Are we finally saluting the fungal kingdom as a co-ruler of GI health and disease?

The human body is host to myriads of fungal species—typically yeasts, moulds and dermatophytes. It has also long been known that Candida spp. present on the skin or mucosal surfaces can end up causing invasive mycotic disease in immunocompromised individuals, critical care patients and in those undergoing abdominal surgery, resulting in candidaemia or deep-seated candidiasis. Meanwhile, the impact of intestinal fungal colonisation and infection on gastrointestinal health and disease remains elusive. Thanks to advances in DNA detection technologies and mass spectrometry, the role of fungi in human gastrointestinal pathology, immunology and ecology is now finally—though slowly—being unravelled.

Over the past few years, communities of intestinal bacteria have been scrutinized meticulously in order to identify their role in human health and disease. This discipline is now commonly referred to as ‘gut microbiome research’, involving analysis of the structure and function of bacteria. Meanwhile, kingdoms of ubiquitous organisms in and on the human body have been more or less ignored;1,2 these kingdoms include fungi and parasitic protists. If we acknowledge the fact that such organisms are common denizens of our gastrointestinal canal,3 why have they failed to catch our attention? Firstly, it’s not unusual to hear people saying that bacteria outnumber microbial eukaryotic organisms a zillion times or so, and that bacteria are therefore seemingly much more important to study. However, while the crude number of colonising eukaryote organisms may be several orders of magnitudes lower than the number of bacteria, we should remember that the genomes of such organisms are typically larger, and the expressed gene repertoire may be much more comprehensive and refined. Secondly, problems related to detection and identification are almost certainly one of the main reasons why we have failed to include eukaryotes in gut microbiome research. Finally, the potentially ‘bittersweet’ nature of fungal colonisation may blur the pathway to knowledge. The bittersweet nature of fungal colonisation is highlighted in a talk given by Dr Gianluca Ianiro at EAGEN Gut Microbiota 2014: EAGAN Advances in Gut Microbiota and Fecal Microbiota Transplantation.4 Dr Ianiro also addresses the fundamental question of why we should bother about the fungal microbiome (the mycobiome) at all. He puts emphasis on the fact that a yeast such as Saccharomoyces cerevisiae var. boullardi is widely used as a probiotic (and possibly the only commercialised probiotic yeast), but that Saccharomyces is also a potential cause of fungaemia, suggesting that the virulence and/or host response to the yeast may vary dramatically. “Nobody is fungus-free,” Huffnagle and Noverr claim in an article published in 2013.5 They go on, “Every individual’s microbiome contains thousands of different species of microbes, of which 99.9% of the total number of microbial cells belong to only a few species. The less abundant (< 0.1%), but more diverse, component of the microbiome has been termed the ‘rare biosphere’. The impact of this rare biosphere on human health is significant because it can act as a reservoir for blooms of pathogenic microbes when the host is compromised.”  Asymptomatic yeast colonisation of mucosal surfaces may develop into a yeast infection in cases where the microbial ecology is skewed, for example during and/or after the use of antibiotics. Although research into the gut mycobiome is still in its infancy, it is clear that species of Candida can coexist with the intestinal bacterial microbiome, bloom during dysbiosis due to use of antibiotics and colonise inflamed intestinal mucosal surfaces. Very recently, Luan and colleagues6 analysed the fungal microbiota by deep sequencing the internal transcribed spacer 1 region (the marker commonly used for DNA-based fungal identification) of fungal DNA extracted directly from rinsed tissue biopsy samples from early-stage and advanced-stage colorectal adenomas as well as from adjacent (normal) tissue. The authors identified that core operational taxonomic units (OTU; taxonomic level of sampling when only DNA data are available) formed separate clusters for advanced and nonadvanced adenomas, for which the abundance of four OTU differed significantly. Both