Atherton, John

Farthing, Michael

Fitzgerald, Rebecca

Fockens, Paul

Koletzko, Sibylle

Manns, Michael

Morino, Mario

Panes, Julian

Seufferlein, Thomas

English

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Major advances in gastroenterology and hepatology over the last 25 Years: Review of 25th UEG Week Anniversary Session

Open Access LMU

UEG NewsMajor advances in gastroenterologyand hepatology over the last 25 Years:Review of 25th UEG Week Anniversary SessionIntroduction, Michael Farthing1As United European Gastroenterology (UEG) cele-brates 25 years as a major provider of internationalconferences, postgraduate education, a leading commu-nicator of discovery science and an advocate of high-quality clinical practice across Europe, it seemed rightto review our achievements in gastroenterology andhepatology.In 2014, UEG commissioned a survey of the impactof gastrointestinal (GI) and liver disease in Europe withthe intention that this should guide future healthcareplanning and research. The presentations in the 25thUEG Week Anniversary Session have updated thatwork, focusing on the major advances that have beenmade in the treatment of inflammatory bowel disease(IBD), Hepatitis C virus infection (HCV), Helicobacterpylori (H. pylori), gastro-oesophageal reflux disease(GERD), the treatment of childhood diarrhoea andthe diagnosis and treatment GI cancer. The extraordin-ary technical advances that have been made in GIendoscopy and laparoscopic surgery are also discussed.In addition to the impact survey, UEG also under-took a scenario planning exercise to further understandthe range of possibilities for the delivery of care in GIand liver disorders. During the final part of the anni-versary session we, like a fortune-teller, gazed into a‘crystal ball’ and imagined how healthcare profes-sionals in our disciplines would deal with the challengesahead.Antibodies in inflammatory bowel diseases,Julian Pane´s2The introduction of the monoclonal antibodies (MAbs)in the treatment of IBD represented a true revolution.MAbs have provided new effective and safe modes oftherapy, but also brought to the field of IBD new para-digms for drug dosing, the redefinition of therapeutictargets, and completely changed the design of drugdevelopment programmes.Initial studies with infliximab for treatment ofCrohn’s disease or ulcerative colitis generated enthusi-asm for its efficacy, but it became apparent that somepatients did not respond or lost response during therapy.One of the early reasons identified for this problem wasthe development of anti-drug antibodies. It became clearthat the pharmacokinetics of MAbs is complex, withmany factors, in addition to immunogenicity, affectingdrug clearance and drug concentration at target tissue,including leakage of antibody into the gut lumen, targetabundance, and drug degradation by metalloproteinasesat sites of inflammation.The development of therapeutic MAbs has alsointroduced the use of objective measures of diseaseactivity and severity, both for patient selection and asan outcome measure. It is also informing the selectionof therapeutic targets in studies and clinical practice,showing that endoscopic remission is associated withsuperior long-term clinical outcomes.Hepatitis C virus: Discovery and extinction,Michael Manns3HCV causes chronic hepatitis which might result inliver cirrhosis, hepatocellular carcinoma, liver trans-plantation or death. Globally, more than 100 millionpeople are chronically infected. The discovery of HCVin 1989 led to the development of hepatitis C antibodytesting (anti-HCV) and subsequently HCV RNA meas-urement, viral genotype and subtype determination.This blood-borne infection was caused by blood andblood products until anti-HCV blood product screen-ing was introduced in 1990. At present, major risk fac-tors are unsafe injection drug use and unsterile medicalprocedures, in particular in countries with a high HCVprevalence. The interplay between basic research andclinical medicine led to the development of diagnostictests and HCV therapies that for the first time enabled acure of a chronic viral infection in man. Milestones ofthis development are virus discovery, the establishmentof diagnostic tests, the identification of the HCV lifecycle and the development of an in vitro repliconsystem that paved the way towards direct-acting anti-viral agents (DAAs). Therapeutic developments hadalready started in 1986 with the use of recombinantinterferon