Chasing up colorectal cancer

CRC claims more than 200,000 lives in Europe alone.

Each year, Europe’s second biggest cancer killer—colorectal cancer (CRC)—claims more than 200,000 lives in Europe alone; yet, early detection may result in a 90–95% survival rate. Implementation of CRC screening programmes across Europe is booming, but what are the nuts and bolts of a good CRC screening programme?

A press release issued by UEG in March 2014 warned that the annual incidence of CRC is predicted to have risen 12% by 2020, at which time it will potentially affect about half a million Europeans.1 CRC is currently the second and third most common cancer in European women and men, respectively, and accounts for 13% of all cancer-related deaths in Europe, resulting in one fatality every 3 minutes. Screening programmes have been implemented in several countries with a view to reducing morbidity and mortality by identifying and treating cases of early-stage CRC. It’s almost a year since a nationwide CRC screening programme was launched in Denmark, with an annual budget of approximately €50M. Starting in March 2014, all Danish citizens aged 50–74 years old are invited to participate in biannual screening.2 Those individuals who are willing to participate receive a screening kit by regular mail, and the test is free and voluntary to complete. The CRC screening programme uses a faecal occult blood (FOB) test (FOBT), and individuals with a positive FOBT are offered a colonoscopy. The Danish screening programme was implemented on the basis of a feasibility study carried out in 2005–2006, in which 2–3% of those screened tested positive for the presence of FOB; of these, 8% and 40% were found to have cancer and polyps, respectively, as demonstrated by colonoscopy.3 In the feasibility study, a chemical test with a sensitivity of only 60% was used. In the ongoing screening programme, however, the faecal immunochemical test (FIT; also known as an immunochemical FOBT) is being used, which is expected to increase sensitivity. Meanwhile, high FIT sensitivity and specificity may be difficult to achieve given the fact that not all CRCs bleed and there are causes of FOB other than cancer and polyps; hence, quite a few false-negatives and false-positives may still be expected with the FIT. Of course, there’s more to achieving a successful screening programme than safeguarding best possible intervention options and optimizing diagnostic performance parameters, such as test cut-off and predictive values. The very nature of the test itself, how the screening programme is presented to the public and overall public health awareness are all factors potentially influencing the success of a screening programme. In the case of CRC, the mere thought of having a colonoscopy may scare people off, and public health awareness may differ substantially between countries, both of which are factors that may significantly affect uptake and thereby overall success rates. Sometimes there are differences in the willingness to participate within the same country that have no obvious explanation. For example, as pointed out by Björn Rembacken in his talk on CRC screening strategies in the West, a striking difference in the uptake rate has been observed in Belgium, where the Flemish appear much more keen on participating than the Walloons.4 In the Danish feasibility study, women were more likely to participate, as were those with higher education and higher income.5 Moreover, a study carried out by The Danish Cancer Society suggests that it takes time for a population to adjust to thinking and speaking of CRC.6 In this study, the most common barriers to accepting screening invitations included:
  • Not wanting to know whether they have CRC
  • Thinking that the test is too awkward to do
  • The need for more information
  • Developing a sense of being ill merely by being offered the test
  • Feeling too old for the test to be relevant
Apart from mitigating issues that have to do with culture and tradition, by removing stigma and taboos through campaigns and the provision of information, what diagnostic tools can be developed to minimize the number of cases with a positive result for FOB but negative findings on colonoscopy? How far are we in terms of developing other non-invasive biomarkers, such as those based on microbiota signatures7 or DNA methylation, for the detection of both CRC and critical precursor lesions? To which extent may individual risk assessment replace invasive and semi-invasive diagnostic methods in terms of identifying patients with early CRC? The UEG Education Library boasts a large catalogue of presentations, abstracts and syllabi focusing on early detection of CRC as a means of improving patient survival and widening the window of therapeutic intervention. For instance, if you want to familiarise yourself with the current status of CRC screening programmes throughout Europe, simply sign in to myUEG, go the Library and search for “CRC AND screening”. I also recommend listening to the presentations included in the session on “Colorectal cancer screening: the future” from UEG Week 2014 (see Further UEG Resources below). References
  1. UEG Press Release. Europe is falling behind America in the fight against colorectal cancer due to low screening uptake. (March 2014, accessed February 2015).
  2. Danish Cancer Society. Screening for colon cancer. (2014, accessed February 2015)
  3. Research Centre for Prevention and Health—The Capital Region of Denmark. Screening for colorectal cancer in the counties of Vejle and Copenhagen—cross evaluation of pilot studies. [Article in Danish]
  4. Rembacken B. CRC screening strategies. Presentation in the East meets West: CRC Screening Strategies session at UEG Week 2013 
  5. Frederiksen BL, Jørgensen T, Brasso K, et al. Socioeconomic position and participation in colorectal cancer screening. Br J Cancer 2010; 103: 1496—1501.
  6. Meyer M. Department of Prevention and Documentation. The Danish Cancer Society. What were the barriers for participating in colorectal cancer screening? A qualitative and quantitative analysis of non-participant barriers to participating in a pilot colorectal cancer screening programme in Vejle and Copenhagen in 2005 and 2006. (April 2007) [Article in Danish].
  7. National Cancer Institute. Analyzing the gut microbiome to help detect colorectal cancer. (January 2015, accessed February 2015)
Further UEG resources “Colorectal cancer screening: The future” session at UEG Week 2014. Fight against colorectal cancer.  Colorectal cancer in Europe. Colorectal cancer incidence and mortality in Europe.  Colorectal cancer – how to spot the symptoms.

The sessile serrated polyp

It is there if you look for it.

Until 1996, serrated polyps were all classified as ‘hyperplastic polyps’ and the larger ones simply as ‘giant hyperplastic polyps’ or ‘variant hyperplastic polyps’. More recently it became evident that serrated polyps do have malignant potential and may be why colonoscopy does not protect well against future right-sided cancer. Much research into their molecular characteristics, clinical features, and malignant potential followed.

Four types of serrated polyp are now recognized. Normal hyperplastic polyps (HPs) are usually small and left sided. Traditional serrated adenomas (TSAs) are also usually left sided, but they are larger than HPs, sometimes pedunculated and have a crypt pattern reminiscent of villous adenomas. Sessile serrated polyps (SSA/Ps) are usually right sided, ≥10mm in diameter and they are sometimes covered with particularly large crypt openings. There are also the unclassified serrated polyps, which tend to be left sided and ≥5mm in diameter.  According to the WHO classification, ‘cytological dysplasia’ may or may not be present in HPs and SSA/Ps, whereas ‘conventional dysplasia’ may or may not be present in TSAs.1 SSA/Ps are thought to be one of the main serrated precursors of right-sided adenocarcinomas. Some studies have suggested that the SSA/P to carcinoma progression takes longer than the conventional adenoma to carcinoma progression, while others suggest a more rapid progression once dysplasia is identified in the SSA/P.2,3 The prevalence of SSA/Ps has varied between several studies from 0.6% to 5.3%.4,5  This is most likely due to the variability in the pathological criteria used and the high variability in  detection rate amongst endoscopists. There is a great deal of interobserver variability in the distinction between SSA/Ps and normal HPs amongst pathologists.6–8 Abdeljawad et al. conducted a retrospective study using their database of all average-risk patients aged >50 years who underwent a screening colonoscopy between August 2005 and April 2012 by a colonscopist with high detection rates for adenomas and serrated polyps (of course, the colonoscopist was Douglas Rex!).9 The plan was to come to a realistic estimate of the true prevalence of SSA/Ps in an average-risk population by combining the expertise of an experienced colonscopist with that of an experienced GI pathologist who has an interest in serrated polyps, and the application of an agreed terminology (the WHO consensus guidelines on serrated polyps). 1,910 average-risk patients underwent screening colonoscopy. A total of 656 serrated polyps were identified in 389 patients. Of the 656 serrated lesions, 599 (91.3%) were HPs, 44 (6.7%) were SSA/Ps, and 13 (2%) were mixed tubular adenomas/hyperplastic polyps. The study excluded diminutive rectal and sigmoid hyperplastic polyps, so it is possible that some of these may also have been SSA/Ps. In addition, the SSA/P detection rate at colonoscopy increased in the final year of the study, presumably as a result of a learning curve. This means that the true prevalence of SSA/Ps may have been underestimated. In conclusion, SSA/Ps are there if you look for them and may be more common than we think! References
  1. Snover D, Ahnen DJ, Burt RW. Serrated polyps of the colon and rectum and serrated (“hyperplastic”) polyposis. In: Bozman FT, Carneiro F, Hruban RH et al. (eds.) WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th ed. Berlin: Springer-Verlag, 2010.
  2. Lash R, Genta R and Schuler C. Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol 2010; 63: 681–686.
  3. Oono Y, Fu K, Nakamura H, et al. Progression of a sessile serrated adenoma to an early invasive cancer within 8 months. Dig Dis Sci 2009; 54: 906–909. 
  4. Hetzel J, Huang C, Coukos J, et al. Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort. Am J Gastroenterol 2010; 105: 2656–2664.
  5. Kumbhari V, Behary J and Hui J. Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians. J Gastroenterol Hepatol 2013; 28: 608–612. 
  6. Khalid O, Radaideh S, Cummings O, et al. Reinterpretation of histology of proximal colon polyps called hyperplastic in 2001. World J Gastroenterol 2009; 15: 3767–3770. 
  7. Wong N, Hunt L, Novelli M, et al. Observer agreement in the diagnosis of serrated polyps of the large bowel. Histopathology 2009; 55: 63–66. 
  8. Sandmeier D, Seelentag W and Bouzourene H. Serrated polyps of the colorectum: Is sessile serrated adenoma distinguishable from hyperplastic polyp in a daily practice? Virchows Arch 2007; 450: 613–618. 
  9. Abdeljawad K, Vemulapali K, Kahi C, et al. Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist. Epub ahead of print 3 July 3 2014. Gastrointest Endosc DOI: http://dx.doi.org/10.1016/j.gie.2014.04.064.

