Mistakes in mouse models of IBD and how to avoid them
Learn how to get the most from experimental colitis models!
In general, mouse models of colitis are used to study its pathophysiology and for the development of new treatment modalities for inflammatory bowel disease (IBD). For the latter it is essential to select a mouse model that has many overlapping features with human IBD.More than 50 experimental colitis models have been developed and they have provided us with very useful insights into IBD physiology, as reviewed by Bouma and Strober1 and others,2–4 but they have limited use in predicting the clinical relevance of therapeutic targets in IBD.5 Experimental colitis models broadly fit into four different groups. First is spontaneous colitis, resulting from a naturally occurring genetic abnormality. Second is induced colitis occurring as a consequence of a targeted mutation or the introduction of a transgene. Third is induced colitis resulting from administration of different exogenous causative agents. Fourth is induction of colitis by manipulation of the immune system. We have learned a great deal from these models about the involvement of genetics, the microbiota and the role of different cells and the mucus layer in the development of IBD. Here we discuss the major mistakes that are made using experimental colitis models, based on our own experience and the scientific literature. Recently increased awareness has developed for the necessity to improve the methodological quality of animal studies.
ERCP & EUS Symposium
Recordings from the last Quality in Endoscopy series cover topics including “Conquering the papilla”, “Diagnostic EUS” and “Pancreatitis”.
Scientific writing practice
32 aspiring researchers met at the House of European Gastroenterology to practice how to craft research papers and abstracts.
Mistakes in colorectal cancer and how to avoid them
Specialist tips on diagnosis, prevention and treatment!
Colorectal cancer (CRC) is one of the most common malignancies and the second leading cause of cancer death in both sexes in developed countries. Over the past 30 years, a great advance in the understanding of this disease has occurred, from colorectal carcinogenesis to diagnosis, prevention and treatment.Although the majority of CRCs are related to environmental factors, up to 25% of cases have a familial component and potential genetic basis, and highly penetrant monogenic germline mutations account for up to 5% of all CRC cases1. Identification and characterization of these hereditary disorders have allowed modification of their natural history, with a substantial decrease in morbidity and mortality among high-risk patients1. Nonetheless, the majority of patients who are at high risk of CRC remain undiagnosed due to lack of suspicion. On the other hand, studies from the past two decades have suggested that besides adenomas, serrated polyps are also precursors of CRC, responsible for up to 15–30% of all malignancies.2 Several studies have demonstrated that serrated polyps are common precursors of colonoscopy interval cancers (cancers diagnosed within the surveillance interval after a complete colonoscopy), mainly due to their challenging clinical management.2 Finally, strategies for CRC prevention have shown efficacy in reducing CRC incidence and mortality, and colonoscopy is an integral part of CRC screening strategies. The main objective of screening colonoscopy is the detection and removal of premalignant lesions or early CRC.3 However, colonoscopy is not perfect, and some lesions may be missed. Colonoscopy quality is an emerging concept, and some quality indicators have been demonstrated to be directly related to the development of interval CRC.3 Here we discuss the major mistakes that are made when gastroenterologists deal with CRC diagnosis, prevention and treatment, and how to avoid them. The list of mistakes and the discussion that follows is evidence based and integrated with our longstanding clinical experience.
Mistakes in dyspepsia and how to avoid them
Expert knowledge at your fingertips!