adenoma size and disease stage were associated with changes in the fungal microbiota. With no control material from healthy individuals available for analysis, the most important take-home message here may not be so much the findings, but the technical approach and the recognition that—similar to bacteria—intestinal eukaryotic communities may be significantly linked to disease processes, including that of colorectal cancer (CRC), in which case the microbiota represents not only a potential means of CRC detection (screening by biomarkers) but also intervention (microbiota manipulation). In a very recent review, Mukherjee and co-workers conclude that fungi may contribute to aggravating inflammatory responses, leading to increased disease severity.7 This process may involve multiple steps and components, including interactions between host immune cells with specific pattern-recognition receptors (e.g. dectin-1—a natural-killer-cell-receptor-like C-type lectin possibly involved in innate immune responses to fungal pathogens through recognition of β-glucan8) and pathogen-associated molecular patterns, including fungal cell wall moieties, such as mannan, glucan and chitin. Intriguing observations published in 2012 in Science by Iliev and co-workers9 suggest that certain polymorphisms in CLEC7A, the gene encoding dectin-1, are associated with medically refractory ulcerative colitis. The presence of live fungi in stools is also interesting from the faecal microbiota transplantation (FMT) perspective. Which organisms—which potential pathogens—are screened for when manufacturing FMT products? This is one of several topics that will be addressed at the UEG-endorsed practice course ‘The Fecal Microbiota Transplantation’, which is taking place in Rome in April.  And while we’re at it, how should we screen for fungi in stool samples? There are probably many opinions on that! Gouba and Drancourt have suggested the use of ‘culturomics’, which involves the use of several different culture media and incubation conditions to increase the efficiency of detection of organisms by culture, later identified by MALDI-TOF-MS to expand the repertoire of species and safeguard comprehensive detection.10 Whether this approach has advantages over metagenomics remains to be revealed. Novel technologies and increased availability of genome data enable precise and sensitive detection and identification of fungal and other microeukaryotic organisms in the gastrointestinal tract and how they interact with each other and the host. Efforts to map differences in fungal diversity in various cohorts are essential to generating hypotheses on the role of fungi in disease. Such studies are often cross-sectional; however, longitudinal studies of the intestinal mycobiota and mycobiome in healthy and diseased cohorts are critical if we are to obtain a more detailed and accurate understanding of exactly how fungi govern our health.
References
  1. Anderson LO, Nielsen HV and Stensvold CR. Waiting for the human intestinal Eukaryotome. ISME J 2013; 7: 1253–1255.
  2. Norman JM, Handley SA and Virgin HW. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 2014; 146: 1459–1469. 
  3. Scanlan PD and Marchesi JR. Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces. ISME J 2008: 2: 1183–1193.
  4. Ianiro G. Gut Mycome. Presentation at the EAGEN Gut Microbiota 2014: EAGEN Advances on Gut Microbiota and Fecal Microbiota Transplantation. 
  5. Huffnagle GB and Noverr MC. The emerging world of the fungal microbiome. Trends Microbiol 2013; 21: 334–341. 
  6. Luan C, Xie L, Yang X, et al. Dysbiosis of fungal microbiota in the intestinal mucosa of patients with colorectal adenomas. Sci Rep 2015; 5:7980. doi: 10.1038/srep07980.
  7. Mukherjee PK, Sendid B, Hoarau G, et al. Mycobiota in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2015; 12: 77–87.
  8. Brown GD. Dectin-1: a signaling non-TLR pattern-recognition receptor. Nat Reviews Immunol 2006; 6: 33–43. 
  9. Iliev ID, Funari VA, Taylor KD, et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 2012; 336: 1314–1317.
  10. Gouba N and Drancourt M. Digestive tract mycobiota: A source of infection. Med Mal Infect 2015; 45: 9–16. 
Additional Information  The photograph of Candida albicans grown on CHROM agar, in which a few hyphae are visible at 40x magnification, is provided courtesy of Rasmus Hare Jensen.