Hepatobiliary, pancreatic and GI tract neoplasms

The course provides knowledge on an integrated approach of imaging in the diagnosis and treatment of cancer.

ESGE is joining forces with ESDO to present the Quality in Endoscopy symposium on Colonoscopy & Colonic Neoplasms.

Hepatologists jump on screening bandwagon

In the UK, endoscopy is riding a wave of investment generated by population-level colorectal cancer screening. Now, it seems that hepatology is also planning to jump on the screening bandwagon.

In 2012 the US Centers for Disease Control and Prevention gave the go-ahead for population-level screening for chronic HCV infection.1 Then, in 2014, the World Health Organisation also recommended an expansion of the current screening strategy beyond those at high risk of HCV infection2. Screening for HCV infection is a sizeable undertaking as up to 150 million people worldwide are thought to have the disease. Although most are asymptomatic, all studies have found that patients infected with HCV have a reduced life expectancy. Understandably, in those countries where most HCV infections result from intravenous drug use, there is not only an increased risk of liver disease, but also an increased risk of death from alcohol, HIV infection, smoking or drug-related events such as overdose, suicide, homicide and trauma.3 In patients with iatrogenic HCV infections, an excess mortality from nonhepatic causes such as renal and heart disease and cancer has also been described.4 What do people with HCV infection usually die from? I must admit that I find it difficult to understand research papers reporting on standardised mortality rates (SMR). It seems counterintuitive that patients who have an SMR of 16.8 of dying from a liver-related cause are still far more likely to die from heart disease (SMR of 1.25).5,6 However, a slightly increased risk of dying from something that is already a frequent cause of death will obviously have a great impact on the total number of deaths. I was surprised to find that up to 85% of patients with chronic HCV infections die from nonhepatic causes.7–14 Is there anything we can do to reduce the risk of progression to liver fibrosis, cirrhosis, liver failure or hepatoma? Yes! Beneficial lifestyle interventions could include attempts to reduce intravenous drug taking, tackle alcohol dependency, help with weight reduction in the obese and treat HIV co-infection aggressively, all of which may reduce the risk of progression.15 In fact, all of the above interventions would be beneficial for patients regardless of infection status. The reason that hepatologists are so enthusiastic about screening for HCV infection is the fantastic sustained virologic response (SVR) rates achieved with the latest antiviral agents, which is now approaching 90%.16 However, it is worth pointing out that the SVR is a surrogate endpoint and sadly we don’t know if this translates into long-term clinical benefit. I find it surprising that this fundamental issue has not yet been clarified. However, I do understand that the issues surrounding antiviral therapy are complex! For example, the patients who are the most likely to achieve an SVR are those who are least likely to have risk factors for progressive disease.17–19 In other words, those who do well on treatment would probably also do well even without treatment. In addition, a proportion of patients who achieve an SVR, nevertheless develop and die from liver-related causes. In one of the largest studies with the longest follow up (8 years), patients with severe hepatic fibrosis but with an SVR, were found to have annual risk of developing hepatocellular carcinoma of 1%.20 This sounded like a good result until I realised that the background incidence of hepatocellular carcinoma in patients with HCV cirrhosis is very similar (1.4–3.3%).21 Once population-level screening for chronic HCV infection has been rolled out there will be some difficult consultations during which unsuspecting people are told that they are now patients with a chronic disease, requiring lifelong monitoring and treatment. Although the long-term clinical benefit of antiviral therapy is uncertain, I would nevertheless expect these difficult conversations to be easier if a safe and well-tolerated treatment was on offer. Sadly this is not the case. The adverse effects of interferon are well known and it is associated with a 4% increase in all-cause mortality.22 Both the guanosine analogues and the protease inhibitors may cause bone marrow suppression, skin reactions, gastrointestinal upset and insomnia in a large proportion of patients.23.24 In 2012, the US Food and Drug Administration reported that telaprevir was the most common reported cause of severe and fatal skin reactions of any drug.25 In one trial, 3% of patients randomly allocated to receive sofosbuvir experienced serious adverse events, with 1% occurring in the peginterferon plus ribavirin arm.26 In a more recent study, combination therapy with sofosbuvir plus ledipasvir was associated with a 0.5–2% rate of serious adverse events.27 As up to 85% of HCV-infected people in the population will die from nonhepatic causes, the newer antiviral therapies must be safer and better tolerated; otherwise, people will conclude that such a government screening programme turns well people into poorly patients. As an endoscopist, I find it reassuring to know that the benefit of colorectal cancer screening has been proven in several large, prospective studies. In view of the uncertainties surrounding population-level screening for HCV infection, I am not alone in wanting to see plans for large, prospective randomised controlled trials to prove it’s worthwhile.28 As a taxpayer, I would also like to be reassured that such screening would be money well spent. References
  1. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep 2012; 61(RR-4): 1–32 
  2. WHO. Guidelines for the screening, care and treatment of persons with hepatitis C infection. www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (2014, accessed 28 January 2015)
  3. Grebely J and Dore GJ. What is killing people with hepatitis C virus infection? Semin Liver Dis 2011; 31: 331–333.
  4. Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012; 206: 469–477.
  5. Amin J, Law MG, Bartlett M, et al. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 2006; 368: 938–945.
  6. Butt AA, Xiaogiang W, Budoff M, et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009; 49: 225–232.
  7. Wiese M, Fischer J, Lobermann M, et al. Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology 2014; 59: 49–57. 
  8. Seeff LB, Hollinger FB, Alter HJ, et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001; 33: 455–463. 
  9. Vogt M, Lang T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341: 866–870.
  10. Barrett S, Goh J, Coughlan B, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection. Gut 2001; 49: 423–430. 
  11. Casiraghi MA, De Paschale M, Romano L, et al. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Hepatology 2004; 39: 90–96. 
  12. Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 2000; 132: 105–111. 
  13. Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997; 90: 4628–4633. 
  14. Lai ME, Origa R, Danjou F, et al. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Haematol 2013; 90: 501–507 
  15. Missiha SB, Ostrowski M and Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008; 134: 1699–1714.
  16. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–1493.
  17. Stattermayer AF, Scherzer T, Beinhardt S, et al. Review article: genetic factors that modify the outcome of viral hepatitis. Aliment Pharmacol Ther 2014; 39: 1059–1070. 
  18. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666–1672. 
  19. Koretz R. Chronic hepatitis: more quotes and misquotes. In: Gitnick G (ed) Current Hepatology. Vol 15. St. Louis: Mosby-Year Book Inc., 1995, pp.49–84.
  20. Van der Meer A, Feld J, Hofer H, et al. The risk for hepatocellular carcinoma among patients with chronic HCV infection and advanced hepatic fibrosis following sustained virological response. In: 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, USA, 1 November–5 November 2013. Abstract 143. 
  21. Everson GT. Management of cirrhosis due to chronic hepatitis C. J Hepatol 2005; 42 (suppl1): S65–S74. 
  22. Di Bisceglie AM, Stoddard AM, Dienstag JL, et al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatology 2011; 53: 1100–1108. 
  23. Brok J, Gluud LL and Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database Syst Rev 2010; 1: CD005445. 
  24. Casey LC and Lee WM. Hepatitis C virus therapy update 2013. Curr Opin Gastroenterol 2013; 29: 243–249. 
  25. Institute for Safe Medication Practices. Perspective on drug hypersensitivity. QuarterWatch 2013 Q1, www.ismp.org/quarterwatch/pdfs/2013Q1.pdf (2014, accessed 28 January 2015) 
  26. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–1887. 
  27. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–1888. 
  28. Koretz RL, Lin KW, Loannidis JPA, et al. Is widespread screening for hepatitis C justified? BMJ 2015; 350: g7809. 

Case 1

These photographs show the stomach (top) and second part of the duodenum (bottom) of a 55-year-old man undergoing gastroscopy to investigate iron deficiency anaemia.

What would you organise next? a)    Gastric biopsies with immunohistochemical staining for e-cadherin b)    Measurement of serum gastrin levels c)    An enteroscopy d)    A capsule endoscopy e)    A colonoscopy

The Intestinal Microbiome—Rosetta Stone or Tower of Babel?