Dyspepsia refers to upper abdominal discomfort that is thought to arise from the upper gastrointestinal tract. Symptoms include epigastric pain or discomfort, bloating, early satiety and/or fullness after meals, repeated belching or regurgitation (often rumination), nausea and heartburn.1 The symptoms of dyspepsia are nonspecific, but most commonly result from one of four underlying disorders: functional (nonulcer) dyspepsia, gastro-oesophageal reflux disease (GORD; 10–20% erosive esophagitis), peptic ulcer disease (5–15%) and malignancy (~1%).2 Dyspeptic symptoms may also result from other problems, such as medication intolerance, pancreatitis, biliary tract disease or motility disorders (e.g. gastroparesis or gastric dumping).Clinical guidelines recommend that endoscopy is not always required for diagnosis; a positive diagnosis of GORD and functional dyspepsia can be based on clinical presentation in the absence of alarm symptoms or features (see below).3,4 In many cases symptoms are increased after meal ingestion (postprandial distress syndrome), being triggered by impaired gastric accommodation and visceral hypersensitivity to gastric distension.5 Other patients have an epigastric pain syndrome in which discomfort is independent of food intake and gastrointestinal function.6 There is an important overlap between functional dyspepsia and other functional gastrointestinal diseases (e.g. irritable bowel syndrome [IBS]) and chronic pain syndromes (e.g. fibromyalgia).7 Psychological disease (e.g. anxiety or somatization disorder) and/or psychosocial stress are also present in a significant proportion of patients who seek medical attention.8,9 Notwithstanding the constructive advice provided by published reviews and guidelines, the broad definition of dyspepsia, lack of diagnostic investigations, uncertain cause of disease, psychosocial issues and paucity of specific treatments make the management of dyspepsia challenging. Here, I discuss 10 common and/or high-impact mistakes that are made in the diagnosis and treatment of patients with dyspeptic symptoms: five related to diagnosis, five related to treatment.
Mistakes in coeliac disease diagnosis and how to avoid them
Learn from leaders in the field!
Coeliac disease is regarded as an autoimmune disorder triggered by gluten, which activates an immune reaction against the autoantigen tissue transglutaminase (transglutaminase 2; TG2) in genetically predisposed subjects. Genetic susceptibility to coeliac disease has been proven by its close linkage with major histocompatibility complex (MHC) class II human leukocyte antigen (HLA) DQ2 and DQ8 haplotypes. The identification of biomarkers for coeliac disease (e.g. endomysial antibodies [EmA] and antibodies to TG2 [anti-TG2]) has changed the epidemiology of coeliac disease from being a rare to a frequent condition, with an expected prevalence of 1% in the worldwide population.1 Nonetheless, the majority of patients who have coeliac disease remain undiagnosed, leaving the coeliac ‘iceberg’ mostly submerged. Coeliac disease can be difficult to diagnose because symptoms vary from patient to patient. Indeed, the heterogeneity among the clinical signs and the lack of specificity of many of the presenting symptoms means that the diagnosis of coeliac disease can be a challenge even for experts.Despite substantial differences in the mode of presentation and the availability of new diagnostic tools, small intestinal biopsy, which shows different grades of mucosal damage, remains the gold standard for coeliac disease diagnosis. A delayed diagnosis of coeliac disease in the elderly can be considered a risk factor for complications including refractory coeliac disease, ulcerative jejunoileitis, collagenous sprue, small bowel carcinoma and enteropathy-associated T-cell lymphoma (EATL). Complicated coeliac disease is not so frequent, being found only in about 1–2% of the total number of coeliac disease patients, but for those who have it the prognosis is very poor, with a low rate of survival after 5 years.2 Here we discuss the major mistakes that are made when diagnosing coeliac disease and how to avoid them. The list of mistakes and the discussion that follows is evidence based and integrated with our clinical experience of more than 30 years in this field.
Advice on Christmas Dinners...
A factual but fun article for the festive period from Mark Fox based on a Q&A session for his local newspaper
Advice on Christmas Dinners and its after effects“A factual but fun article for the festive period from Mark Fox based on a Q&A session for his local newspaper. Merry Christmas!”
How have nurse endoscopists benefitted endoscopy services?
