Peter D. Siersema

Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.

BACKGROUND & AIMS We previously established long-term culture conditions under which single crypts or stem cells derived from mouse small intestine expand over long periods. The expanding crypts undergo multiple crypt fission events, simultaneously generating villus-like epithelial domains that contain all differentiated types of cells. We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon. METHODS Based on the mouse small intestinal culture system, we optimized the mouse and human colon culture systems. RESULTS Addition of Wnt3A to the combination of growth factors applied to mouse colon crypts allowed them to expand indefinitely. Addition of nicotinamide, along with a small molecule inhibitor of Alk and an inhibitor of p38, were required for long-term culture of human small intestine and colon tissues. The culture system also allowed growth of mouse Apc-deficient adenomas, human colorectal cancer cells, and human metaplastic epithelia from regions of Barretts esophagus. CONCLUSIONS We developed a technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract. These tools might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia. Studies of these cultures indicate that there is no inherent restriction in the replicative potential of adult stem cells (or a Hayflick limit) ex vivo.

Increasing incidence of Barrett’s oesophagus in the general population

Background: Barrett’s oesophagus (BO) predisposes to oesophageal adenocarcinoma. Epidemiological data suggest that the incidence of BO is rising but it is unclear whether this reflects a true rise in incidence of BO or an increase in detection secondary to more upper gastrointestinal endoscopies performed. This study aimed to examine the changes in BO incidence relative to the number of upper gastrointestinal endoscopies performed in the general population. Methods: We conducted a cohort study using the Integrated Primary Care Information database. This general practice research database contains the complete and longitudinal electronic medical records of more than 500 000 persons. Results: In total, 260 incident cases of BO were identified during the study period. The incidence of BO increased from 14.3/100 000 person years in 1997 (95% confidence interval (CI) 8.6–22.4) to 23.1/100 000 person years (95% CI 17.2–30.6) in 2002 (r2 = 0.87). The number of upper gastrointestinal endoscopies decreased from 7.2/1000 person years (95% CI 6.7–7.7) to 5.7/1000 person years (95% CI 5.4–6.1) over the same time period. This resulted in an overall increase in detected BO per 1000 endoscopies from 19.8 (95% CI 12.0–31.0) in 1997 to 40.5 (95% CI 30.0–53.5) in 2002 (r2 = 0.93). The incidence of adenocarcinoma increased from 1.7/100 000 person years (95% CI 0.3–5.4) in 1997 to 6.0/100 000 person years (95% CI 3.3–10.2) in 2002 (r2 = 0.87). Conclusion: The incidence of diagnosed BO is increasing, independent of the number of upper gastrointestinal endoscopies that are being performed. This increase in BO incidence will likely result in a further increase in the incidence of oesophageal adenocarcinomas in the near future.

Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease

Background & aims Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. Methods Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. Results INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. Conclusions FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.

High lifetime risk of cancer in primary sclerosing cholangitis

BACKGROUND/AIMS Primary sclerosing cholangitis (PSC) patients are at risk for developing cholangiocarcinoma (CCA) and colorectal carcinoma (CRC). Our aim was to assess the risk of malignancies and their influence on survival. METHODS Data from PSC patients diagnosed between 1980 and 2006 in two university hospitals were retrieved. The Kaplan-Meier method and a time-dependent Cox regression model were used to calculate risks of malignancies and their influence on survival. RESULTS Two hundred and eleven patients were included, 143 (68%) were male and 126 (60%) had inflammatory bowel disease (IBD). Median transplantation-free survival was 14 years. The risk of CCA after 10 and 20 years was 9% and 9%, respectively. In patients with concomitant IBD the 10-year and 20-year risks for CRC were 14% and 31%, which was significantly higher than for patients without IBD (2% and 2% (P=0.008)). CCA, cholangitis, and age at entry were independent risk factors for the combined endpoint death or liver transplantation. Risk factors for the endpoint death were CCA, CRC, age, and symptomatic presentation. CONCLUSIONS Patients with PSC and IBD have a high long-term risk of developing CRC and this risk is about threefold higher than the risk for CCA. Both malignancies are associated with decreased survival.

Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study.

Objective The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients. Design Crohns disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3-month costs per patients with a 95% CI obtained using non-parametric bootstrapping. Results A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC. Conclusions We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.

Coated self-expanding metal stents versus latex prostheses for esophagogastric cancer with special reference to prior radiation and chemotherapy: a controlled, prospective study

BACKGROUND Self-expanding metal stents seem to be safer than conventional prostheses for palliation of malignant esophagogastric obstruction. However, recurrent dysphagia caused by tumor ingrowth in uncoated types remains a problem. In addition, prior radiation and/or chemotherapy may entail an increased risk of complications. METHODS Seventy-five patients with an esophagogastric carcinoma were randomly assigned to placement of a latex prosthesis under general anesthesia or a coated, self-expanding metal stent under sedation. At entry, patients were stratified for location of the tumor in the esophagus or cardia and for prior radiation and/or chemotherapy. RESULTS Technical success and improvement in dysphagia score were similar in both groups. Major complications were more frequent with latex prostheses (47%) than with metal stents (16%) (odds ratio 4.07: 95% CI [1.35, 12.50], p = 0.014). Recurrent dysphagia was not different between latex prostheses (26%) and metal stents (24%). Hospital stay was longer, on average, after placement of latex prostheses than metal stents (6.3 +/- 5.2 versus 4.3 +/- 2.3 days; p = 0.043). Only prior radiation and/or chemotherapy increased the risk of specific device-related complications with respect to the esophagus (12 of 28 [43%] versus 8 of 47 [17%]; odds ratio 3.66: 95% CI [1.24, 10.82], p = 0.029). CONCLUSIONS Coated, self-expanding metal stents are associated with fewer complications and shorter hospital stay as compared with latex prostheses, and prior radiation and/or chemotherapy increases the risk of device-related complications with respect to the esophagus.

Endoscopic ablation therapy for Barrett’s esophagus with high-grade dysplasia: a review

ABSTRACTBesides esophagectomy and antireflux therapy with intensive endoscopic surveillance, endoscopic ablation therapy is a new treatment modality for Barretts esophagus (BE) with high-grade dysplasia (HGD). Endoscopic surgical ablation can be performed by either a thermal, chemical, or mechanical method. This article describes the current management of patients with BE and HGD and the various methods of endoscopic ablation, including multipolar electrocoagulation, argon plasma beam coagulation, contact laser photoablation, and photodynamic therapy. It also summarizes the results of 37 patient studies, case reports, and abstracts on experimental endoscopic therapies for BE. The advantages and disadvantages of the various treatment possibilities are considered, and the future direction of the management of BE is discussed.

Treatment options for esophageal strictures

Esophageal strictures are a problem commonly encountered in gastroenterological practice and can be caused by malignant or benign lesions. Dysphagia is the symptom experienced by all patients, regardless of whether their strictures are caused by malignant or benign lesions. The methods most frequently used for palliation of malignant esophageal strictures are stent placement (particularly in patients with an expected survival of 3 months or less) and brachytherapy (in patients with a life expectancy of more than 3 months). Brachytherapy has been shown to be beneficial in patients with an expected survival of longer than 3 months with regard to (prolonged) dysphagia improvement, complications and quality of life. The mainstay of benign esophageal stricture treatment is dilation. Although dilation usually results in symptomatic relief, recurrent strictures do occur. In order to predict which types of strictures are most likely to recur, it is important to differentiate between esophageal strictures that are simple (i.e. focal, straight strictures with a diameter that allows endoscope passage) and those that are more complex (i.e. long (>2 cm), tortuous strictures with a narrow diameter). These complex strictures are considered refractory when they cannot be dilated to an adequate diameter. Novel treatment modalities for refractory strictures include temporary stent placement and incisional therapy.