One of the hot topics in modern-day research is the mapping and understanding of the human intestinal microbiome and its role in health and disease. Studies have suggested that the development of several diseases and conditions depends on how our microbiomes are influenced and shaped, but interpreting the data generated by such studies may not be that simple. Are we holding the key to understanding metabolic, immunological and pathological processes, or do the data produced so far preclude any type of generalization? Are we unraveling the code necessary to develop obesity, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), or are we looking at a chaos of data, different terminologies and methodologies?

UEG Week 2014 was the first UEG event that I’ve attended in person, and the meeting was so packed with interesting sessions, I felt like cloning myself and deploying my clones to follow the many parallel tracks on offer. But alas, like all my fellow attendees, I had to choose, and rarely have I felt so spoiled for choice! Luckily, accessing the UEG Education Library has allowed me to look up a lot of the material that I was unable to see in person. Of the 52 ‘microbiota’ files available from UEG Week 2014 that can be discovered in the library, 10 are video-recorded presentations. As I take a huge interest in the role of the gut microbiota in health and disease, I've been indulging in these to update myself with some of the most recent advances in the field. In one of his presentations at UEG Week 2014, Professor Antonio Gasbarrini starts out by asking several questions about the gut microbiota in relation to coeliac disease, an autoimmune enteropahty triggered by gluten proteins. Do patients with coeliac disease have a different gut microbiota to healthy people? Does the microbiota have a role in the pathogenesis of coeliac disease? Can a gluten-free diet (GFD) alter the composition of gut microbiota? He stresses that a GFD does alter the microbiota and that, in healthy individuals, just a few weeks on a GFD may in fact lead to a decrease in beneficial bacteria such as Bifidobacteria/Lactobacilli and an increase in Enterobacteriaceae, thus affecting immune-metabolic responses. Moreover, a decrease in short-chain fatty acids is seen, possibly conferring a decrease in the immunomodulatory role of the microbiota. It appears that an altered microbiota is a characteristic feature of coeliac disease, that Bifidobacteria is decreased, at least in children, along with upregulation of other bacterial species, while any causal link between microbiota composition and disease development remains to be established. At least one HLA genotype is known to select for early microbiota composition, so it is possible that this is in fact one of the mechanisms underlying the genetic component of the disease. As do so many other scientists nowadays, Professor Gasbarrini stresses that while it may be important to know the structure of the microbiome, it is probably more important to know about the function of the microbiome. He also stresses the importance of sampling by highlighting the fact that identification of microbial communities may differ in the same individual depending on whether analysis of faecal or bioptic samples (mucosal biopsies, for instance) has been performed. Regarding the function of the microbiome, there are two talks on the microbiota in the context of IBD by Professor Joël Doré, who expands on the existence of Crohn’s disease-specific signature genes that are much less abundant in Crohn’s disease patients than in healthy controls. However, single genes not being very informative, scientists of the MetaHIT Consortium recently took to ‘binning’ genes identified by metagenomic analysis of roughly 400 faecal samples into co-abundance gene groups (CAGs), enabling a comprehensive discovery of new microbial organisms, viruses and co-inherited genetic entities, and facilitating assembly of microbial genomes without the need for reference sequences.1 From these CAGs, a total of 741 metagenomic ‘units’ or ‘species’ could be derived, four of which have been identified as highly discriminatory identifiers of ulcerative colitis when compared with healthy individuals. In our lab, we have also been analysing these data, only with a view to identifying parasitic protist signatures rather than bacterial signatures in these CAGs, and we have just submitted our results for publication. Once the results are out, I’ll be back with more on this; it is safe to say already that we have found some very striking associations, with colonisation by certain parasitic protists being significantly linked to certain microbiota profiles and clinical phenotypes of study individuals. However, just like Professor Doré points out, in most cases we do not know whether such observations reflect causality or mere consequence; this is mostly due to the cross-sectional nature of such studies, but the prognostic/diagnostic value of such findings should, or course, be subject to scrutiny. Being one of the heavy mantras of recent years, Faecalibacterium prausnitzii has been shown to be a direct predictor of Crohn’s disease relapse following infliximab withdrawal. In one study, Crohn’s disease patients with F. prausnitzii levels above the median were less prone to relapse than those with F. prausnitzii levels below the median, indicating that F. prausnitzii may represent a predictive factor for relapse.2 Professor Doré highlights that this is a trend not only in Crohn’s disease but also in ulcerative colitis. In the second talk by Professor Doré, you can learn more about the anti-inflammatory properties conferred by F. prausnitzii and its potential applicability as a diagnostic/prognostic marker. Professor Doré also gave a presentation on diet as a major modulator of the gut microbiota. He included a very educational slide on the functions of the human intestinal microbiota that are essential to health and wellbeing, and a slide summarising the diseases conferred by low gut species richness/gene count, such as Crohn’s disease, ulcerative colitis, IBS, obesity, Type-1 diabetes, Type-2 diabetes, coeliac disease, allergy and autism, etc., although the situation might not be entirely clear for coeliac disease, for example, as demonstrated by the talk by Professor Gasbarrini. In this talk, you can learn more about the so-called ‘enterotypes’, and you will find a few take-home messages regarding the impact of diet on microbiota development. Four of the video-recorded presentations are from the session “The role of microbiota in non-alcoholic fatty liver disease”. If terms such as ‘microbiota’, ‘microbiome’ and ‘metagenome’, scare you off, you are offered a useful introduction from Dr Alexander Moschen. And in case these conspicuous accomplishments have slipped your attention, in this talk you are also introduced to the famous and heavily cited mouse studies by Bäckhed and colleagues3 and Turnbaugh and colleagues4 on the influence of gut microbiota on energy uptake. For me, Dr Moschen delivers one of the big take-home messages in this series of presentations, which again relates to microbiota structure and function: just because different people have different microbiota, this may not mean that these microbiota do different things. Rather, different species assemblages appear to lead to similar functional profiles (i.e. the metabolic properties of a given microbiota can be more or less identical to those metabolic properties characteristic of a microbiota of a different composition). Focusing mainly on IBS, Dr Purna Kashyap presents studies showing that the gut microbiota can influence mechanisms characteristic of IBS, including gastrointestinal motility and secretion, visceral hypersensitivity and intestinal permeability, and that the microbiota influences entero-endocrine cells, stimulates the release of neurotransmitters like GABA, and mediates activation of immune cells, all affecting CNS function. Giving a thorough account of some of his own work too, Dr Kashyap shows that the effect of the gut microbiota on intestinal motility may in part be due to the effect on the host serotonergic system and that diet-related changes in microbiota fermentation products may alter host serotonergic pathways and gastrointestinal function. Finally, I would like to recommend the presentation “Probiotics and antibiotics in IBS: Do they work?”, which was delivered by Dr Viola Andresen. Dr Andresen summarizes data from randomized controlled trials on the effect of rifaximin on non-constipated IBS patients, which includes a significant improvement of particularly (refractory) bloating, but also stool consistency and global symptoms. There may be some uncertainty as to whether the effect of rifaximin in IBS patients is due to alleviation related to unidentified small intestinal bacterial overgrowth (SIBO), and in general, the link between IBS and SIBO remains obscure, primarily due to a paucity of data. However, a study using animal experimental models that appeared in Gastroenterology almost a year ago proposed that rifaximin modulates the ileal bacterial community (leading to a relative abundance of Lactobacillus), reduces subclinical inflammation of the intestinal mucosa and improves gut barrier function to reduce visceral hypersensitivity.5 Although expensive, among its many advantages, rifaximin has few side effects, if any, and more studies on the use of this antibiotic in the management of functional bowel diseases are anticipated. The language of the intestinal microbiome is being developed. Deciphering its many signs and symbols requires patience, but hopefully, this will eventually provide us with the tools and knowledge necessary to manipulate the gut microbiota to prevent, alleviate and cure a variety of diseases and promote health. Presentations on the microbiota at UEG Week 2014 Gasbarrini A. Microbiota in coeliac disease. From New challenges in gluten sensitivity: From bench to bedside.  Dore J. Microbiota signatures in IBD. From IBD: What's new in 2014?  Dore J. Microbiota: The key player in IBD? From New insights into the pathophysiology of inflammatory bowel diseases.  Dore J. Diet: Major modulators of gut microbiota. From Diet, immunity and systemic disease.  Moschen AR. Microbiota composition in obesity and related disorders. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Gasbarrini A. Antibiotics, pre- and probiotics in NAFLD. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Tilg H. Innate immunity in NAFLD. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Serino M. Metabolic infection. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Kashyap P. Impact of gut microbiota on gut function and dysfunction. From Normal and abnormal cross-talk at the mucosal border: Relevance for GI function and dysfunction.  Andresen V. Probiotics and antibiotics in IBS: Do they work? From Altered intestinal microbiota composition in IBS: Does it affect clinical practice?  References
  1. Nielsen HB, Almeida M, Juncker AS, et al. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nat Biotechnol 2014; 32: 822–828. 
  2. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis 2014; 20: 978-986. 
  3. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101: 15718–15723.
  4. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444: 1027–1031. 
  5. Xu D, Gao J, Gillilland M 3rd, et al. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology 2014; 146: 484–496. 