I remember the incredulity on the faces on my European colleagues 20 years ago when I told them that the UK was to start training nurse endoscopists. They doubted that it was desirable (or even possible!) to train nurses. Of course, by then the American Society for Gastrointestinal Endoscopy (ASGE) had for many years endorsed flexible sigmoidoscopy by ‘nonspecialists,’1,2 but little evidence of their effectiveness had been published.3Unsurprisingly, it was the relentlessly increasing demand for endoscopy that made the introduction of nurse endoscopists necessary in the UK. Some 20 years ago, the demand for gastroscopy approached 10 per 1,000 population per year and the demand for colonoscopy was expected to increase from an average of 2.5 to 10 colonoscopies per 1,000 population per year.4 In addition, the implementation of the NHS National Bowel Cancer Screening programme would further inflate the demand for endoscopy. For this reason, a British Society of Gastroenterology (BSG) Working Party5 gave the green light for nurse endoscopy, together with the United Kingdom Central Council (UKCC)6 and the General Medical Council (GMC). However, it was a cautious start because endoscopy was seen as a risky procedure that was associated with a 1:2,000 risk of death.7 The BSG, GMC and UKCC all agreed that nurse endoscopists were only to act as “technicians”. The responsibility for the patient’s management remained with “the supervising doctor” who had to be “immediately available within the hospital” (an oxymoron of course) in the event of complications or to give advice. Now we know that they were wrong and that the “interpretation of findings does not rely on the experience and training of an appropriately qualified doctor.”5 Endoscopy can be taught! Indeed, throughout the UK, nurse endoscopists now work independently, interpreting findings without the immediate supervision of a clinician. The uptake of nurse endoscopy has been steady in the past 20 years. In Leeds we have seven nurse endoscopists who undertake about 22% of our gastroscopies, 27% of our colonoscopies and all of our flexible sigmoidoscopies. ERCP, enteroscopy, EUS and most therapeutic endoscopy procedures that pose a significant risk of complications are carried out by consultants who are increasingly dedicating their time purely to endoscopy. Now we know more about the performance of nurse endoscopists. There is irrefutable evidence that the caecal intubation rate, adenoma detection rate, complication rate and patient satisfaction scores are comparable among nurses and doctors.8–10 In Leeds, the ‘raw’ caecal intubation rate for both our nurse endoscopists and consultants is 92% and the average polyp detection index (total number of polyps found/total number of patients) is also virtually identical (34.5 for nurses and 33.5 for consultants). In view of the reassuring published literature that has become available over the years, I was bemused to read a recent survey from New Zealand in which only 30% of doctors welcomed the introduction of nurse endoscopists.11 A huge majority believed that doctors would always deliver a better quality of endoscopy and that overall costs would spiral out of control if nurses were to be trained in endoscopy. Of course, endoscopy is a valued source of extra income for gastroenterologists in New Zealand, which makes me wonder if this may have had an influence on the outcome of the survey. Nevertheless, the statistics, reassuring as the may be, do not do nurse endoscopists justice. As a lead endoscopist, it is a relief to have a stable workforce that is fully committed to endoscopy. Most of my gastroenterology colleagues rush between ward rounds and outpatient clinics, phoning patients and their relatives in between. They have little time and energy to invest in endoscopy. By contrast, if an endoscopy list needs back filling, one of our nurse endoscopists will take it on. If an endoscopy audit is required, a nurse endoscopist can make the time. If there is an endoscopy-related problem, a nurse endoscopist will be willing to get involved. The truth is that without nurse endoscopists, endoscopy services will not be able to make the quantum leap from ‘Cinderella speciality’ to a core hospital service that is on an equal footing with radiology. My advice to any anxious colleagues who worry about the emergence of the nurse endoscopist is to welcome them, because with their help we can make endoscopy bloom! References
- Maule WF. Screening for colorectal cancer by nurse endoscopist. NEJM 1994; 330(3):183–187.
- DiSario JA and Sanowski RA. Sigmoidoscopy training for nurses and resident physicians. Gastrointest Endosc 1993; 39(1):29–32.
