British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma.

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.

Introduction.

Cholangiocarcinoma (CCA) is a lethal cancer arising in the bile ducts within and just outside the liver. It occurs worldwide and falls into two etiologically defined groups, one related to chronic liver fluke infection and the other not. Liver fluke-related CCA is found in continental Southeast Asia (caused by Opisthorchis viverrini with infection leading to opisthorchiasis), East Asia (Clonorchis sinensis), and Eastern Europe and Russia (Opisthorchis felineus). Both O. viverrini and C. sinensis are classified as group one carcinogens, while recent data from O. felineus suggest the same. In Southeast Asia, an estimated 67.3 million people are at risk of O. viverrini infection and subsequently developing CCA. When the three liver fluke species are considered, an estimated 700 million people are at risk of infection and developing CCA globally. The northeast of Thailand (Isan) is the world's hot spot of liver fluke infection and CCA. Early detection, diagnosis, and surgical intervention/curative treatment of CCA are critical to increase life expectancy and quality of life of people in the region and globally. Despite concentrated recent efforts focusing on a multidisciplinary approach to understand the ecology, epidemiology, biology, public health, and social significance of infection by cancer causing liver flukes, it remains an underestimated and under-resourced public health problem. In addition, it is still believed to be a regional problem without global significance-this is not the case. This book focuses on O. viverrini as the main causative agent of CCA in Southeast Asia, but many aspects detailed in the following chapters also relate to the two other liver fluke species. Our aim is to produce a holistic framework including the basic biology of O. viverrini and its relation to the epidemiology of the disease through diagnosis to treatment, including palliative methods, pathology, and control.

Synopsis.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer worldwide. Despite the severity of the disease and its impact on individuals, families, and communities, there remains an overall lack of awareness and interest in this disease. The information contained in the chapters of this book shows that this is indeed a significant public health and socioeconomic problem with varying levels of country-specific awareness. In Southeast Asia liver fluke, O. viverrini related CCA is endemic with the highest incidence worldwide in northeast Thailand, yet it is treatable and preventable. The chapters highlight significant advances in our knowledge of the biology and epidemiology of the O. viverrini species complex, intermediate hosts, systematics, population genetics, and the complexity of the three-host life cycle. A comprehensive conceptual framework has been developed to assist in understanding the complexity of molecular mechanisms of CCA carcinogenesis and cancer development which can result in improvement of targeted CCA therapy. There have been many advances in understanding the pathology of CCA in the biliary tract, including advances in prognosis and molecular pathogenesis. The development of different modalities and their advantages for diagnosis have increased diagnostic accuracy, providing reliable information allowing appropriate treatment and management programs to be selected for each patient. Particularly exciting is the recent development of a urine antigen assay which has revolutionized the diagnostic approach of opisthorchiasis due to its simplicity, the non-invasive nature of sample collection, and its ease of use in field settings. Significant in-roads and advances have been made in the surgical and systemic treatment of CCA patients. Additionally, a sophisticated data collection and analysis system, the Isan Cohort, has been developed and established for the treatment and control of CCA. Importantly, a greater understanding has been made of the social, community, religious, and anthropological issues initiating and sustaining the eating behavior of raw, partially cooked, and/or fermented fresh water fish. Specially designed education programs/curricula, based on currently available multidisciplinary hard data targeting school children, have been introduced since the inception of the Cholangiocarcinoma Screening and Care Program (CASCAP) and the subsequent strategic Fluke Free Thailand Model. The education program is being expanded to other provinces in Thailand and in the near future to other Southeast Asian countries, initially to Lao PDR, where the Fluke Free Lao PDR program has already been implemented. Despite advances that have been made in many disciplines focused on O. viverrini related CCA, raising awareness of CCA at all levels, particularly across endemic regions, is still needed, as is raising the awareness of CCA globally. As parasites and parasite related diseases have no borders, it is critical that an effective common strategic plan is instigated and established between all countries where liver fluke, O. viverrini related CCA is a significant public health problem, thereby increasing the quality of life and life expectancy of millions of people who suffer from this insidious disease.