Postgraduate Course on the road from inflammation to cancer in the upper GI tract

During the Polish Society of Gastroenterology Congress in September 2014, EAGEN and EHMSG (formerly known as EHSG) held the joint Postgraduate Course "The road from inflammation to cancer in the upper GI tract." The aim of the course was to share knowledge and experience in this increasingly relevant field, with the participation of speakers from high-end specialty European centres, EAGEN and EHMSG. Recordings from each individual session of the course can now be found in the UEG Education library.

The Postgraduate Course was opened by Professor Jaroslaw Regula and was interactive in nature, including discussion time after the sessions and voting on questions posed by the speakers regarding the clinical cases presented.1 The relevance of inflammation leading to cancer was reinforced by Professor Peter Malfertheiner, who reported that infections leading to cancer are responsible for one out of every five cancer deaths worldwide.1 Session 1 began with an introductory lecture from Professor Tomica Milosavljević, who provided a general perspective on the inflammation and cancer axis.2 He started with the history of the field, addressing the two paradigms of the link between inflammation and cancer—chronic inflammation (extrinsic) and intratumoural inflammation (intrinsic)—as well as the molecular events and pathways regulating this axis. Professor Colm O’Morain delivered a case-based lecture, discussing therapeutic strategies to eradicate Helicobacter pylori and raising awareness of eosinophilic oesophagitis.3 Professor Lars Lundell adressed GORD, considering management and risk factors for progression, presenting and discussing two clinical cases.4 Next, Professor Heinz Hammer delivered a talk on food impaction.5 He guided the audience through the possible causes, criteria for endoscopic intervention and methods for removing impacted food. Eosinophilic oesophagitis and oesophageal eosinophilia were also discussed and an overview of treatment options provided. Dr. Jochen Weigt, presenting a case of Barrett’s esophageal cancer and dysplasia, initiated session 2.6 His presentation addressed the rationale for staging, problems with staging procedures, and treatment options, raising the discussion of the true value of chromoendoscopy (acetic acid staining) versus dedicated white-light high-definition endoscopy. Next, Professor Juan Malagelada presented two cases of dyspepsia, addressing diagnostic approaches, prevalence and also the pathophysiology of functional dyspepsia.7 He also covered the associated abdominal manifestations and putative influencing factors, as well as therapy for functional dyspepsia. Dr. Tamara Matysiak-Budnik completed session 2, by presenting three clinical cases of gastric malignancy, underscoring the relevance of early detection and the importance of multimodality treatment.8 The Healthy Stomach Initiative, which is striving to spread preventive measures for greater stomach health throughout the world, was also promoted. Session 3, the final session of the course, started with a lecture by Dr. Gunther Krejs on the topic of familial gastric cancer, providing clinical and practical advice.9 Next, Professor Malfertheiner delivered a lecture on “Helicobacter pylori and cancer: what studies are needed?”10 He indicated that we are currently still challenged by H. pylori and its consequences, highlighting the need for further studies. Professor Malfertheiner stressed that in both less developed and also in more developed regions of the world, H. pylori is the most frequent infectious agent ultimately leading to cancer, and remains as the most important risk factor for gastric cancer. The lecture also covered the general pathophysiology of gastric adenocarcinoma, atrophic gastritis and the assessment of risk of gastric cancer development, and the pathways from H. pylori infection to gastric cancer. Importantly, Professor Malfertheiner proposed several basic and clinical studies needed in this context, concluding with the message being promoted by the Healthy Stomach Initiative that what is needed is a healthy stomach that is H. pylori free. Presentations at "The road from inflammation to cancer in the upper GI tract" EAGEN and EHMSG Postgraduate Course
  1. Malfertheiner P and Regula J. Welcome. 
  2. Milosavljević T. Introductory lecture: the road from inflammation to cancer. 
  3. O’Morain C. Case based lecture: patient with heartburn: history, endoscopy, medical/interventional therapy. 
  4. Lundell L. Case based lecture: patient with severe reflux: history, diagnostic work-up, therapy. 
  5. Hammer H. Case based lecture: patient with oesophageal food impaction. 
  6. Weigt J. Case based lecture: Patient with Barrett oesophagus and cancer – history, endoscopy, medical/interventional therapy. 
  7. Malagelada J. Case based lecture: Patient with dyspeptic symptoms – how does the stomach signal discomfort and disease. History, diagnosis, endoscopy, medical/interventional therapy. 
  8. Matysiak-Budnik T. Case based lecture: Patients with gastric malignancies: history, diagnosis, endoscopy, medical/interventional therapy. 
  9. Krejs G. Case based lecture: Familial gastric cancer – clinical and practical advices. 
  10. Malfertheiner P. Helicobacter pylori and cancer: what studies are needed? 

Highlights of the ESPGHAN Pediatric Hepatology Summer School 2014

ESPGHAN aims to promote the health of children, focusing on the gastrointestinal tract, liver and nutritional status. Since its foundation in 1968, ESPGHAN has been engaging scientific exchange among trainees, young doctors and scientists involved in paediatric gastroenterology, hepatology and nutrition, by means of summer schools, research forums and workshops. The 2014 Pedriatric Hepatology Summer School, which was organized by Professor Pietro Vajro and the ESPGHAN Hepatology Committee, focused on the latest multidisciplinary approaches for the diagnosis and management of paediatric hepatobiliary disorders.

Several recordings from this year’s Pedriatric Hepatology Summer School are now available in the UEG Education library. They include state-of-the-art lectures, specifically tailored for the paediatric hepatologist, on: liver development, anatomy and biology by Professor Stefania Nori;1 liver function tests by Doctor Valerio Nobili;2 and gene therapy for inherited liver diseases by Professor Nicola Brunetti-Pierri.3 Also featured is a collection of recordings on cholestasis, introduced by Professor Thierry Lamireau.4 He explains that cholestasis is thought to affect between 1/2,500 to 1/5,000 neonates, being much more frequent in premature babies, with causes being extrahepatic, intrahepatic or even both. Intrahepatic cholestasis can be triggered by infection or by a wide range of genetic, metabolic and endocrinological factors. In his presentation, Professor Lamireau showcases step-by-step practical biological and clinical procedures for the diagnosis and treatment of each pathology.5 In turn, biliary atresia is the main pathology leading to extrahepatic cholestasis. Professor Björn Fischler illustrates disease pathogenesis and the multiple problems associated with the currently available surgical treatment for extrahepatic cholestasis, highlighting the importance of screening procedures for early diagnosis.6 So, how should cholestasis be managed? Professor Fischler addresses this issue, starting by outlining the consequences of ongoing cholestasis, namely the lack of bile acids in the gut and the retention of toxic hydrophobic bile acids in the liver, and then moving on to the specific management of cholestasis and malnutrition, as well as cholestatic pruritus.7 At the 2014 Summer School, Dr Alex Knisely hosted an interactive voting session on clinical cholestasis cases.8 He introduced the special problems in early life that may lead to cholestasis and the challenges of taking biopsy samples in young infants, before moving to the presentation and discussion of five different clinical cases based on biological and biochemical analyses, as well as liver biopsies. Dr Danièle Pariente’s presentation provides an extended and comprehensive overview of paediatric hepatology imaging modalities, namely ultrasonography, computed tomography and magnetic resonance imaging.9 She addresses each modality’s advantages and drawbacks, as well as indications and limits, in parallel with the presentation of clinical cases. Dr Pariente then goes on to define the imaging strategies in neonates and children in cases of cholestasis (with practical examples on cholelithiasis, choledochal cysts, neonatal cholestasis, biliary atresia); portal hypertension (extrahepatic portal vein obstruction, wedged cirrhosis, congenital hepatic fibrosis, obliterative portal venopathy and Budd-Chiari Syndrome); and liver tumors (hepatoblastoma; hepatic hemangioma; focal nodular hyperplasia; adenomas).   In the final presentation from this series, Professor Fischler discusses hepatitis B, highlighting the large prevalence of this disease in children, particularly in developing and more-heavily populated countries.10 He also considers the challenges of effective vaccination as a preventative measure. Four clinical cases are presented and discussed. If you’d like to discover more paediatric hepatology content from ESPGHAN, please feel free to browse the UEG Education Library, which includes presentations from the ESPGHAN 2013 Summer School and Liver Conference, as well as its 46th Annual Meeting, also held in 2013. Presentations at ESPGHAN Pediatric Hepatology Summer School 2014
  1. Nori S. The liver and the hepatobiliary tree: Development, anatomy and biology issues for the pediatric hepatologist. 
  2. Nobili V. Common LFTs in pediatric Hepatology. 
  3. Brunetti-Pierri N. Gene therapy for inherited liver diseases. 
  4. Lamireau T. Cholestasis: Generalities. 
  5. Lamireau T. Focus on INTRA-hepatic cholestasis. 
  6. Fischler B. Focus on EXTRA-hepatic cholestasis. 
  7. Fischler B. Cholestasis: Management. 
  8. Knisely A. Clinical Cases and Interactive Voting Session. 
  9. Pariente D. Interactive Overview in Pediatric Hepatology Imaging. 
  10. Fischler B. Chronic Viral Hepatitis B.

