjee S, Howell J, et al., 2019, The emerging burden of liver disease in cystic fibrosis patients: a UK nationwide study, PLoS ONE, Vol: 14, ISSN: 1932-6203
ObjectiveCystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of CFLD in the UK using national registry data and identify risk factors for progressive disease.MethodsA longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008–2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression.ResultsPrevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008–2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5–53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis.ConclusionsThis study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.
Wadsworth CA, Dixon PH, Taylor-Robinso SD, et al., 2019, Polymorphisms in natural killer cell receptor protein 2D (NKG2D) as a risk factor for Cholangiocarcinoma, Journal of Clinical and Experimental Hepatology, Vol: 9, Pages: 171-175, ISSN: 0973-6883
Background and aims: Understanding of the significant genetic risk factors for Cholangiocarcinoma (CC) remains limited. Polymorphisms in the natural killer cell receptor G2D (NKG2D) gene have been shown to increase risk of CC transformation in patients with Primary Sclerosing Cholangitis (PSC). We present a validation study of NKG2D polymorphisms in CC patients without PSC. Methods: Seven common Single Nucleotide Polymorphisms (SNPs) of the NKG2D gene were genotyped in 164 non-PSC related CC subjects and 257 controls with HaploView. The two SNPs that were positively identified in the previous Scandinavian study, rs11053781 and rs2617167, were included. Results: The seven genotyped SNPs were not associated with risk of CC. Furthermore, haplotype analysis revealed that there was no evidence to suggest that any haplotype differs in frequency between cases and controls (P > 0.1). Conclusion: The common genetic variation in NKG2D does not correlate significantly with sporadic CC risk. This is in contrast to the previous positive findings in the Scandinavian study with PSC-patients. The failure to reproduce the association may reflect an important difference between the pathogenesis of sporadic CC and that of PSC-related CC. Given that genetic susceptibility is likely to be multifaceted and complex, further validation studies that include both sporadic and PSC-related CC are required.
Appleby R, Moghul I, Khan S, et al., 2019, Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: a prospective observational study, PLoS ONE, Vol: 14, ISSN: 1932-6203
BackgroundNon-alcoholic fatty liver disease (NAFLD) may be associated with changes in bile acid (BA) metabolism. Hepatic BA production, measured by serum levels of the precursor 7α-hydroxy-4-cholesten-3-one (C4), is regulated by the farnesoid-X-receptor (FXR)-dependent ileal hormone fibroblast growth factor 19 (FGF19). Low FGF19 and high C4 are features of chronic BA diarrhea. Obeticholic acid, an FXR agonist, stimulates FGF19 and has shown therapeutic potential in both BA diarrhea and in NAFLD. We hypothesized there are associations of FGF19, C4 and BA diarrhea with NAFLD.Methods and findings127 patients with known NAFLD were recruited prospectively. Clinical features, including metformin use, markers of NAFLD severity and BA synthesis were analyzed. The overall incidence of chronic diarrhea was 25%, with features of BA diarrhea in 12%. FGF19 negatively correlated with C4 (rs = -0.43, p = 0.001) and with alanine aminotransferase (rs = -0.22, p = 0.03), but not with either NAFLD fibrosis or Fibroscan scores. High C4 was associated with a higher NAFLD fibrosis score (p < 0.05), and with diarrhea (p = 0.001). The median NAFLD fibrosis score was higher in those with diarrhea (p = 0.002). Metformin use, in 44% overall, was particularly associated with diarrhea (in 36% vs 17%, p = 0.02), and a lower median FGF19 (74 vs 105 pg/mL, p < 0.05).ConclusionsIncreased hepatic BA production and diarrhea, but not low FGF19, were associated with increased NAFLD fibrosis score, indicating dysregulation of the FXR-FGF19 axis and suggesting hepatic FGF19 resistance. Metformin use was an important factor in a subgroup, lowering FGF19, and resulting in bile acid diarrhea.
Howell J, Atkinson SR, Pinato DJ, et al., 2018, Identification of mutations in circulating cell-free tumor DNA as a prognostic biomarker in hepatocellular carcinoma, Publisher: WILEY, Pages: 29-29, ISSN: 0815-9319
Shabeer LL, Khan SA, 2018, MEDICAL STUDENTS' PERCEPTION OF UNDERGRADUATE HEPATOLOGY TEACHING IN THE UK - A NATIONAL SURVEY, Annual General Meeting of the British-Society-of-Gastroenterology, Publisher: BMJ PUBLISHING GROUP, Pages: A278-A278, ISSN: 0017-5749
Rizvi S, Khan SA, Hallemeier CL, et al., 2018, Cholangiocarcinoma - evolving concepts and therapeutic strategies, NATURE REVIEWS CLINICAL ONCOLOGY, Vol: 15, Pages: 95-111, ISSN: 1759-4774
Forlano R, Manousou P, Mullish BH, et al., 2017, Assessment of non invasive markers of fibrosis against collagen quantitation and NASH-CRN scoring in liver biopsies of NAFLD patients, The AASLD Liver Meeting 2017, Publisher: Wiley, Pages: 334A-334A, ISSN: 0270-9139
Mullish BH, Forlano R, Yee M, et al., 2017, Development of an algorithm for the prediction of cardiovascular events in patients with NAFLD: the role of mean platelet volume, The AASLD Liver Meeting 2017, Publisher: Wiley, Pages: 1175A-1176A, ISSN: 0270-9139
Kumar N, Khamri W, Sadiq F, et al., 2017, Circulating Natural Killer cells in Hepatocellular Carcinoma are hypofunctional with an exhausted phenotype, 68th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 355A-355A, ISSN: 0270-9139
Hughes T, O'Connor T, Namwat N, et al., 2017, Opisthorchiasis and cholangiocarcinoma in South East Asia: an unresolved problem, International Journal of General Medicine, Vol: 2017, Pages: 227-237, ISSN: 1178-7074
The prevalence of cholangiocarcinoma (CCA) in Southeast Asia is much higher than other areas of the world. Eating raw, fermented or undercooked cyprinid fish, infected with the liver fluke, Opisthorchis viverrini sensu lato, results in chronic biliary inflammation, periductal fibrosis, and increased cancer risk. There may be associated glomerulonephritis. The process of infection is difficult to disrupt because eating practices have proven extremely difficult to change, and the life cycle of the fluke cannot be broken due to high prevalence in canine and feline reservoir hosts. Fecal analysis and ELISA tests can be used to diagnose opisthorchiasis. Diagnosis of CCA is complex, partly due to the lack of definitive imaging characteristics and also due to the difficulty of obtaining samples for cytology or histology. This cancer has proven to be resistant to common chemotherapy treatments and so the two avenues of treatment available are surgical resection and liver transplantation, both requiring early detection of the tumor for the best chances of success. Late presentation of symptoms reduces the chances of successful surgical intervention. While liver fluke infections can be treated with praziquantel, individuals will often become re-infected, and multiple reinfections can be more harmful than a singular, long term infection. A key research need is for the detection and characterization of novel biomarkers in all parts of the carcinogenic pathway for early diagnosis.