Current epidemiology of cholangiocarcinoma in Western countries.

Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths due to intrahepatic cancers are rising at a higher rate than deaths due to extrahepatic cancers. This may be due to rising cases of liver disease and misclassification of the different cancer types.

BMAT's predictive validity for medical school performance: A retrospective cohort study.

BACKGROUND: Although used widely, there is limited evidence of the BioMedical Admissions Test's (BMAT) predictive validity and incremental validity over prior educational attainment (PEA). We investigated BMAT's predictive and incremental validity for performance in two undergraduate medical schools, Imperial College School of Medicine (ICSM), UK, and Lee Kong Chian School of Medicine (LKCMedicine), Singapore. Our secondary goal was to compare the evidence collected with published evidence relating to comparable tools. METHODS: This was a retrospective cohort study of four ICSM (1188 students, entering 2010-2013) and three LKCMedicine cohorts (222 students, 2013-2015). We investigated associations between BMAT Section 1 ('Thinking Skills'), Section 2 ('Scientific Knowledge and Applications') and Section 3a ('Writing Task') scores, with written and clinical assessment performance across all programme years. Incremental validity was investigated over PEA (A-levels) in a subset of ICSM students. RESULTS: When BMAT sections were investigated independently, Section 2 scores predicted performance on all written assessments in both institutions with mainly small effect sizes (standardised coefficient ranges: ICSM: 0.08-0.19; LKCMedicine: 0.22-0.36). Section 1 scores predicted Years 5 and 6 written assessment performance at ICSM (0.09-0.14) but nothing at LKCMedicine. Section 3a scores only predicted Year 5 clinical assessment performance at ICSM with a coefficient <0.1. There were no positive associations with standardised coefficients >0.1 between BMAT performance and clinical assessment performance. Multivariable regressions confirmed that Section 2 scores were the most predictive. We found no clear evidence of incremental validity for any BMAT section scores over A-level grades. DISCUSSION: Schools who wish to assess scientific knowledge independently of A-levels may find BMAT Section 2 useful. Comparison with previous studies indicates that, overall, BMAT seems less useful than comparable tools. Larger scale studies are needed. Broader questions regarding why institutions adopt certain admissions tests, including those with little evidence, need consideration.

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis.

BACKGROUND & AIMS: Cholangiocarcinoma (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. METHODS: A 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. RESULTS: A 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). CONCLUSION: This 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. LAY SUMMARY: Cholangiocarcinoma (CCA) is a cancer arising in the bile ducts inside (intrahepatic CCA) and connected to the liver (extrahepatic CCA). It is a very aggressive cancer: 95% of patients die within 5 years. CCA rates are increasing globally, but the causes of CCA are poorly understood. The few risk factors that are known account for only a minority of cases. In this study, we found that the strongest risk factors for both intrahepatic and extrahepatic CCA are cysts and stones in the bile ducts, cirrhosis, and hepatitis B and C viruses. Some risk factors for CCA, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of CCA.

Cholangiocarcinoma: Epidemiology and risk factors.

Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host-specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co-occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide.

Discovery and validation of urinary metabotypes for the diagnosis of hepatocellular carcinoma in West Africans.