FMT: balancing scientific success with successful regulation

Eww! If the thought of gulping down helminth eggs in an effort to mitigate the symptoms of IBD, psoriasis and other autoimmune diseases wasn’t unpalatable enough, we now face the reality of having someone else’s faeces fertilizing our guts! Nevertheless, it appears that the incentive for using these types of ‘paleo’ therapeutic approaches is increasing, driven mainly by problems related to antimicrobial resistance, faltering immunological pathways and intestinal dysbiosis, all of which may be intrinsically linked. Meanwhile, authorities are struggling to develop regulations in the face of multiple trials supporting the efficacy of faecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infections (CDI).

A few weeks ago, @Liz_Atchley uttered on Twitter “If I'm ever in need of a fecal transplant, just let me die”. Same week, @beardbrain went ‘"There Is No ‘Healthy’ Microbiome". So don't get that fashionable fecal transplant unless you really need it!”’ The last tweet refers to an article that appeared in the New York Times.1 What the article actually said was that it appears that there is no single healthy microbiome, that the microbiome in each individual may undergo dynamic changes, and that perfectly healthy people may differ greatly in terms of microbiota structure and diversity. In fact, each of us appears to have a unique gut microbiome that may, however, be perturbed (e.g. by antimicrobials or certain types of diets), leading to disease, possibly including metabolic syndrome. Meanwhile, there is solid scientific evidence that some patient groups, especially patients with recurrent CDI, benefit from FMT aiming to correct intestinal dysbiosis—microbiota alterations—by instilling fecal microorganisms from a healthy individual into the intestine of a patient. In the US, a total of 15%—20% of antibiotic-related cases of diarrhea and most cases of pseudomembranous colitis can be attributed to CDI, which is involved in three million cases of diarrhea and colitis per year, with many thousands succumbing to infection.2 Recurrence of CDI appears to be common, affecting around 15%—20% of cases. In their current CDI guidelines, The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) recommends the use of FMT rather than vancomycin or fidaxomicin in patients who have experienced at least two CDI recurrences (i.e. three CDI episodes in a single patient).3,4 The EAGEN Gut Microbiota 2014 meeting took place in Rome in September, and some of the talks are now available in the UEG Education Library (please see below for the list of presentations). In one of the presentations, Dr Luca Pani from the Italian Medicines Agency not only ‘brutally’ explains the bread and butter of FMT and dishes out compelling facts on FMT success rates, but also expands on the vast potential applicability of FMT, which may prove valuable in preventing, mitigating, and/or treating complex disorders, such as multiple sclerosis, colorectal cancer, metabolic syndrome and disorders stemming from imbalances in the gut–brain axis.2 Moreover, Dr Pani importantly touches upon the intricate issues related to regulating FMT procedures, and asks several important questions. Should food and drug administrations control FMTs? Who are the FMT manufacturers? How about donor exclusions and testing of donor stool—which of the 40,000 species in stool should we allow to enter the recipient? Can single ‘active ingredients’ be identified or does the success of FMT rely on the combined actions/influence of diverse microbial communities? There have been discussions about whether FMTs are in fact tissue transplants or medicines, and there is also a continuum of varieties of FMT, from the infusion of donor faeces screened for pathogens prior to administration, to cocktails of enteric bacteria specifically chosen for and selectively grown on agar plates. Are we talking full-spectrum microbiota or defined microbiota ecosystems? Instead of FMT, are we moving towards ‘Next-Generation Microbiota Therapeutics’5 such as ‘RePOOPulate’, a synthetic stool produced by a ‘Robogut’6? Apparently, FMT regulations vary from being very strict, such as those developed by the US FDA, to being more or less absent in most other countries. In Austria, FMT is regarded as a therapeutic intervention that is not to be considered a pharmaceutical drug and is therefore exempt from regulation by the Austrian Medicines Act.4 As Dr Pani explains, the statistics on FMT for successfully treating C. difficile infections are clear—no need for P values anymore.2 Success stories keep coming in, which will eventually make FMT more palatable to the general public, and so it probably won’t be long before FMT will be triaged by health care professionals, medical companies, and national FDA agencies. Efforts aiming to relax regulations and ensure standardization as much as possible will be crucial in order to reduce the incidence of DIY-related mishaps and to quickly gain more insight into the therapeutic potential of FMT. Hungry for more? Then why not sit back and update yourself on FMT constituents, indications, feasibility, safety, practicality, and regulations, and—maybe first and foremost—examples of professional experience with FMT by having a look at the accepted articles section in Clinical Microbiology and Infection. I also recommend watching the talk on FMT and recurrent CDI by Lawrence Brandt given at the Gut Microbiota for Health 2nd World Summit.7
References
  1. Yong E. There Is No ‘Healthy’ Microbiome. The New York Times. November 1, 2014.
  2. Pani L. Microbial transplantation as a new therapy option in medicine: The views of the Italian Medicines Agency (AIFA). Opening lecture at EAGAN Gut Microbiota 2014.
  3. Debast SB, Bauer MP, Kuijper EJ, et al. European Society of Clinical Microbiology and Infectious Diseases: Update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014; 20 (Suppl 2):1–26
  4. Kump PK, Krause R, Allerberger F, et al. Fecal microbiota transplantation—the Austrian approach. Clin Microbiol Infect Epub ahead of print 1 October 2014. DOI: 10.1111/1469-0691.12801
  5. Petrof EO and Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology 2014; 146; 1573–1582
  6. Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013; 1:3
  7. Brandt L. Fecal Transplantation for the treatment of Clostridium difficile infection. Presentation at the Gut Microbiota for Health 2nd World Summit Madrid 2013.
EAGEN Gut Microbiota 2014 Presentations Pani L. Microbial transplantation as a new therapy option in medicine: the views of the Italian Medicines Agency (AIFA).  Putignani L. Gut bacteriome—Gut aerobs.  Delogu G. Gut bacteriome—Gut anaerobs.  Langella P. Gut bacteriome—Focus on Fecalibacterium prausnitziiCani P. Gut bacteriome—Focus on Akkermansia muciniphilia. Ianiro G. Gut mycome. Bruno R. Gut virome.  Gasbarrini A. The intestinal barrier in different physiological and pathological conditions.  Barbara G. Consequences of increased intestinal permeability.  Lopetuso L. Esophageal gastric barrier. Further UEG Education Resources Surawicz CM. Regulatory and safety issues. Presentation from Faecal microbial transplantation: An old therapy comes of age at UEG Week 2014 Mattila E. FMT for Clostridium difficile infection. Presentation from Faecal microbial transplantation: An old therapy comes of age at UEG Week 2014 Vermeire S. Modulation of the Intestinal Microbiota by Faecal Transplantation: What Can We Expect? Keynote Lecture at ESPGHAN Conference 2013. Further Reading Brandt LJ. American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol 2013; 108: 177–185. DOI:10.1038/ajg.2012.450 Kapel N, Thomas M, Corcos O et al. Practical implementation of faecal transplantation. Clin Microbiol Infect Epub ahead of print 1 October 2014. DOI: 10.1111/1469-0691.12796 Kelly CR, Kunde SS and Khoruts A. Guidance on preparing an investigational new drug application for fecal microbiota transplantation studies. Clin Gastroenterol Hepatol 2014; 12: 283–288 Lagier JC. Fecal microbiota transplantation: from practices to legislation before considering industrialization. Clin Microbiol Infect Epub ahead of print 1 October 2014. DOI: 10.1111/1469-0691.12795 Singh R, Nieuwdorp M, Ten Berge IJ, et al. The potential beneficial role of faecal microbiota transplantation in diseases other than Clostridium difficile infection. Clin Microbiol Infect Epub ahead of print 7 November 2014. DOI: 10.1111/1469-0691.12799.

HCV treatment in the post-transplant setting:

Developing niche markets for therapy.

Patients who have active hepatitis C at the time of liver transplantation invariably become re-infected, with the subsequent risk of graft failure. The side effects of interferon (IFN)-based therapies are significant, hence the drive to develop new and effective therapies. Two recent studies have looked at the role of two different IFN-free regimes for the treatment of post-transplant patients infected with HCV.

