Nové poznatky o tlustém střevě prof. Jaroslaw Regula – Gastro Update Europe 2019, Budapest

Colorectal cancer is increasing worldwide, also in Europe where incidence and mortality were analysed from 1990 to 2016 in over 140 million people (20 countries) of whom over 180,000 had colorectal cancer diagnosed. The cancer incidence increased for the age group 20–29 years (y) by almost 8%, 30–39 y by almost 5% and 40–49 y by 1.6%. The young-onset colorectal cancer was mainly due to rectal cancer in white individuals. Such puzzling rise in young-onset colorectal cancer could also be seen in population-based registries from several high-income countries, showing a decreasing incidence in people aged 50–74 y, but an increasing incidence in the 20–49 y old group. One can only speculate what the reasons could be for this distressing phenomenon: obesity causing smoldering inflammation, microbiome changes due to antibiotic use, inappropriate western-style diet, food contaminants, radiation exposure, more frequent predisposing genetic abnormalities or other reasons? The question was even raised in the literature, whether the more frequent early-age onset should require lowering the starting age for screening, but so far relevant guidelines remained unchanged.

Many studies have shown the colorectal cancer preventive activity of acetylsalicylic acid. Whether another anti-platelet agent, clopidogrel, was also cancer preventive was analysed in a large Spanish nested case-control study, involving over 15,000 colorectal cancers and 60,000 randomly matched controls. When drug use was longer than one y, the adjusted odds ratio for acetylsalicylic acid was 0.79 and for clopidogrel 0.65. Why clopidogrel may decrease the incidence of colorectal cancer is unknown. The well-known and generally accepted prophylactic activity of acetylsalicylic acid was seriously questioned by the shocking results of a recent American study, involving close to 20,000 people above 70 y, comparing a low dose of 100 mg/day (d) vs. placebo for the duration of approx. 4.7 y. In the acetylsalicylic acid group the hazard ratio’s for all cause mortality was 1.14; overall cancer related death 1.31; and colorectal cancer-related death 1.77. Why the drug was not helpful in preventing colorectal cancer in the elderly and why it even shortened overall survival was unexpected, puzzling and shocking, and begs for confirmation and explanation.

Whether a healthy lifestyle is useful in colorectal cancer prevention was studied in over 40,000 patients compared to over 3,000 controls. The healthy lifestyle score was derived from five modifiable lifestyle factors: smoking, alcohol consumption, diet, physical activity, and body fatness. The genetic risk score was based on 53 known risk variants, based on genome-wide association studies. The higher the lifestyle score, the lower the cancer risk, independently of the genetic risk score. It is not known whether the mentioned lifestyle factors are of equal importance but regular physical activity seems important as also shown by other studies. Also diet is important as shown in the nurses/health professionals follow-up study involving over 120,000 participants. Based on questionnaires the consumed diet pattern was classified as pro-inflammatory or as anti-inflammatory. Interestingly, the pro-inflammatory diet increased the risk of Fusobacterium nucleatum positive colorectal cancers. Presumably the pro-inflammatory diet altered the intestinal microbiome, favoring the outgrow of F. nucleatum, shown also in other studies to be commonly associated with colorectal cancer.

A novel quality metric to measure the impact of organised screening for colorectal cancer was recently proposed. The method is based upon the determination of the proportion of colorectal cancers, detected either by: screening; non-adherence (due to non-existing or non-adherence to existing screening programs); or interval cancers (screening done but cancer arose before the next recommended control). An example of this metric may be seen in a recent American study. Of 572 cancers, 34.4% were screen detected, 59.4% non-adherent and 6.1% interval cancer. Such metric data can now be compared between centers to evaluate and compare the screening efficacy. Obviously, the percentage screen-detected should be as high as possible and the percentage of interval cancers as low as possible. In real life it turns out to be quite difficult to lower the interval percentage, explaining the ongoing search for methods to improve the neoplasia detection rate during endoscopy. As pan-chromo-endoscopy is not very appealing for many colonoscopists, a variant was developed adding Methylene blue MMX® to the polyethylene glycol bowel prep solution, leading to more uniform colonic staining. Adding 200 mg Methylene blue MMX® vs. placebo was evaluated in a multicenter controlled trial involving over 1,200 patients.

Methylene blue MMX® added to the bowel prep significantly increased the adenoma detection rate. Whether this method will become the standard for screening requires further study.

Chronic use of acetylsalicylic acid or anticoagulants (warfarin or direct oral anticoagulants (DOACs)) is common in screenees. Whether they interfere with Fecal immunochemical testing (FIT) for occult blood loss is somewhat controversial in the literature. To find out if FIT testing is reliable in users of those drugs, the positive predictive value was evaluated in 4,908 Norwegian individuals, including 1,008 acetylsalicylic acid users, 147 warfarin users and 212 DOAC users. The positive predictive value both for cancer and for advanced adenoma was significantly lower in the acetylsalicylic acid and DOAC users. Both patients and providers need to take note of this information when analysing the FIT results. The mechanisms explaining the phenomenon remain to be explored.

Not covered at the meeting but worthwhile mentioning are several recent data stressing the importance of additional ablation of the resection margins after colorectal polyp resection or the inclusion of an extra few mm of normal mucosa when cold resection is used to decrease the neoplasia recurrence rate, which may range up to 30% after removal of large flat lesions.

Symptomatic uncomplicated diverticular disease (SUDD) is a new disease entity, the pathophysiology of which is poorly understood. Indeed some 20% of patients with colonic diverticulosis develop symptoms without obvious signs of inflammation. To differentiate SUDD from irritable bowel syndrome may be challenging. Using biopsies from the diverticular area compared to distant sites, immunochemical investigations revealed accumulation of macrophages in the peridiverticular mucosa. Nerve fiber sprouting was increased only in the diverticular region in SUDD patients, suggesting a role in symptom generation. The cause of these subtle mucosal alterations remains enigmatic but currently there is high research interest for mucosal interaction with the microbiome. In the same line is the interest in the efficacy of long-term rifaximin treatment (800 mg/d/7 d every month) for 8 y, as studied in 346 Italian SUDD patients compared to 470 similar patients, treated on demand by other means. There was significant improvement with rifaximin in the score for pain and bloating and stool frequency. These are intriguing results, begging for confirmation and for clarification of the underlying mechanism.

The Gastro Update Europe 2020 will be held on June 5–6, 2020 in Bratislava, Slovakia. For more information visit www.gastro-update-europe.eu.

Prof. Guido Tytgat, MD, PhD

Department of Gastroenterology and

Hepatology

Academic Medical Center

Meibergdreef 9

1105 AZ Amsterdam

The Netherlands

 g.n.tytgat@amc.uva.nl