alfa when the disease was still called non-A, non-B hepatitis and the virus had not been dis-covered. Cure rates gradually improved over the yearsUnited European Gastroenterology Journal2017, Vol. 5(7) 1053–1056! Author(s) 2017Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2050640617737268journals.sagepub.com/home/uegdue to higher doses and longer durations of interferonalfa, the addition of ribavirin, the use of long-actingpegylated interferons (PEG-IFN) and finally DAAs.Three different classes of DAAs target three differentsteps in the HCV replication cycle: the NS3/4 protease,the HCV polymerase and the NS5A protein, which isunique for HCV infection. In 2014, the first all-oralinterferon-free regimen became available and in 2017combinations of two or three DAAs have allowed forthe cure of HCV infection close to 100% for all geno-types and all patient populations, including decompen-sated liver disease in 8–16 weeks and almost withoutany side effects. As of today HCV is still a major globalhealth burden. The discovery of HCV and the subse-quent development of diagnostic tests and HCV thera-pies was a masterpiece of modern translationalmedicine that should facilitate global HCV eradication.Helicobacter pylori: The Nobel bug,John Atherton4The landmark description of H. pylori by Robin Warrenand Barry Marshall in their letters to the Lancet in 1983heralded a revolution in the understanding and practiceof gastroenterology. Most peptic ulceration – particu-larly duodenal ulceration – is an infectious diseasecaused by a bacterium that is acquired in childhoodand carried lifelong. A simple combination of antibiotics(usually with a proton pump inhibitor) not only healsulcers but prevents their recurrence: it cures the disease.Even more significantly, gastric adenocarcinoma – untilrecently the second biggest cancer killer in the world – isalso largely an infectious disease. AsH. pylori prevalenceis falling so, dramatically, is the incidence of gastriccancer. This is one of the biggest public health successesof our generation.However, all is not perfect. H. pylori has lived in ourstomachs at least since humans emerged from Africa,and most likely throughout our evolution. As we haveco-evolved with it, our physiology and immunologyhave adapted to its presence. Without it, our stomachsare, on average, more acidic and H. pylori-free humansmore frequently develop complications of GERD –Barrett’s oesophagus and oesophageal adenocarcin-oma. H. pylori also stimulates a regulatory immuneresponse and the lower level of this in H. pylori-freeindividuals may explain why some allergic diseases,notably childhood asthma, are more common in thosewho are H. pylori negative. Avoidance of gastric canceris likely to greatly outweigh these considerations: anH. pylori-free individual is likely to be a healthier indi-vidual – but not one who is at reduced risk of alldiseases.Endoscopy: A technical revolution,Paul Fockens5The impact of the advances in flexible gastrointestinalendoscopy in the past 25 years on patients with GIdisease, has been larger than any other development inour specialty. Thinking back, patients with acute ulcerbleeding were scoped to identify the cause of bleedingand then went for surgical therapy. Nowadays endoscopyis both the first and second line of treatment in any ulcerbleeding. Patients with a dysplastic Barrett’s oesophagusall used to go for esophageal resection because of ‘invis-ible’ cancers in 40%. Now they are diagnosed and treatedendoscopically with mucosal resection and/or ablation.Stones in the common bile duct (CBD) were an indica-tion for open surgical exploration, a technique that in2017 hardly any surgeon still masters and ERCP (endo-scopic retrograde cholangio-pancreatography) is takingcare of 99% of CBD stones now. Another bright exampleis that large flat colonic polyps were either missed (andbecame interval cancers) or went for surgical resectionwith considerable morbidity and mortality. In 2017,we detect them and more than 90% can be treatedendoscopically. Gastroenterology and hepatology arelarger than GI endoscopy alone, but high definition GIendoscopy has become a most important technique fordetection and treatment of early neoplastic changes in theGI tract and has replaced surgery in multiple other areas,reducing the burden for our patients.Treating diarrhoea in children: A globallife-saver, Sibylle Koletzko6Diarrhoea is the cause of death in 1 out of 10 childrendying under