Charlton et al. studied the role of the NS5B polymerase inhibitor sofosbuvir and ribavirin given for 24 weeks for the treatment of HCV patients post-liver transplantation.1 The 40 patients included in the study were infected with a mixture of HCV genotypes (GT): 29 (73%) GT1a, 22 (55%) GT1b, 6 (15%) GT3 and 1 GT4. A total of 16 patients (40%) were classified as having cirrhosis. Overall, an SVR12 (sustained virologic response at week 12 post-treatment; representative of successful viral clearance) was achieved in 70% of patients; viral eradication was successful in 73% of GT1a patients, 55% of GT1b patients and 100% of GT3 patients. It was the single patient infected with HCV GT4 who failed to achieve an SVR12. There were no episodes of graft failure or rejection, with no significant study-related side effects. Some modification of the immunosuppressants tacrolimus and ciclosporin was required, but not in all cases. Kwo et al. looked at the benefit of the ABT-450/r (ritonavir), ombitasvir, dasbuvir and ribavirin regime, given for 24 weeks to GT1-infected patients post-liver transplantation.2 ABT-450/r is a ritonavir-boosted protease inhibitor, ombitasvir is an NS5A inhibitor and dasabuvir is a non-nucleoside NSB5 polymerase inhibitor. In combination with ribavirin, this regime has produced favourable outcomes in phase 3 trials in GT1-infected non-transplant patients.3,4 34 patients (29 infected with HCV GT1a and 5 with GT1b) were enrolled in the study by Kwo and colleagues. No patients with cirrhosis were included. Overall, an SVR12 was achieved in 97% of the treatment group, with 100% seen in the GT1b cohort, and 1 patient who relapsed in the GT1a cohort (97%). Again, no cases of graft failure or rejection were seen, and most adverse events were mild to moderate. All patients had their baseline tacrolimus and ciclosporin dosing modified, but there was no mention of any undue long-term effects resulting from this modification. Both of these studies included a small number of patients, who were heterogenous with regard to their baseline characteristics. For this reason, no firm conclusions can be drawn. However, the SVR rates achieved are encouraging, as are the tolerability and drug–drug interaction profiles, and most importantly the absence of graft rejection or failure. Treatment options and combinations have progressed rapidly since these studies were designed. The latest EASL guidelines recommend the use of sofosbuvir with either daclatasvir or simeprevir for post-transplant patients (excluding those with GT2 disease).5 The ABT-450 regime is at yet unlicensed, and it is unclear how commissioning bodies will decide which therapies are cost-effective based on the many therapeutic options now available. What seems certain though is that the next year will see research focused at targeting special populations (e.g. those with HIV co-infection or renal failure) and hard-to-treat groups (e.g. those with GT3 infection), with the aim being to target new, niche markets. References
  1. Charlton M, Gane E, Manns MP, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis c virus infection after liver transplantation. Gastroenterology Epub ahead of print 7 October 2014. DOI:10.1053/j.gastro.2014.10.001.
  2. Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med Epub ahead of print 11 November 2014. DOI: 10.1056/NEJMoa1408921. 
  3. Feld J, Kowley KV, Coakley, E et al. Treatment of HCV with ABT-450/r-ombitasvir and dasbuvir with ribavirin. N Engl J Med 2014; 370: 1594–1603.
  4. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis c with cirrhosis. N Engl J Med 2014, 370: 1973–1982.
  5. EASL. EASL Recommendations on Treatment of Hepatitis C 2014, http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html (2014, accessed 9 December 2014). 

Medical mishaps

… mistakes also happen when providing health care.

Mistakes happen. This is the reason why my Volvo has large rubber bumpers and why pencils have rubbers. Indeed, I, amongst many others, may have been born for this very reason. It has long been recognised that mistakes also happen when providing health care. Of course, there are lots of reasons that such mistakes occur, including sleep deprivation, being rushed, having illegible hand writing, delivering complex care, language barriers and treating elderly patients who have lots of interacting comorbidities.

Estimates vary, but the now famous Harvard Study concluded that 1% of hospital admissions result in an adverse event.1 I must admit to being sceptical about this figure, which would equate to more Americans being killed in US hospitals every 6 months than died in the entire Vietnam War. By contrast, on ward rounds it is clear to me that what actually kills people is being old, frail and diseased. And herein lies the root of my scepticism. The study takes no account of the expected risk of death in the absence of a medical error. A rarely quoted study by Hayward and Hofer,2 tried to examine care more objectively. The authors derived three interesting and illuminating conclusions. First, most deaths reportedly due to medical errors occurred at the end of life or in critically ill patients in whom death was likely regardless of the care received. Indeed, two-thirds of cases reviewed in their study had a "do-not-resuscitate" order in place at the time of death. Second, the level of agreement that a death was 'preventable' was poor (kappa value 0.25). The authors concluded, "…most of the 'errors' identified represent outlier opinions in cases in which the median reviewer believed either that an error did not occur or that it had little or no effect on the outcome." They dryly commented that if there were a large enough reviewer panel, there would always be someone of the opinion that each death was preventable. Third, the probability that an error definitely had contributed to a death was considered rare. The reviewing clinicians estimated that only 0.5% (95% CI, 0.3–0.7%) of patients who died would have lived an extra 3 months if their care had been optimal. This would represent roughly 1 patient per 10,000 admissions to the seven Veterans Affairs medical centres included in the study. The above conclusions will not be surprising to doctors who look after patients. But surely we should always be alert and pounce on every medical mishap to continuously improve practices and reduce the risk of further errors? The hunt for hospital mishaps may, however, have unforeseen consequences. I am aware of three problematic issues. The first issue is that identifying particular patterns of care that result in truly preventable deaths is difficult. It's far easier to identify 'minor' problems and the 'minor' individual responsible. For this reason nursing staff are the most frequently reprimanded team members. Paradoxically, nurses are the least likely not to internalise the reprimand and forgive themselves, and are the most likely to become depressed afterwards. I have seen nurses leave our NHS after a reprimand. There is already a national shortage of nurses because young people don’t want to spend a lifetime working shifts, doing physically and emotionally draining jobs in a punitive environment that comes down hard on every mistake. Qualified nurses don't need a push through the door; they are already leaving frontline services for less demanding jobs in the private sector. Personally, I regret not going into the financial sector where, for example, bringing your bank into financial ruin or the whole world into deep recession is rewarded with a warm handshake and a fat pension. Trying to fix problems in complex settings using hindsight and anecdotes is the second issue as it may lead to processes that worsen care. British nurses now seem to spend more time completing care plans and paperwork than directly caring for patients. To reduce prescription errors, we now have a bewildering 6-page colour coded prescription chart with a myriad of tiny boxes to prescribe anything from oxygen, to compression stockings, to drugs, with ample opportunity to get confused and make a mistake. In my opinion, almost all processes that are put in place to reduce risk, result in an increase in the complexity and time it takes to achieve the task. Surely, the reverse should be the case? Never before in the history of medicine have so many patients with so much disease been given such complex care by so few nurses within such a short space of time! The third and final issue is the overestimation of life expectancy. It is often lamented that doctors overestimate the life expectancy of their patients, but sick patients and their relatives have even more unrealistic expectations—they don't expect to die at all! Paradoxically, it is the elderly who have the least to gain from receiving numerous medical interventions, are the most likely to suffer an adverse event and the least likely to survive when something goes wrong. In spite of all this, when the 'unexpected' happens, it is presumed that it must be due to an error. The creeping mistrust is fuelled by our medical obligation to disclose every medical mishap. The relatives of an octogenarian who succumbs to a hospital acquired infection after a hip replacement will have little doubt that, "The reason my grandfather died was because the nurse didn't dress his wound on time/he didn't get his tablets in the evening/the hospital gave him pneumonia." How can we continuously reduce errors, encourage more young people to become healthcare professionals and provide sufficient time to complete every task, whilst encouraging the elderly to be realistic in their expectations? Unfortunately, this is a circle that cannot easily be squared. In the future, health care will undoubtedly be provided by robots! References 
  1. Brennan TA, Leape LL, Laird NM et al. Incidence of Adverse Events and Negligence in Hospitalized Patients — Results of the Harvard Medical Practice Study I. NEJM 1991; 324: 370–376.
  2. Hayward RA and Hofer TP. Estimating hospital deaths due to medical errors: preventability is in the eye of the reviewer. JAMA 2001; 286: 415–420. 

Can't get to the caecum! Now what?

Colon capsule endoscopy versus CT colonography.

Endoscopists usually resort to performing CT colonography (CTC) in cases of incomplete colonoscopy. Colon capsule endoscopy (CCE) is a new technique that has potential advantages over CTC.

Achieving a caecal intubation rate >90% is an essential requirement for demonstrating competency in colonoscopy. However, even the more experienced endoscopist who routinely achieves a higher caecal intubation rate occasionally encounters problems. Being unable to reach the caecum could be due to patient-related factors, such as previous abdominal or pelvic surgery, unusual anatomy and pain threshold. As up to 50% of colonic neoplasia develop in the proximal colon, caecal intubation with adequate mucosal visualization is mandatory before colonic pathology can be excluded. Options for failed or incomplete colonoscopy involve using a different technique to repeat the procedure (e.g. using a gastroscope if there is troublesome sigmoid diverticular disease or using a more pliable paediatric colonoscope). However, CTC has been endorsed by the AGA as the ideal next step for cases of incomplete colonoscopy. Spada and colleagues from the Catholic University in Rome, compared the performance of CCE with CTC after incomplete colonoscopy in a small, but prospective, single-blind trial that enrolled 100 patients.1 All patients underwent both CCE and CTC on the same day. CCE was always performed first and a second attempt at colonoscopy was performed in patients who had a positive finding. The primary end point in this study was the per-patient diagnostic yield of CCE and CTC for ≥6 mm polyps/mass undetected by previously incomplete colonoscopy. Post-CCE/CTC colonoscopy was used as the gold standard. Secondary end points were completion rate, rate of missed cancer at 1-year clinical follow up, level of bowel preparation and safety. For polyps ≥6mm, Spada et al. showed a two-fold increase in the diagnostic yield of CCE compared with CTC (24.5% versus 12.2%). However, there was no difference in the detection rate for lesions >10mm. The higher sensitivity of CCE was not associated with higher false-positive results. Both techniques were comparable in terms of completion rate and safety; neither method missed a cancer on follow up. Though the study has some limitations (single center, possible false negatives with both techniques, exclusion of patients with poor bowel preparation and strictures), it shows that the detection and characterization of smaller lesions is possible with CCE. CCE may, therefore, be an option for patients with incomplete colonoscopy. References
  1. Spada C, Hassan C, Barbaro B, et al. Colon capsule versus CT colonography in patients with incomplete colonoscopy: a prospective, comparative trial. Published Online First 24 June 2014. Gut doi:10.1136/gutjnl-2013-306550.
Further UEG Education Resources 
  1. Colon Capsule Demo. Presentation by Dirk Hartmann at UEG Week Berlin 2013 
  2. Colon Capsule Endoscopy: Could it become a gold standard? Presentation by Cristiano Spada at UEG Week Berlin 2013
  3. Colon Capsule: Any indication? Presentation by Cristiano Spada at UEG Week Barcelona 2012

Decide on the Spot!