UNLABELLED: There is no clinically applicable biomarker for surveillance of hepatocellular carcinoma (HCC), because the sensitivity of serum alpha-fetoprotein (AFP) is too low for this purpose. Here, we determined the diagnostic performance of a panel of urinary metabolites of HCC patients from West Africa. Urine samples were collected from Nigerian and Gambian patients recruited on the case-control platform of the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) program. Urinary proton nuclear magnetic resonance ((1) H-NMR) spectroscopy was used to metabolically phenotype 290 subjects: 63 with HCC; 32 with cirrhosis (Cir); 107 with noncirrhotic liver disease (DC); and 88 normal control (NC) healthy volunteers. Urine samples from a further cohort of 463 subjects (141 HCC, 56 Cir, 178 DC, and 88 NC) were analyzed, the results of which validated the initial cohort. The urinary metabotype of patients with HCC was distinct from those with Cir, DC, and NC with areas under the receiver operating characteristic (AUROC) curves of 0.86 (0.78-0.94), 0.93 (0.89-0.97), and 0.89 (0.80-0.98) in the training set and 0.81 (0.73-0.89), 0.96 (0.94-0.99), and 0.90 (0.85-0.96), respectively, in the validation cohort. A urinary metabolite panel, comprising inosine, indole-3-acetate, galactose, and an N-acetylated amino acid (NAA), showed a high sensitivity (86.9% [75.8-94.2]) and specificity (90.3% [74.2-98.0]) in the discrimination of HCC from cirrhosis, a finding that was corroborated in a validation cohort (AUROC: urinary panel = 0.72; AFP = 0.58). Metabolites that were significantly increased in urine of HCC patients, and which correlated with clinical stage of HCC, were NAA, dimethylglycine, 1-methylnicotinamide, methionine, acetylcarnitine, 2-oxoglutarate, choline, and creatine. CONCLUSION: The urinary metabotyping of this West African cohort identified and validated a metabolite panel that diagnostically outperforms serum AFP.

Comparing robotic, laparoscopic and open cystectomy: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis comparing outcomes between Open Radical Cystectomy (ORC), Laparoscopic Radical Cystectomy (LRC) and Robot-assisted Radical Cystectomy (RARC). RARC is to be compared to LRC and ORC and LRC compared to ORC. MATERIAL AND METHODS: A systematic review of the literature was conducted, collating studies comparing RARC, LRC and ORC. Surgical and oncological outcome data were extracted and a meta-analysis was performed. RESULTS: Twenty-four studies were selected with total of 2,104 cases analyzed. RARC had a longer operative time (OPT) compared to LRC with no statistical difference between length of stay (LOS) and estimated blood loss (EBL). RARC had a significantly shorter LOS, reduced EBL, lower complication rate and longer OPT compared to ORC. There were no significant differences regarding lymph node yield (LNY) and positive surgical margins (PSM.) LRC had a reduced EBL, shorter LOS and increased OPT compared to ORC. There was no significant difference regarding LNY. CONCLUSION: RARC is comparable to LRC with better surgical results than ORC. LRC has better surgical outcomes than ORC. With the unique technological features of the robotic surgical system and increasing trend of intra-corporeal reconstruction it is likely that RARC will become the surgical option of choice.

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case-control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran-Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10(-4) (rs3815676) and for ABCB4 it was 4.6×10(-7)(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.

Live surgical education: a perspective from the surgeons who perform it.

OBJECTIVE: To evaluate the experience and views regarding live surgical broadcasts (LSB) among European urologists attending the European Association of Urology Robotic Urology Society (ERUS) congress in September 2012. MATERIALS AND METHODS: An anonymous survey was distributed via email inviting the participants of the ERUS congress with experience of LSB to share their opinions about LSB. The outcomes measured included; personal experience of LSB, levels of anxiety faced and the perceived surgical quality. The impact of factors, such as communication/team-working, travel fatigue and lack of specific equipment were also evaluated. RESULTS: In all, 106 surgeons responded with 98 (92.5%) reporting personal experience of LSB; 6.5% respondents noted 'significant anxiety' increasing to 19.4% when performing surgery away from home (P < 0.001). Surgical quality was perceived as 'slightly worse' and 'significantly worse' by 16.1% and 2.2%, which deteriorated further to 23.9% and 3.3% respectively in a 'foreign' environment (P = 0.005). In all, 10.9% of surgeons 'always' brought their own surgical team compared with 37% relying on their host institution; 2.4% raised significant concerns with their team and 18.8% encountered significantly more technical difficulties. Lack of specific equipment (10.3%), language difficulties (6.2%) and jet lag (7.3%) were other significant factors reported. In all, 75% of surgeons perceived the audience wanted a slick demonstration; however, 52.2% and 42.4% respectively also reported the audience wished the surgeon to struggle or manage a complication during a LSB. CONCLUSIONS: A small proportion of surgeons had significantly heightened anxiety levels and lower perceived performance during LSB, which in a 'foreign' environment seemed to affect a greater proportion of surgeons. Various factors appear to impact surgical performance raising concerns about the appropriateness of unregulated LSB as a teaching method. To mitigate these concerns, surgeons' performing live surgery feel that the operation needs to be well planned using appropriate equipment; with many considering bringing their own team or operating from home on a video link.