the age of 5 worldwide. In 2015, diarrhoeakilled 1400 young children per day, or 526,000 per year(UNICEF, One is too many. Ending child deaths frompneumonia and diarrhoea, November 2016). Diarrhoeais most deadly in the poorest places in the world such assub-Saharan Africa and South Asia. Many childrencould be saved through rather basic interventions.The younger the child, the greater is the risk that fluidand electrolyte losses will lead to health-threateningdehydration. Fluid losses from diarrhoea and vomitingcan be as high as three times the circulating bloodvolume. The type of dehydration – isotonic, hypotonicor hypertonic – is independent of the causative organism(viral or bacterial), and in all three situations treatmentwith oral rehydration solution (ORS) is safe and effective.ORS was developed after the discovery of the coupledco-transport of sodium and glucose in the enterocytes.In the presence of glucose or galactose, sodium is moreeffectively taken up from the intestinal lumen by thesGLT1 transporter. Water then passively follows the1054 United European Gastroenterology Journal 5(7)sodium influx. Since 2004, UNICEF and the WorldHealth Organization have promoted low-osmolarityORS and zinc, in addition to continued feeding, butlittle progress has been made in the broad implementa-tion over the last decade, with only 2 out of 5 affectedchildren being treated with ORS. Besides improvingaccessibility, particularly in rural areas of poor countries,education of health care providers and parents is crucialfor implementation of good diarrhoea management.Preventive measure such as providing clean water, pro-moting breast feeding and a vaccination programmeagainst rotavirus infection will further decrease thedeadly burden of diarrheal diseases.Gastrointestinal cancer treatment goespersonal, Thomas Seufferlein7For many years, 5-fluorouracil (5-FU)-based chemo-therapy was the mainstay for the treatment of GItumours, achieving moderate results. Over recentyears, this has substantially changed. New chemother-apeutic agents have been introduced. Furthermore,based on data from signal transduction research, so-called targeted agents have been developed that addressspecific properties of a given tumour such as theEpidermal Growth Factor receptor or the humanepidermal growth factor receptor 2. Now, there is aplethora of drugs that target the majority of signallingnetwork components in cancer. Large-scale tumoursequencing has also developed rapidly over the pastyears and allows us to identify the molecular alterationsin a given tumour. These approaches revealed thatapart from the conventional pathological classificationthere is a novel molecular classification of cancer. Usingsuch a classification, a whole cancer entity such as pan-creatic or colorectal cancer is reclassified into subgroupsaccording to their specific molecular profile. This allows,in principle, the tailoring of the treatment to the alter-ations present in the particular subgroup. Apart fromthe tumour itself, the tumour stroma and the host arealso increasingly the focus of therapeutic approaches.Antiangiogenic agents targeting the nutrient supplyof tumours have been in use for many years in GIoncology. Recently, immuno-oncology has achievedtremendous results – also in certain GI cancers. Aftermany years of searching for a master tumour antigenthe inhibition of immunological checkpoints is now atthe forefront of interest. Using so-called checkpoint inhi-bitors targeting the programmed cell death protein1/programmed death ligand-1 system, surprising resultscould be achieved in subgroups of tumours, e.g. in colo-rectal cancer with microsatellite instability. Here, almostall heavily pretreated patients with metastatic colorectalcancer achieved long-term survival when their tumourexhibited this molecular feature. Consequently, this treat-ment was approved for this subgroup by the Food andDrug Administration and the European MedicinesAgency. Thus, there is very exciting progress in the fieldand we are well on the road to a personalized treatmentof GI malignancies. There are of course unresolved issuesto tackle. First of all, not all tumours with a given muta-tion respond to a specific targeted drug. Here weneed a better understanding of tumour heterogeneity.Furthermore, we have to find ways to make immuno-logically ‘cold’ tumours (alas, the majority of GI cancers)accessible to the immune system.Gastroesophageal reflux disease: Reducingacid and