Gastroenterology & Hepatology

Prof. dr. Maikel P. Peppelenbosch, Prof. dr. M.J. Bruno

The gastrointestinal tract can be affected by a large variety of disorders, many of which are characterized by chronic active inflammation, ultimately leading to morphological and functional changes. A considerable proportion of these chronic inflammatory disorders promote the development of dysplasia and neoplasia of the affected organ. Together, the gastrointestinal tract is more frequently affected by chronic inflammation and malignancy than any other organ system in the human body. This induces a great need for further insight into the mechanisms underlying infections, inflammation and malignancy of the digestive tract, as well as methods for prevention, early diagnosis and treatment.

The research within this theme focuses on the causes and the mechanisms underlying chronic inflammation and the processes, which lead to morphological and functional disturbances, and neoplasia development of the affected organ. Diagnosis, treatment, screening and surveillance are key items within this focus. Clinical topics within this theme include Barrett’s esophagitis and esophageal carcinoma, chronic Helicobacter pylori gastritis and gastric cancer, chronic inflammation biliary tract including pre- and post-transplantation disorders, chronic pancreatitis and pancreatic cancer, and inflammatory bowel disease and colonic neoplasia. Research projects within this theme are diverse and include laboratory research, as well as clinical and epidemiological studies. One of the ongoing projects is a large colon cancer prevention study in the Rijnmond area.

Prof. dr. R.A. de Man, Prof. dr. H. Metselaar, dr. J. Kwekkeboom

Effective treatment of chronic viral hepatitis was largely lacking until fifteen years ago. In our day however, the medical world has gained significantly more knowledge about the pathogenesis of liver inflammation and viral hepatitis, leading to appropriate medication and treatment in many cases. Thus, hepatitis B can now be treated effectively in over 30% of patients and can be kept under control permanently in 70 to 80% of these patients. With regard to chronic hepatitis C, 50-80% of patients may recover by now.

Our research focuses on two major issues, a/ mapping the cells that ‘pick up’ the hepatitis B and C viruses and present these to the immune system, and b/ exploration of the influence of regulatory T-cells on viruses causing hepatitis. The scientific knowledge obtained from these studies direct translates into patient care. Concerning research in the field of liver transplantation (medical) biologists and clinicians closely co-operate in two fields: one is prevention and treatment of recurrent hepatitis C virus (HCV) in liver transplants, the other is optimalisation of immune suppression with the aim of attaining transplant tolerance.

Dr. C.J. van der Woude, dr. P. Dewint

Chronic inflammatory bowel diseases are very common and their incidence is still further rising. The etiology of these diseases is multifactorial, with interactions between gut flora, multigenetic host factors, and environmental factors all contributing. Patients with inflammatory bowel diseases are preferentially treated with combination drug therapy, mostly including immunosuppressive drugs. Surgery and endoscopical treatment is however often needed. The past decades have generated a wealth of knowledge about the causes of two types of IBD, Crohn’s disease and ulcerative colitis. These appear to have much in common. In both types the intestinal immune system reacts vigorously to harmless stimuli, such as the normal intestinal flora. Our research focuses on epidemiology and genetics of IBD, as well as on the effects of immunosuppressives on the mucosal level. The combination of outpatient clinic and laboratory makes a unique exchange of expertise. The joint efforts will gradually give more insight into the diseases from young to old.

Dr. A.M. Woltman, Dr. A. Boonstra, Dr. L.J. W. van der Laan, prof.dr. R.A. de Man, Dr. R.J. de Knegt

Viral hepatitis is a major global health problem with more than 500 million patients chronically infected. Both chronic hepatitis B and C lead to liver cirrhosis, liver failure and hepatocellular carcinoma, accounting for approximately 1 million deaths annually. The importance of developing adequate therapy for these diseases is obvious and the Rotterdam Liver Unit is one of the foremost groups in the world to develop such treatments. Taking full advantage of recent knowledge acquired in clinical and immunological medicine, our studies combine epidemiological and fundamental research in a cross-disciplinary approach while collaborating with the most experienced centers in the field of viral hepatitis.