Carruthers J, Bottle R, Laverty AA, et al., 2017, Nation-wide trends in non-alcoholic steatohepatitis (NASH) in patients with and without diabetes between 2004-05 and 2014-15 in England, Diabetes Research and Clinical Practice, Vol: 132, Pages: 102-107, ISSN: 1872-8227
AimsThere are no national studies evaluating the epidemiology of non-alcoholic steatohepatitis (NASH) in England. NASH is becoming an increasingly important health issue given the inexorable rise in obesity and diabetes. We evaluated the rates of NASH in people with and without diabetes from 2004–2005 to 2014–2015.MethodsWe identified cases of biopsy-proven NASH in people with and without diabetes in England over an eleven-year period using Hospital Episode Statistics. We estimated incidence rates for each year. Negative binomial regression models were fitted to test trends.ResultsOver the study period, people without diabetes recorded a 3% reduction in admission rates per year (incidence rate ratio (IRR) (95% CI) 0.97 (0.96–0.98), p < 0.001), whilst there was an increase in admission rates in people with diabetes (IRR (95% CI) 1.01 (1.00–1.02), p = 0.04). In people with diabetes, this upward trend was driven by people over 65 years (IRR (95% CI) 1.03 (1.02–1.04), p < 0.001) and men (IRR (95% CI) 1.01 (1.0–1.02), p = 0.03). Inpatient mortality declined for people with diabetes by 2% per year after adjusting for age, sex and year (IRR (95% CI) 0.98 (0.95–0.99), p = 0.03). The 2% decline per year in inpatient mortality for people without diabetes did not achieve statistical significance after adjustment (IRR (95% CI) 0.98 (0.95–1.01), p = 0.175).ConclusionsThere was a decline in NASH-related hospital admissions amongst people without diabetes over eleven years, whilst rates increased in people with diabetes. These observations highlight the increasing burden of NASH.
Mullish BH, Forlano R, Yee M, et al., 2017, Development Of An Algorithm For The Prediction Of Cardiovascular Events In Patients With NAFLD: The Role Of Mean Platelet Volume., BASL 2017 Annual Meeting
Khan SA, McClements S, Reccia I, et al., 2017, The next generation of hepatocellular cancer experts: what do they think?, Hepatic Oncology, Vol: 3, Pages: 213-215, ISSN: 2045-0923
Forlano R, Mullish BH, Angkathunyakul N, et al., 2017, PWE-094 The severity of steatosis does not influence liver stiffness measurements in patients with non-alcoholic fatty liver disease, British Society of Gastroenterology Annual Meeting, Publisher: BMJ Publishing Group, Pages: A174-A174, ISSN: 1468-3288
Forlano R, Maurice J, Mullish BH, et al., 2017, The severity of steatosis does not influence liver stiffness measurements in patients with Non-Alcoholic Fatty Liver Disease, International Liver Conference, Publisher: Elsevier, Pages: S586-S587, ISSN: 0169-5185
Carruthers J, Bottle R, Laverty AA, et al., 2017, Nationwide trends in non-alcoholic steatohepatitis in patients with and without diabetes between 2004 and 2014 in England, Diabetes UK Annual Professional Conference, Publisher: Wiley, Pages: 67-67, ISSN: 1464-5491
Howell JA, Khan SA, Knapp S, et al., 2016, The clinical role of circulating free tumor DNA in gastrointestinal malignancy, Translational Research, Vol: 183, Pages: 137-154, ISSN: 1931-5244
Circulating cell-free DNA (cfDNA) is DNA released from necrotic or apoptotic cells into the bloodstream. While both healthy cells and cancer cells release cfDNA, tumors are associated with higher levels of tumor-derived circulating cell-free DNA (ctDNA) detectable in blood. Absolute levels of ctDNA and its genetic mutations and epigenetic changes show promise as potentially useful biomarkers of tumor biology, progression, and response to therapy. Moreover, studies have demonstrated the discriminative accuracy of ctDNA levels for diagnosis of gastrointestinal cancer compared with benign inflammatory diseases. Therefore, ctDNA detected in blood offers a minimally invasive and easily repeated "liquid biopsy" of cancer, facilitating real-time dynamic analysis of tumor behavior that could revolutionize both clinical and research practices in oncology. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in gastrointestinal malignancies.
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