complications, Rebecca Fitzgerald8The widespread availability of proton pump inhibitor(PPI) therapy has revolutionized the treatment of gas-troesophageal reflux disease (GERD). This class ofdrugs was first discovered in 1975 and in the 1980sthey were shown to be superior to H2 receptor antag-onists. In 1996 Omeprazole became the world’s biggestselling pharmaceutical and by 2004 over 800 millionpatients had been treated worldwide.For patients presenting to Gastroenterologists, diag-nosis of reflux symptoms has become much moresophisticated. Reflux and motility assessment has beentransformed by ambulatory pH tools including wirelessprobes, multi-probe pH catheters, spectrophotometers todetect bile reflux and impedance-pH monitoring, which iscurrently considered to be the most accurate and detailedmethod to assess gastroesophageal reflux. Patients cannow be sub-categorized into GERD, NERD (non-ero-sive reflux disease) and reflux hypersensitivity, permittinga more personalized treatment approach.When required, anti-reflux surgery is largelylaparoscopic with a number of endoscopic modalitiesavailable including magnetic sphincter augmentationand transoral incisionless fundoplication.In 2017 GERD presents a global economic burden.The challenge is to ensure that PPIs are not over-used –this is not only economically important but essential toavoid long-term complications, particularly in theelderly, and to ensure that patients are appropriatelyinvestigated for complications such as pre-malignantBarrett’s oesophagus.Laparoscopic surgery: A diagnostic andtherapeutic success, Mario Morino9In April 1989, Jacques Perissat presented at the SagesCongress in Louisville the video of a laparoscopicFarthing et al. 1055cholecystectomy. K.A. Forde, Sages’ President, definedthat moment as ‘a singular event that changed the historyof surgery perhaps for all time.’ In the following years,abdominal surgery was stormed by the so-called laparo-scopic revolution: all abdominal surgical procedures wereperformed by laparoscopy by an international group ofenthusiast minimal invasive surgeons.The reason for such a huge success was the undeni-able advantages of laparoscopy: reduced pain, quickerrecovery, shorter postoperative ileus, shorter hospitalstay, better cosmesis, and a better early quality of life.These advantages were self-evident to every patient.Randomized controlled trials were difficult to perform:for some procedures such as cholecystectomy, fundo-plication, Heller myotomy, bariatric, IBD resections,adrenalectomy, splenectomy, etc. patients were reluc-tant to accept randomization, favouring laparoscopicaccess.Oncologic digestive surgery was a different story.The typical advantages of laparoscopy were related toearly postoperative courses; surgeons and oncologistswere sceptical of long-term results. But in the years2000–2010 robust RCTs confirmed that laparoscopywas superior to open surgery in terms of early clinicalresults without affecting long-term disease-free survivalin colorectal cancer. These data prompted the diffusionof oncological procedures: nowadays, laparoscopyrepresents 50% of colorectal oncological surgery world-wide, while hepatic resections, partial and totalgastrectomies and distal pancreatic resections are stead-ily gaining popularity.After 25 years of continuous advances in minimalinvasive surgery including robotics, transanal, 3D, etc.we can affirm that the surgical trend towards a reduc-tion in the trauma of surgical access represents one ofthe major revolutions of surgery and will continue inthe near future as a consequence of technical, techno-logical and clinical progress.Watch the full recording of the session via UEGWeek24/7. https://www.ueg.eu/anniversary-session-recording/Notes1. Honorary Professor of Medicine, University College London2. Department of Gastroenterology, Hospital Clinic Barcelona,Spain3. Department of Gastroenterology, Hepatology and Endocrinology,Hannover Medical School, Germany4. University of Nottingham, Faculty of Medicine and HealthSciences, Nottingham, United Kingdom5. Department of Gastroenterology & Hepatology, AcademischMedisch Centrum, the Netherlands6. Dr. von Hauner Children’s Hospital, University Hospital, LMUMunich, Munich Germany7. Klinik fu¨r Innere Medizin I, Universita¨tsklinikum Ulm, Germany8. MRC Cancer Unit, University of Cambridge, UK9. University Hospital of Turino, Department of Surgical Sciences,Italy1056 United European Gastroenterology Journal 5(7)