Routine but risky: a multi-centre analysis of the outcomes of cranioplasty in the Northeast of England.

BACKGROUND: Cranioplasty is undertaken as a routine secondary operation following craniectomy. At a time when decompressive craniectomy is being evaluated by several large trials, we aimed to evaluate the morbidity associated with cranioplasty and investigate its potential effect on outcome. METHODS: The outcomes of 166 patients undergoing cranioplasty at two centres in the United Kingdom between June 2006 and September 2011 were retrospectively analysed. Outcome measures included mortality, morbidity and functional outcome determined by the modified Rankin score (mRS) at last follow-up. A logistic regression analysis was performed to model and predict determinants related to neurological outcome following cranioplasty. RESULTS: Sixty-seven out of 166 patients (40.4 %) experienced at least one complication during a median follow-up time of 15 months (inter-quartile range 5-38 months). Thirty six patients (21.7 %) developed infection requiring antibiotics, with 27 (16.3 %) requiring removal of the cranioplasty. Nine of 25 patients (36 %) with bi-frontal defects developed an infection whereas 21 of the 153 patients (16.4 %) with a defect other than bi-frontal developed an infection (Chi square p = 0.009). Further surgery in the two groups was required in 16.4 % and 11.7, % respectively. Pseudomeningocoele (9 %), seizures (8.4 %) and poor cosmesis (7.2 %) were also commonly observed. Logistic regression analysis identified initial operation (p < 0.03), mRS at the time of cranioplasty (p < 0.0001) and complications (p < 0.04) as being predictive of neurological outcome at last follow-up. Age at the time of cranioplasty and the timing of cranioplasty were not predictive of last mRS score at follow-up. CONCLUSIONS: Cranioplasty harbours significant morbidity, a risk that appears to be higher with a bifrontal defect. The complications experienced influence subsequent functional outcome. The timing of cranioplasty, early or late, after the initial operation does not impact on the ultimate outcome. These findings should be considered when making decisions relating to craniectomy and cranioplasty.

Iatrogenic vertebral artery injury secondary to vessel tortuosity in a grossly degenerate cervical spine.

Iatrogenic vertebral artery (VA) injury is a rare but significant complication of anterior cervical spine surgery. In the grossly degenerate cervical spine the VA may adopt a tortuous pathway thus predisposing to inadvertent injury during surgery. Here we illustrate such a case and discuss potential management strategies.

Cholangiocarcinoma across England: Temporal changes in incidence, survival and routes to diagnosis by region and level of socioeconomic deprivation.