Twenty years ago we were not able to treat any patient with chronic viral hepatitis, whereas nowadays some 50% of the patients can kept in long-term remission. Our challenge is to find an adequate treatment to achieve a full cure of disease in all patients. In the clinic, we investigate new antiviral drugs as well as immune modulating agents to increase the response rate. In this field our group has published many landmark studies during the last decade. In the laboratory, our research is mainly devoted to understanding the apparently inadequate immune response of chronic viral hepatitis. Gaining better understanding of these mechanisms, will eventually contribute to innovations in treatment regimens. Research is focused on the role of dendritic cells (DC), (regulatory) T cells and NK cells. Patients with chronic viral hepatitis exhibit an impaired DC function and increased percentages of regulatory T cells as compared to healthy volunteers. This may contribute to the insufficient T cell response in these chronic infections. NK cells also play a pivotal role in anti-viral responses, but their role in anti-HBV responses is as yet largely unknown.

Our facility, being the largest clinic and laboratory for chronic viral hepatitis in The Netherlands, offers a unique environment to combine fundamental and clinical research. There is intensive collaboration with important liver groups around the globe and with our translational approach we will be able to elucidate key pathways to eradicate viral hepatitis. Let’s hope that you can help us to further invigorate and energize the unexplored scientific field of the battle against viral hepatitis!

Research themes include:

• effect of antiviral therapy on the immune response to HBV
• mechanism of immunological tolerance to HBV

B.P.L. Wijnhoven, W.N.M. Dinjens

Department of Surgery and Pathology, Erasmus MC Rotterdam.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard of care for patients with potentially curable esophageal cancer. In about 30% of the patients, a pathologically complete response (pCR) is seen in the resection specimen, i.e. no viable tumor cells can be detected. In these patients, it is questionable whether an esophagectomy is indicated, which exposes the patient at risk for complications without impacting on survival. To assess whether a patient still bears viable tumor, the detection of tumors-specific TP53 mutations in cell free DNA (cfDNA) from patients’ serum could be useful. It can be anticipated that in patients with a pCR, the tumor-derived cfDNA is initially increased in the serum due to tumor cell lysis. cfDNA derived from tumor can be recognized by specific TP53 mutations, which are present in mostly all esophageal carcinomas. In an available series of esophageal carcinomas the TP53 mutation status will be determined in diagnostic pretreatment biopsies by Ion Torrent Next Generation Sequencing (NGS). The identified TP53 mutations will be investigated quantitatively by digital PCR in longitudinally collected sera before, during and after nCRT. The results will be compared with nCRT response as determined in the resection specimen. Potentially, the results of this study can lead to the early identification of complete responders and non-responders, which both will have important impact on patient treatment.

This project will both involve practicing laboratorial activities; DNA isolation, PCR, sequencing, data analysis, as well as database managing and performing statistical analysis.

Dr. A. Boonsta, dr. D. Sprengers, prof.dr. R.A. de Man, dr. B.E. Hansen

Liver disease is a major problem worldwide and in particular viral hepatitis, excessive alcohol consumption and obesity are important factors that can lead to the development of liver fibrosis, cirrhosis or hepatocellular carcinoma (HCC). HCC is the most common type of liver cancer and it is the fourth most common cause of cancer-related death worldwide. Because these types of tumors are only discovered in late stage, curative treatments are often no longer possible and mortality is high. Currently, it is not possible to detect HCC in an early stage through surveillance strategies, because there are no reliable serum biomarkers yet. The detection and diagnosis of HCC is now done with the help of advanced imaging techniques, which means that many patients are not screened and are therefore only diagnosed in a late stage of disease. Only a third of people diagnosed are eligible for potentially curative treatment. There is thus a clear need to develop tests to identify patients at high risk for HCC development early on.

The search for a clinically more applicable biomarker is therefore in full swing, as is the better mapping of risk factors that play a role in the development of HCC. By combining research from clinical data, pathology and laboratory research, we want to learn more about the development of HCC in patients with liver disease. Extensive databases are also available with data on experimental serum biomarkers measured in material from national and international patient cohorts. The knowledge from this project will contribute to an earlier diagnosis of HCC and therefore also to better and timely treatment of the disease.

More information can be found at www.escalon.eu and www.viralhepatitis.nl, or obtained from dr. Andre Boonstra (p.a.boonstra@erasmusmc.nl) or Bettina Hansen (b.hansen@erasmusmc.nl).