- Committee on Training, Gross GWW, Bozymski EM, et al. Guidelines for training non-specialists in screening flexible sigmoidoscopy. Gastrointest Endosc 2000;51(6):783–785.
- Barrison IG, Bramble MG, Wilkinson M, et al. Provision of endoscopy related services in district general hospitals: BSG Working Party Report 2001.
- British Society of Gastroenterology. Report of the British Society of Gastroenterology Working Party—The nurse endoscopist. 1994.
- UKCC. The Scope Of Professional Practice. London UKCC 1992.
- Quine MA, Bell GD, McCloy RF, et al. Prospective audit of upper gastrointestinal endoscopy in two regions of England: safety, staffing, and sedation methods. Gut 1995; 36(3):462–467.
- Hui AJ, Lau JY, Lam PPY, et al. Comparison of colonoscopic performance between medical and nurse endoscopists: a non-inferiority randomised controlled study in Asia. Gut 2015; 64(7): 1058–1062.
- Massl R, van Putten PG, Steyerberg EW, et al. Comparing quality, safety, and costs of colonoscopies performed by nurse vs physician trainees. Clin Gastroenterol Hepatol 2014; 12(3): 470–477.
- Schoenfeld P; Lipscomb S; Crook J; et al. Accuracy of polyp detection by gastroenterologists and nurse endoscopists during flexible sigmoidoscopy: a randomized trial. Gastroenterology 1999; 117(2): 312–318.
- Khan MI, Khan R and Owen W. Doctors and the nurse endoscopist issue in New Zealand. NZ Med J 2012; 125(1357): 88–97.
Colonoscopy & Neoplasia
A new symposium in the QinE series features leaders & rising stars on pressing topics in the field.
Pretty but probably poisonous
What is the most likely histology of the lesion?
The beautiful polyp shown in the photograph (figure 1) was found in the rectum of a middle-aged man who was on a polyp surveillance programme.WHAT IS THE MOST LIKELY HISTOLOGY OF THE LESION? a) Hyperplastic polyp b) Tubular adenoma c) Tubulovillous adenoma d) Villous adenoma e) Traditional serrated adenoma
Possible pancreatitis or could it be cancer?
A retired man with an unusual cause of jaundice...
A 65-year-old man presents with obstructive jaundice. He admits to drinking up to half a bottle of wine every day. The photograph shows the findings of the abdominal CT that is organised (figure 1). Subsequently, an endoscopic retrograde cholangiopancreatography (ERCP) is arranged to place a common bile duct (CBD) stent and obtain ampullary biopsy samples. Unfortunately the obstruction, just distal to the first part of the duodenum, prevents access to the papilla (figure 2).WHAT IS THE LIKELY DIAGNOSIS? a) Acute pancreatitis b) Autoimmune pancreatitis c) Chronic pancreatitis d) Carcinoma of the head of the pancreas e) Duodenal adenocarcinoma
Medical writing in 4 sessions
Engage with the expert in the field, Abe Fingerhut. 4 compelling online sessions provide a formalised approach to this critical but often neglected skill.
Confusion over a rectal biopsy sample
How would you manage this nodule?
The nodule shown in the photograph was found in the rectum of an elderly, asymptomatic patient undergoing a gastroscopy and colonoscopy because of mild iron-deficiency anaemia (figure 1). Biopsy samples were taken from the nodule and the H&E stain is shown (figure 2).HOW WOULD YOU MANAGE THIS NODULE? a) Ignore the polyp b) Sample it again c) Remove it by endoscopic mucosal resection d) Remove it by endoscopic submucosal dissection e) Remove it surgically
Access Bacelona recordings
The ESDO Cancer workshop, held at UEG Week 2015, presented innovative strategies in GI cancers, with a focus on molecular pathology.
Access free of charge
Early Detection of Pancreatic Cancer—How?
What's the outlook for the development of biomarkers?