Background & Aims: While cholangiocarcinoma (CCA) incidence and mortality rates are increasing globally, whether there are regional/temporal variations in these rates for different biliary tract cancer (BTC) subtypes, or whether they differ by sex, socioeconomic status, or route to diagnosis (RtD) remains unknown. In this work, we aimed to perform an in-depth analysis of data on the incidence, mortality, survival and RtD of CCA and other BTCs. Methods: Data on all BTCs diagnosed in England between 2001 and 2018 were extracted from NHS Digital's National Cancer Registration Dataset. Age-standardised incidence rates (ASRs), mortality rates (ASMRs) and net survival rates were calculated, and Kaplan-Meier overall survival estimates and RtD trends were analysed. Analyses were stratified by sex, socioeconomic deprivation, tumour subtype and region. Results: The ASR for CCA rose from 2.9 in 2001-2003 to 4.6 in 2016-2018 and from 1.0 to 1.8 for gallbladder cancers (GBCs). ASMR trends mirror those of incidence, with most deaths due to iCCA. Over 20% of patients with CCA were under 65 years old. The ASRs and ASMRs were consistently higher in the most socioeconomically deprived group for CCA and GBC. The most common RtD was the emergency route (CCA 49.6%, GBC 46.2% and ampulla of Vater cancer 43.0%). The least deprived patients with CCA and ampulla of Vater cancer had better overall survival (p <0.001). Net survival rates rose for all BTCs, with 3-year net survival for CCA increasing from 9.2% in 2001 to 12.6% in 2016-2018. There was notable geographical variation in ASRs, ASMRs and net survival for all BTCs. Conclusions: BTC incidence and mortality rates are increasing, with differences observed between tumour types, socioeconomic deprivation groups, RtDs and geographical regions. This highlights the need for targeted interventions, earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals. Impact and implications: Cholangiocarcinoma (CCA) incidence and mortality rates are rising globally, particularly for intrahepatic CCA. However, it has not previously been reported if, within a single country, there are temporal and regional differences in incidence, mortality and survival rates for different biliary tract subtypes, and whether these differ by sex, socioeconomic status, or route of diagnosis. In this study we show that mortality rates for patients with CCA continue to rise and are almost 40% higher in the most socioeconomically deprived compared to the least; additionally, we observed regional variation within England in incidence, mortality and survival. This study is relevant to researchers and policy makers as it highlights regional variation and inequality, as well as emphasising the need for earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals.

Endoscopic radiofrequency ablation for cholangiocarcinoma.

PURPOSE OF REVIEW: To describe the use of endobiliary radiofrequency ablation (RFA) in the treatment of malignant disease of the bile duct and offer a comprehensive review of the emerging evidence on the safety and effectiveness of this new technique. RECENT FINDINGS: Ex-vivo and in-vivo porcine studies have been reported, confirming the feasibility of the technique, gathering preliminary safety data and defining appropriate power settings for human studies. Moderate-sized case series have now reported the use of RFA in mixed cohorts of human individuals with pancreatic cancer, cholangiocarcinoma and other malignant diseases of the bile duct. Endoscopic and percutaneous approaches have both been investigated. Small case series of blocked self-expanding metal stent clearance using RFA have been published. SUMMARY: Intraductal RFA, via both endoscopic and percutaneous approaches, is feasible. Complication rates appear to be comparable with the current standard endoscopic and percutaneous approaches to palliation of malignant strictures of the bile duct. The current body of literature is germinal, but warrants the further investigation of planned clinical trials.

Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.

The British Society of Gastroenterology guidelines on the management of cholangiocarcinoma were originally published in 2002. This is the first update since then and is based on a comprehensive review of the recent literature, including data from randomised controlled trials, systematic reviews, meta-analyses, cohort, prospective and retrospective studies.

Epidemiology of cholangiocarcinoma.

Cholangiocarcinoma (CCA) represents a heterogenous set of malignancies arising from the biliary tract. Classification of CCA subdivides tumours into intrahepatic (iCCA) and extrahepatic (eCCA), with eCCA further categorised as perihilar (pCCA) and distal (dCCA) lesions. Tumour subtypes show distinct epidemiological, genetic and clinical characteristics. Global incidence and mortality are rising, with the highest rates seen in Asian populations compared to the West. There has been a divergence in recent mortality trends observed between CCA subtypes, with rising rates of iCCA seen compared with eCCA. There are several drivers for these differing trends, including specific risk factors, misclassification of CCA subtypes and variation in diagnosis and surveillance. Risk factors for CCA can be divided into hepatobiliary, extra-hepatic and environmental, with hepatobiliary diseases conferring the largest risk. Surgery represents the only curative treatment for CCA, but can only be offered to early-stage candidates who are otherwise fit; the majority of patients are therefore treated with chemotherapy and, recently, immunotherapy. Due to late-stage presentation of disease, prognosis is poor, with 5-year survival <20%.