Morino, M.

Institutional Research Information System University of Turin

07 January 2023AperTO - Archivio Istituzionale Open Access dell'Università di TorinoOriginal Citation:Major advances in gastroenterology and hepatology over the last 25 Years: Review of 25th UEGWeek Anniversary SessionPublished version:DOI:10.1177/2050640617737268Terms of use:Open Access(Article begins on next page)Anyone can freely access the full text of works made available as "Open Access". Works made availableunder a Creative Commons license can be used according to the terms and conditions of said license. Useof all other works requires consent of the right holder (author or publisher) if not exempted from copyrightprotection by the applicable law.Availability:This is the author's manuscriptThis version is available http://hdl.handle.net/2318/1655676 since 2018-01-05T12:19:39Z     This is the author's final version of the contribution published as:  MARIO MORINO,  Major advances in gastroenterology and hepatology over the last 25 years: Review of 25th UEG Week Anniversary Session. Laparoscopic surgery: A diagnostic and therapeutic success United European Gastroenterology Journal 5(7): 1055-1056,2017   -  DOI: 10.1177/2050640617737268     The publisher's version is available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676554/   When citing, please refer to the published version.   Link to this full text:  http://hdl.handle.net/2318/1655676           This full text was downloaded from iris-Aperto: https://iris.unito.it/   Major advances in gastroenterology and hepatology over the last 25 Years: Review of 25th UEG Week Anniversary Session  Laparoscopic surgery: A diagnostic and therapeutic success, Mario Morino9 9University Hospital of Turino, Italy In April 1989, Jacques Perissat presented at the Sages Congress in Louisville the video of a laparoscopic cholecystectomy. K.A. Forde, Sages’ President, defined that moment as ‘a singular event that changed the history of surgery perhaps for all time.’ In the following years, abdominal surgery was stormed by the so-called laparoscopic revolution: all abdominal surgical procedures were performed by laparoscopy by an international group of enthusiast minimal invasive surgeons. The reason for such a huge success was the undeniable advantages of laparoscopy: reduced pain, quicker recovery, shorter postoperative ileus, shorter hospital stay, better cosmesis, and a better early quality of life. These advantages were self-evident to every patient. Randomized controlled trials were difficult to perform: for some procedures such as cholecystectomy, fundoplication, Heller myotomy, bariatric, IBD resections, adrenalectomy, splenectomy, etc. patients were reluctant to accept randomization, favouring laparoscopic access. Oncologic digestive surgery was a different story. The typical advantages of laparoscopy were related to early postoperative courses; surgeons and oncologists were sceptical of long-term results. But in the years 2000–2010 robust RCTs confirmed that laparoscopy was superior to open surgery in terms of early clinical results without affecting long-term disease-free survival in colorectal cancer. These data prompted the diffusion of oncological procedures: nowadays, laparoscopy represents 50% of colorectal oncological surgery worldwide, while hepatic resections, partial and total gastrectomies and distal pancreatic resections are steadily gaining popularity. After 25 years of continuous advances in minimal invasive surgery including robotics, transanal, 3D, etc. we can affirm that the surgical trend towards a reduction in the trauma of surgical access represents one of the major revolutions of surgery and will continue in the near future as a consequence of technical, technological and clinical progress.  

Major advances in gastroenterology and hepatology over the last 25 Years: Review of 25th UEG Week Anniversary Session

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