World Pancreatic Cancer Day is being held on November 13. It is estimated that 367,000 new cases of pancreatic cancer will be diagnosed worldwide in 2015 and the dismal survival rate means that only 2–10% of patients will be alive 5 years after diagnosis.Globally, pancreatic cancer is the seventh most common cause of cancer-related death, and while death rates for many cancers are dropping, the death rate for pancreatic cancer is rising in Europe and the United States.1 The mortality of pancreatic cancer may, at least in part, be explained by the fact that early diagnosis is challenging. However, advances in the development of various biomarkers appear to hold promise for future screening of high-risk individuals, which—according to Cancer Research UK—includes patients with hereditary pancreatitis, a high incidence of pancreatic cancer in their family or a family history of at least one person with pancreatic cancer plus a linked cancer syndrome (e.g. a BRCA2 mutation).2 It has been reported that levels of serum cancer antigen 19-9 (CA19-9) are elevated in approximately 80% of patients with pancreatic cancer,3 and CA19-9 has been useful for therapeutic monitoring and early detection of recurrent disease after treatment in patients with known pancreatic cancer.4 However, CA19-9 is not a specific biomarker for pancreatic cancer. Moreover, patients who are negative for Lewis antigen a or b (approximately 10% of patients with pancreatic cancer) are unable to synthesize CA19-9. Although measurement of serum CA 19-9 levels is useful in patients with known pancreatic cancer, the use of this biomarker as a screening tool has yielded disappointing results.4 In addition to genetic alterations, dysregulation of specific epigenetic mechanisms is critical to tumour development. Comparing patients who have pancreatic cancer with healthy individuals and patients with chronic pancreatitis, Schultz et al. described differences in microRNA expression in whole blood with a view to identifying microRNA panels (classifiers) for diagnosing pancreatic cancer.3 microRNAs—non-coding 17–25-nucleotide-long RNAs that regulate gene expression—play important roles in tumour development and metastasis, and several have been described as specific to pancreatic cancer. Schultz and colleagues validated microRNA panels against CA19-9 sero-status and disease, and identified two panels for diagnosing pancreatic cancer using combinations of four and ten microRNAs in whole blood, respectively. The investigators call for further studies that could validate the use of these biomarkers as a screening tool for early-stage pancreatic cancer detection. More on the role of microRNAs in pancreatic tumour growth and progression can be found in a paper by Frampton and colleagues that was published in The Lancet in February 2015.5 Even more recently, in an article in Nature, Melo and colleagues6 suggested the use of a proteoglycan molecule (glypican-1 [GPC1]) anchored in the membrane of extracellular vesicles—exosomes—circulating in the bloodstream as a cancer biomarker. In particular, the team claimed that detection of GPC1+ exosomes in the blood could distinguish patients with early-stage and late-stage pancreatic cancer from patients with benign pancreatic disease and healthy individuals. The assay appeared more reliable than that based on CA19-9 detection. Compared with healthy donors, serum CA19-9 levels were increased in patients with cancer, but CA19-9 levels were also significantly increased in the serum of patients with benign pancreatic disease. Moreover, CA19-9 levels failed to distinguish patients with pancreatic cancer precursor lesions from healthy donors. An expanded interpretation of this important study, including a discussion of semantic issues, can be found in an accompanying News & Views article by Clotilde Théry.7 Apart from microRNAs, epigenetic features such as DNA methylation, satellite repeats and histone modifications might serve as biomarkers for early diagnosis of pancreatic cancer.8 Reviewing genes aberrantly methylated in pancreatic cancer, Henriksen and her team concluded that investigations into hypermethylated markers in cell-free DNA in plasma or serum are still limited by the availability of only a handful of small studies, which lack well-defined control groups, and