60 seconds to make the correct decision.

A 16 year old severely handicapped boy is referred for a PEG as he has become increasingly difficult to feed without regurgitation and vomiting.

The PEG is scheduled to be carried out under general anaesthesia. At the procedure, this stricture is unexpectedly found in the low oesophagus. You can not traverse the stricture with your diagnostic 9.8mm endoscope.

WHAT WOULD YOU DO NEXT? 
a) abandon the procedure and refer the case back to the original team
b) refer for a radiologically placed percutaneous feeding tube
c) dilate the stricture but not place a PEG
d) reintubate with a superslim endoscope and place a PEG
e) dilate the stricture and place a standard PEG feeding tube
This is a recent "real case" of mine!  Endoscopy is unforgiving. You now have 60 seconds to make the correct decision. Any further consideration will come across as "dithering" to the attending anaesthetic and endoscopic team. If you make the wrong decision, the report will become a testimony to your poor judgement which will be placed in the patient records for eternity ...
You have 50 seconds left to decide .

SVR: 24, 12 or maybe 4?

A shortened SVR time point with sofosbuvir?

How long does it take to determine whether the treatment for chronic hepatitis C (HCV) has been successful? In the past, patients had to wait 24 weeks to assess whether they had achieved a sustained virological response (SVR24). A recent article by Yoshida et al. looks at the data to support using a shortened SVR time point with sofosbuvir, in the new wave of HCV treatments.

The traditional wait for 6 months following a demanding treatment regime to see if it has been successful is clearly unsatisfactory. Over the past few years there has been a move towards using a 12-week post-treatment marker as a predictor of long-term viral eradication (SVR12). The use of this time point has been endorsed by regulatory authorities for drug development,1 and features in the latest EASL guidelines on HCV.2 However, the high concordance in SVR rates at 12 and 24 weeks has principally been obtained from interferon (IFN)-based studies. Data are limited for the new direct-acting antivirals, which is a shortcoming in the IFN-free era that we are now entering. The study by Yoshida et al. provides welcome insight into this area, confirming good concordance rates for viral eradication with sofosbuvir at both 4 and 12 weeks compared with the standard 24 weeks.3 This is encouraging because the oral HCV polymerase inhibitor sofosbuvir is integral to most new drug regimes for the treatment of chronic hepatitis C. In their retrospective analysis, Yoshida and colleagues pooled data on SVR rates from 863 patients involved in phase 3 trials of sofosbuvir. The treatment cohort included treatment naive and experienced patients who were infected with HCV genotype 1, 2 or 3 (a handful were infected with HCV genotype 4–6). Patients infected with HCV genotype 1 received IFN in addition to sofosbuvir and ribavirin, whereas those infected with HCV genotype 2 or 3 received sofosbuvir and ribavirin therapy alone. Concordance rates were similar across all genotypes, and between IFN and non-IFN regimes. In all, 98% of patients who achieved an SVR at week 4 also achieved an SVR at week 12, and 99.7% of those with an SVR at week 12 achieved viral eradication at 24 weeks. However, about 10% of all patients in the trials relapsed post-treatment. Most relapses occurred by post-treatment week 4, but many other relapses occurred between week 4 and 12 of follow up, with only a minority (2.3%) occurring after week 12. The authors therefore conclude that an SVR4 can be unreliable and that SVR12 is preferable. One of the reasons this study stood out to me was my experience seeing the same relapse pattern at week 12 in a patient who was treated with one of the new oral-based regimes. Despite having a fantastic response throughout treatment and up to week 4, I had to break the news that he had relapsed at week 12 and consequently failed his third course of treatment. As yet, little is known to be able to explain to patients why this happens, and patients infected with HCV genotype 3 seem to be uniquely hard to treat, with disappointing cure rates in clinical trials when compared with patients infected with the other genotypes. Data from the Early Access Programme in the UK, and from other compassionate use programmes of the new oral HCV treatments, are eagerly awaited. Hopefully these data will provide an improved understanding of the real-world responses to treatment and better predictors of viral response.  References 
  1. Chen J, Florian J, Carter W, et al. Earlier sustained virological response end points for regulatory approval and dose selection of hepatitis C therapies; Gastroenterology 2013; 144: 1450–1455.
  2. EASL Recommendations on Treatment of Hepatitis C 2014, http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html (2014, accessed 13 November 2014).
  3. Yoshida EM, Sulkowski MS, Gane EJ, et al. Concordance of sustained virological response 4, 12 and 24 weeks post-treatment with sofosbuvir-containing regimes for hepatitis C virus. Hepatology. Epub ahead of print 14 October 2014. DOI: 10.1002/hep.27366
Further UEG Education Resources 
  1. The new drugs for HCV: Can we achieve interferon-free HCV treatment? Presentation by Christophe Hezode at UEG Week Berlin 2013.

Treatment failure in patients with chronic hepatitis E

Are we a step forward?

Ribavirin (RBV) is used for the treatment of patients with chronic hepatitis E, but RBV is associated with treatment failure and associated mortality. A new in vitro study identifies a virulence mutation in the hepatitis E virus (HEV) genome that may explain why treatment failures occur.

Awareness and detection of acute HEV infection is increasing, including in some regions where the infection was hitherto thought to be rare.1 Indeed, HEV is now thought to be most common cause of acute viral hepatitis. Most infected individuals remain asymptomatic and in most symptomatic patients the infection clears spontaneously; however, patients with chronic liver disease or haematological malignancies, solid organ recipients and other immunocompromised patients are at risk of developing a chronic HEV infection. Debing et al. studied the blood samples of 15 solid organ recipients with a chronic HEV infection who were treated with RBV, which is generally the treatment of choice.2 Two patients did not respond to treatment and one of them died. In both nonresponders, a nucleotide substitution was detected that resulted in a G1634R mutation in the C-terminal region of the HEV polymerase. To further assess the significance of this mutation, the 1634R mutation was introduced into a HEV genotype 3 replicon. RBV sensitivity did not differ between the 1634R construct and the wild-type replicon, but the luminescence signals yielded by the 1634R construct were consistently higher than those yielded by the wild-type replicon, suggesting that viral replication was increased. Similar observations were made when two hepatoma cell lines were transfected with 1634R, 1634K (the predominant amino acid at this position in genotype 1 HEV) or wild-type replicons. Quantification of viral RNA released from transfected Huh7 cells showed that 1634R and 1634K variants replicated to higher titres than the wild type at every time point. Finally, the fitness of G1634 and 1634R variants was assessed using direct competition assays. This demonstrated a relative fitness gain for 1634R of 7–9%. This study provides the first evidence of a viral polymerase mutation that contributes to increased HEV replication. Although there was no difference in RBV sensitivity, the authors suggest that it is the increased viral replication that leads to treatment failure. This is not entirely unexpected. In an abstract presented at UEG Week 2012, viral load was linked with the risk of acute liver failure.3 Another area of the HEV genome under scrutiny in relation to acute liver failure is the region encoding capsid proteins; the occurrence of nucleotide substitutions in this region was studied in another abstract presented at UEG Week 2013.4 The study by Debing et al. raises further questions. Could mutations at the 1634 locus help predict the outcomes of patients with a chronic HEV infection? Would combination antiviral therapy benefit these patients or should they be offered one of the newer antivirals? The current study is probably one of the first steps in the quest to find the answers.    References
  1. Salunke SS, Hunt AC, Laing RB, et al. Hepatitis E: An emerging infection in North of Scotland? Gut 2013;62:A186.
  2. Debing Y, Gisa A, Dalleier K, et al. A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with Ribavirin treatment failure in organ transplant recipients. Gastroenterology 2014; 147:1008–1011.e7. 
  3. Borkakoti J, Hazam RK, Kar P, et al. Viral load of hepatitis E virus: a key agent in acute liver failure during pregnancy. Gut 2012;61 (Suppl 3):A36.
  4. Borkakoti J, Ahmed G and Kar P. Nucleotide substitutions in the hepatitis E virus genome: a prime agent in acute liver failure. United European Gastroenterology Journal 2013;1 (Suppl 1):A299.
Further UEG Education resources
  1. Hepatitis E: Who, when and how to treat? Presentation by Robert A De Man at UEG Week Vienna 2014
  2. Hepatitis E. Presentation by Rakesh Aggarwal at UEG Week Berlin 2013

Finding the right level

Infliximab levels antibodies to infliximab and disease activity in Crohn's disease.