Endoscopic biopsy for coeliac disease diagnosis:

How many bites does it take?

A definitive diagnosis of coeliac disease is made based on the presence of characteristic histological changes in biopsy samples taken from the proximal small bowel in patients who have clinical features of gluten sensitivity. New findings suggest that the best biopsy samples for the diagnosis of coeliac disease are obtained using the single-biopsy technique.

Guidelines for the diagnosis and management of coeliac disease recommend that a minimum of four biopsy samples are taken from the second part of the duodenum and the bulb.1,2 A ‘well-oriented’ biopsy specimen is defined as a piece of intestinal mucosa that encompasses four consecutive, parallel, crypt-to-villous units that can be visualized along their entire length; however, the majority of specimens taken lack such quality, which decreases their diagnostic yield.3 In order to decrease procedural time, endoscopists usually take two bites per pass of the biopsy forceps (double-biopsy technique), as opposed to taking one bite per pass of the biopsy forceps (single-biopsy technique). Previous studies of the quality of biopsy specimens obtained by single versus multiple bites taken from both the upper4–6 and lower7 gastrointestinal tract have generated conflicting results. Melissa Lattore and colleagues from Columbia University, New York, USA, have now compared the double-biopsy and single-biopsy techniques in terms of the quality of biopsy samples obtained for the diagnosis of coeliac disease.In this study, four biopsy samples were taken from each patient: two were obtained using the double-biopsy technique and two were obtained using the single-biopsy technique. All specimens were obtained using the same equipment and the pathologist was blinded to the indication and biopsy technique. Duodenal bulb biopsies were excluded to eliminate any confounders. The authors determined that the single-biopsy technique was superior to the double-biopsy technique in yielding more well-oriented specimens and decreasing procedural specimen loss. Another relevant finding was the better sensitivity for detecting subtle mucosal changes indicating coeliac disease as intraepithelial lymphocytosis in samples obtained with the single-biopsy technique. They explain their findings by pointing out that the needle at the centre of the biopsy forceps—which is meant to help retain specimens—causes fragmentation and limits the capacity of the forceps to accommodate tissue once a second bite is taken. I also had this idea, but dismissed it, saying I was thinking too much, so I’m glad someone else did! So, what does this mean? The study was single centred and not randomized, but the change in practice proposed is easily applied. It is possible that limiting yourself to taking a single biopsy when using spiked forceps gives better histology throughout the gastrointestinal tract. Certainly for coeliac disease, where only 12–17% of patients currently get diagnosed,9,10 it is worth considering. References
  1. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. Epub ahead of print 20 June 2014. DOI: 10:1136/gutjnl-2013-306578.
  2. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013; 108: 656–676. 
  3. Gonzalez S, Gupta A, Cheng J, et al. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease. Gastrointest Endosc. 2010; 72: 758–765. 
  4. Padda S, Shah I and Ramirez FC. Adequacy of mucosal sampling with the “two-bite” forceps technique: a prospective, randomized, blinded study. Gastrointest Endosc. 2003; 57: 170–173. 
  5. Fantin AC, Neuweiler J, Binek JS, et al. Diagnostic quality of biopsy specimens: comparison between a conventional biopsy forceps and Multibite forceps. Gastrointest Endosc. 2001; 54: 600–604.
  6. Chu KM, Yuen ST, Wong WM, et al. A prospective comparison of performance of biopsy forceps used in single passage with multiple bites during upper endoscopy. Endoscopy. 2003; 35: 338–342.
  7. Hookey LC, Hurlbut DJ, Day AG, et al. One bite or two? A prospective trial comparing colonoscopy biopsy technique in patients with chronic ulcerative colitis. Can J Gastroenterol. 2007; 21: 164–168.
  8. Latorre M, Lagana SM, Fredberg DE, et al. Endoscopic biopsy technique in the diagnosis of celiac disease: one bite or two?. Epub ahead of print 28 January 2015. Gastrointest Endosc. DOI: 10.1016/j.gie.2014.10.024.
  9. Association of European Coeliac Societies. Improving Diagnosis of Coeliac Disease (accessed 25 February 2015). 
  10. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012; 107: 1538–1544.

A suspicious sigmoid stricture?

Watch the video & decide!

This patient is undergoing an emergency flexible sigmoidoscopy after admission with sudden onset of vomiting and abdominal distension.

Watch the video WHAT IS THE DIAGNOSIS? a) Ischaemic stricture b) Crohn’s stricture c) Malignant stricture d) Diverticular stricture e) None of the above This is a most peculiar sigmoidoscopy! There is a narrowing of the lumen in the mid-sigmoid that the endoscopist is able to traverse. On the other side of the stricture you find yourself looking at… small bowel mucosa! The patient has suffered a colonic perforation that has given rise to a fistula into the ileum, so option e is the correct answer. Diverticular disease used to be a condition that was firmly in the surgical camp. However, uncomplicated diverticulitis is increasingly managed with conservative therapy and it appears that we don’t even need to give antibiotics in all cases.1 Only about a quarter of patients develop complications requiring surgery. Remarkably, patients who are well but have free air in the abdomen that is visible on X-ray, may be treated with antibiotics and bowel rest2  and abscesses are usually drained radiologically. In a case such as this, with a combined small bowel and colonic obstruction, surgery is indicated. The traditional operation is the Hartmann procedure with a proximal colostomy. The drawback is that a proportion of patients who undergo this procedure will never have their bowel continuity restored. In view of this, many colorectal surgeons have advocated that a primary anastomosis can be an equally safe but a better alternative in selected cases. There is no evidence from clinical trials to inform us which is the better option. However, the construction of a primary anastomosis is more demanding and requires the sound clinical judgment of an experienced colorectal surgeon to decide when this option is likely to fail. The Postgraduate Course of the UEG Week 2013 dedicated a complete session to the topic of diverticular disease (Diverticular disease: Important, poorly understood and badly managed) and is well worth a look. Just sign in to myUEG, put ‘Diverticular disease’ into the UEG Education Library search box and hit enter! References
  1. Chabok A, et al. Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. Br J Surg 2012; 99: 532–539. 
  2. Costi R, et al. Challenging a classic myth: pneumoperitoneum associated with acute diverticulitis is not an indication for open or laparoscopic emergency surgery in hemodynamically stable patients. A 10-year experience with a nonoperative treatment. Surg Endosc 2012; 26: 2061–2071. 

Case 2

The photograph shows what was found in the rectum of a 65-year-old homosexual man who was complaining of bright red rectal bleeding. He admitted to drinking two to three whiskeys per day. He was not taking any medication and his only past history was of prostatic carcinoma, which was treated 2 years previously. There was no relevant family history.

How would you initially manage the patient? a) Rectal steroids b) Rectal aminosalicylates c) Cautery using a heater probe or argon coagulator d) Antibiotics e) Surgical resection

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.
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