that no single gene has been identified as a diagnostic marker.9 To read more about the many challenges related to identifying biomarkers for early diagnosis of pancreatic cancer, I recommend looking up a review by Jenkinson and colleagues.10 There are also a couple of interesting sessions from the recently concluded UEG Week 2015 in Barcelona that I’d like to highlight—all are available online. To learn more about ‘liquid biopsies’, including cell-free DNA, exosomes, and circulating tumour cells, you could look up the talk delivered by Aldo Scarpa, “Molecular diagnostics: From tissue biomarkers to liquid biopsies, single genes and panels”, which was part of the session “Pancreatic cancer: Where are we and what is the future?”11 There’s also an update session on therapy, including talks on chemotherapy, surgical resection, preoperative and palliative treatment, and neoadjuvant and adjuvant treatment.12 Finally, I would like to direct your attention to a talk that was given by Jean-Luc van Laethem, entitled “Pancreatic cancer in annual review”.13 Challenges aside, sensitive and specific biomarkers of early pancreatic cancer that can be obtained non-invasively appear critical to reducing the morbidity and mortality associated with pancreatic cancer. As we mark the 2015 World Pancreatic Cancer Day, we should set our hopes on it not being too long until one or more biomarkers prove valid for use in screening. References
- Schultz NA, Dehlendorff C, Jensen BV, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 2015; 311: 392–404.
- Hidalgo M. Pancreatic cancer. N Eng J Med 2010; 362: 1605–1617.
- Frampton AE, Castellano L, Colombo T. Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression. Lancet 2015; 385 Suppl 1: S37.
- Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523: 177–182.
- Théry C. Cancer: Diagnosis by extracellular vesicles. Nature 2015; 523: 161–162.
- Fukushige S, Horii A. Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers. Cancer Lett 2014; 342: 231–237.
- Henriksen SD, Madsen PH, Krarup H, et al. DNA hypermethylation as a blood-based marker for pancreatic cancer: A literature review. Pancreas 2015; 44: 1036–1045.
- Jenkinson C, Earl J, Ghaneh P, et al. Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015; 9: 309—315.
- Pancreatic cancer: Where are we and what is the future? Session at UEG Week 2015.
- Therapy update: Pancreatic cancer Session at UEG Week 2015.
- Pancreatic cancer in annual review Presentation by Jean-Luc van Laetham in the Pancreas: What’s new in 2015? Session at UEG Week 2015.
A coeliac conundrum
What would you do next for this middle-aged woman previously diagnosed with coeliac disease?
A middle-aged woman presented with loose stool and weight loss. Initially, she refused an endoscopy and a diagnosis of coeliac disease was made on the basis of a high tissue transglutaminase (tTG) antibody titre. She was started on a gluten-free diet (GFD) but her symptoms remained despite adherence to the GFD. After several months she agreed to undergo an endoscopy. The images show the endoscopic view of the duodenal mucosa (figure 1) and the corresponding histology slide (figure 2) stained with haemotoxylin and eosin (H&E).WHAT WOULD YOU DO NEXT? a) Refer the patient for a dietary review b) Request a clonal analysis of the intraepithelial lymphocytes c) Refer for HLA DQ2/DQ8 testing d) Refer the patient for capsule endoscopy e) Add prednisolone to the dietary restrictions
An interesting ileal finding
What are the treatment options for this lesion discovered during colonoscopy?
A 50-year-old woman is undergoing a colonoscopy because of loose stool. When the tip of the endoscope enters the terminal ileum, the lesion in the photograph is found. The patient asks you if any treatment will be necessary.WHAT DO YOU TELL THE PATIENT? a) The lesion is likely to be a lipoma and can probably be ignored b) The lesion is likely to be adenomatous and should be removed by endoscopic mucosal resection (EMR) c) The lesion is likely to be a neuroendocrine tumour (NET) and should be removed surgically d) The lesion is likely to be a gastrointestinal stromal tumour (GIST), requiring annual surveillance e) None of the above
Small things, vast impact: gut microbiota in health & disease
All things microbiota related at UEG Week 2015!