With the widespread use of biologics such as Infliximab (IFX) for the treatment of IBD, research has focused on why some individuals respond well to their use, whilst others lose response over time or don't respond at all. Attention has focused on the role of antibodies to IFX (ATI) and whether they are responsible, at least in part, for this phenomenon, and whether monitoring and measuring ATI is useful for frontline clinicians treating patients.

The development of anti-TNF drugs (biologics) to treat chronic inflammatory conditions such as Crohn's disease has brought about dramatic changes in disease management. However, over the past 10 years there has been growing recognition that disease activity may be inversely related to the circulating drug levels. In patients with Crohn's disease, low or undetectable serum trough levels of IFX are associated with worse clinical outcomes. ATI are thought to increase the clearance of IFX, resulting in low serum trough levels. As part of a multinational research group, Vande Casteele et al. investigated the clinical relevance of ATI in patients who had adequate IFX concentrations.1 In this observational study, 1,487 trough serum samples from 483 patients with Crohn's disease were analysed using a fluid phase mobility shift assay, which is sensitive for the identification of ATI in the presence of IFX. They found that IFX trough concentrations >2.79 mg/mL during maintenance therapy were associated with remission, as measured by a C-reactive protein concentration of <5mg/L.  In addition, an ATI concentration level <3.15 U/mL was also associated with remission. Multivariate analysis showed that both the IFX trough concentration and ATI concentration were independent predictors of remission. The authors concluded that any detectable concentration of ATI was associated with greater disease activity, even in the presence of an adequate IFX trough concentration. They also postulated that ATI impair the effect of IFX via an alternative mechanism than by simply increasing its clearance. This suggestion is in keeping with the conclusion of Van Moerkecke et al. reporting on IFX levels and primary non-response at UEG Week 2009.2 These results support the role of therapeutic drug monitoring in patients with Crohn's disease who are receiving IFX. The results also provide justification for dose intensification with IFX in those patients without ATI but with a low IFX trough level and evidence of ongoing disease activity.  Patients with both low IFX trough levels and high ATI levels may benefit from conversion to a different TNF antagonist or 'class' of biologic agent. In an era of personalised medicine, adjusting medications according to the particular pharmacokinetics and immune adaptations of the individual receiving the medication may become the future gold standard. References 
  1. Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease. Gut Epub ahead of print 21 October 2014. DOI: 10.1136/gutjnl-2014-307883. 
  2. Van Moerkecke W, Cleynen I, Compernolle G, et al. Trough levels of infliximab in a cohort of primary non-responders. Gut 2009; 58 (Suppl II): A70.

Endoscopic happenings at UEG Week 2014

I am limbering up for a dose of endoscopy at UEG Week. The ESGE has already sent me free complimentary access to their eLearning unit "Colonoscopy – the Basics". Clearly they are trying to tell me something.

Hopefully you have now downloaded the UEG Week 2014 App, which allows you to choose between 20 different pathways. The UEG Week Vienna Pathways Tool can also be downloaded. I am particularly looking forward to the endoscopy pathway. On Saturday during the postgraduate teaching programme there will be two live endoscopy sessions in the afternoon. The live endoscopists can then relax until Tuesday morning when there will be wall-to-wall live endoscopy in Hall A. These Live sessions do not always go to plan and they are a great opportunity to see experts get into and out of difficulties. Alex Meining is in charge and has told me that he has a record 36 cases lined up. He promises "polyps, polyps, polyps (small ones, ugly ones, polyps in the ileum, polyps in the rectum, polyps in Barrett's, polyps in the stomach), several IBD patients with strictures, new endoscopes (a new gastroscope and the three-lens screening colonoscope from FUSE, Olympus brand new extra-wide-angle scope, etc.). (Only) one ESD, a POEM, pancreatic cysts (with drainage, inspection of IPMN with Spy and confocal). In addition, there are pancreatic and biliary strictures of various types, contrast-enhanced EUS and various EUS-FNAs using various needles". Sounds like the kind of real-life stuff that is always interesting to see how other approach. Don't forget UEG Week Live and UEG 24/7—streaming many sessions as they happen and then making them available later on. Note, however, that none of the live endoscopy sessions are live streamed. On Monday, I'm looking forward to the acute upper GI bleeding therapy update in Hall D. I've got high hopes for the Hemospray device, which I hope will allow me to stay in bed when injection and thermal therapy has failed. In my mind the only outstanding question is "Do we need to organise an early re-check the next morning?" My guess is yes, that white powder will not stay on forever! We have two free paper sessions on new imaging and diagnostic modalities in upper and lower GI endoscopy on Monday afternoon. Not sure why the organisers haven't put the two sessions in the same hall though? Nevertheless, it's great to see that technology arms race is still in place. Sadly, there is a clash between the upper GI update and the update on gastro and duodenal endotherapy. I have the greatest respect for duodenal endotherapy, which is Tiger country indeed. It would be great if there were something that reduces the risk of late bleeding! For a large mucosal defect I spray thrombin, but this stuff is ridiculously expensive. On Tuesday morning Lars Aabakken and I will be hosting a session dedicated to the future of colorectal cancer screening. We'll give you an update on what to do with sessile serrated lesions, and presentations on the thorny issue of how to prevent and deal with local recurrences. Hopefully we can get a consensus on how many times we should try to get rid of a local recurrence before we give up. These are just some of the endoscopic happenings at UEG Week 2014. There are lots more to choose from including updates on Barrett's, EUS, ERCP, capsule and small bowel disease. Endoscopy continues to develop in numerous simultaneous directions driven by new technologies. I think that it has overtaken radiology in complexity, variety and colour! Please give us some feedback on which endoscopy sessions you're enjoying throughout the meeting. The easiest way may be to tweet using any of the hashtags: #UEGWeek #endoscopy #UEGEducation. Alternatively, just grab me for a chat!

Moving through the oesophagus at UEG Week 2014

If this is not your first time at UEG Week, you will already know that coffee breaks and lunch are on us! Just don’t spend too much time on them, as we have an extensive programme on the oesophagus and all things related waiting for you as well!

The postgraduate teaching programme on Sunday is your entrée. It starts with novel approaches and views on dysphagia and eosinophilic oesophagitis in patients with normal endoscopy, followed by a case presentation session on new options in gastro-oesophageal reflux disease (GORD). In the afternoon, you will be served an update on the management and outcomes of upper gastrointestinal bleeding (UGIB). Starting Monday, the oesophagus offering becomes truly 'buffet style' and you may want to take a look at the UEG Week Vienna Pathways Tool to help tailor your schedule to your appetite. For instance, this might be a good opportunity to get a therapy update on acute upper GI bleeding, starting at 11:00 in Hall D. Alternatively, you may walk into Hall B for views on the optimal management of patients with belching, aerophagia, rumination and hiccups. Can't decide? Here's a tip. Look for sessions with a 'Live' symbol. These will be streaming live on the UEG website and made available after the meeting via UEG 24/7. This is also a good day for you to grab your congress lunch and join Professor Mark Fox and colleagues in a round table discussion on dysphagia, based on a case presentation. Please come early though, as seats are limited. During the afternoon, there are two free paper sessions that might interest you: "Clinical and molecular factors in oesophago-gastric cancer outcomes", starting at 14:00 in Lounge 5, and "New diagnostic modalities in upper GI endoscopy", starting at 15:45 in Hall G/H. Continuing with your oesophageal main course, Tuesday kicks off with a therapy update on GORD, the implications of molecular pathogenesis on endoscopic therapy for Barrett's oesophagus, and a session on the risk factors and management of upper GI bleeding. If you are interested in novel endoscopic interventions in the oesophagus, please be sure to attend a free paper session on this topic at 11:00 in Hall O. Right after lunch at 14:00, you might want to join the discussion on whether function tests for the upper GI tract are indeed necessary or not (Hall B) or perhaps you might rather attend a free paper session on risk stratification and ablation in Barrett's oesophagus (Hall O). Moving towards the end of the day, a symposium on evidence-based treatment of achalasia takes place. No meal is complete without dessert! On Wednesday, the oesophagus pathway wraps up, starting with fresh and innovative views on the challenges and new frontiers in GORD and Barrett's oesophagus. You are also in for an integrated pathologist's versus endoscopist's view on oesophageal squamous cell carcinoma, early Barrett's neoplasia and early gastric carcinoma in the 11:00 symposium in Hall I/K. To return home with a sweet taste in your mouth, UEG Week 2014 ends with three cherries on top of the cake: a symposium on adenocarcinomas of the oesophago-gastric junction, another on endoscopic resection of upper GI tumours, and a free paper session on eosinophilic oesophagitis and other immune-mediated upper GI diseases.      We hope you enjoy the oesophagus 'course' at this year's UEG Week and look forward to your comments and tweets! (#UEGWeek #oesophagus #UEGEducation).
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