Efficacy and safety of biodegradable stents for refractory benign esophageal strictures: the BEST (Biodegradable Esophageal Stent) study

BACKGROUND Benign esophageal strictures refractory to standard dilation therapy present a challenging problem. Temporary plastic and metal stents have been proposed with inconclusive results. OBJECTIVE To evaluate the efficacy and safety of a new biodegradable stent for the treatment of refractory benign esophageal strictures (RBESs). DESIGN AND SETTING Prospective study from 2 European endoscopy centers. PATIENTS AND INTERVENTION Twenty-one patients (11 men/10 women, mean age 60.2 ± 17.6 years) with RBESs defined according to the Kochman criteria treated by placement of a biodegradable stent (Ella stent). MAIN OUTCOME MEASUREMENTS Clinical and endoscopic follow-up was scheduled at 1, 2, 3, and 6 months and later only in case of dysphagia recurrence. Pre- and poststenting dysphagia status was graded according to a 5-point scale. Minor and major complication rates were prospectively assessed. RESULTS Stent insertion was technically successful in all of the patients. At 4 and 7 weeks, stent migration occurred in 2 patients (9.5%). At 3-month endoscopy, the stent appeared to be almost completely fragmented in all remaining patients. The median pre- and poststenting dysphagia scores were 3 (range 3-4) and 1 (range 0-2), respectively (P < .01), with a median follow-up of 53 weeks (range 25-88 weeks). In detail, 9 of 20 patients (45%) were dysphagia free at the end of the follow-up. No major complications occurred. Severe poststenting pain requiring analgesics developed in 3 patients, and minor bleeding was observed in 1 patient. LIMITATIONS Limited follow-up; nonrandomized study. CONCLUSIONS In this preliminary study, the biodegradable stent showed a favorable risk/benefit ratio, achieving complete relief of dysphagia in nearly 50% of RBES patients without the occurrence of major complications. The use of this stent may be a valuable alternative to repeat endoscopic dilation. Larger studies with longer follow-up are needed.

Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial

BACKGROUND Although colonoscopy is the accepted standard for detection of colorectal adenomas and cancers, many adenomas and some cancers are missed. To avoid interval colorectal cancer, the adenoma miss rate of colonoscopy needs to be reduced by improvement of colonoscopy technique and imaging capability. We aimed to compare the adenoma miss rates of full-spectrum endoscopy colonoscopy with those of standard forward-viewing colonoscopy. METHODS We did an international, multicentre, randomised trial at three sites in Israel, one site in the Netherlands, and two sites in the USA between Feb 1, 2012, and March 31, 2013. Patients aged 18-70 years referred for colorectal cancer screening, polyp surveillance, or diagnostic assessment underwent same-day, back-to-back tandem colonoscopy with standard forward-viewing colonoscope and the full-spectrum endoscopy colonoscope. The patients were randomly assigned (1:1), via computer-generated randomisation with block size of 20, to which procedure was done first. The endoscopist was masked to group allocation until immediately before the start of colonoscopy examinations; patients were not masked. The primary endpoint was adenoma miss rates. We did per-protocol analyses. This trial is registered with ClinicalTrials.gov, number NCT01549535. FINDINGS 197 participants were enrolled. 185 participants were included in the per-protocol analyses: 88 (48%) were randomly assigned to receive standard forward-viewing colonoscopy first, and 97 (52%) to receive full-spectrum endoscopy colonoscopy first. By per-lesion analysis, the adenoma miss rate was significantly lower in patients in the full-spectrum endoscopy group than in those in the standard forward-viewing procedure group: five (7%) of 67 vs 20 (41%) of 49 adenomas were missed (p<0·0001). Standard forward-viewing colonoscopy missed 20 adenomas in 15 patients; of those, three (15%) were advanced adenomas. Full-spectrum endoscopy missed five adenomas in five patients in whom an adenoma had already been detected with first-pass standard forward-viewing colonoscopy; none of these missed adenomas were advanced. One patient was admitted to hospital for colitis detected at colonoscopy, whereas five minor adverse events were reported including vomiting, diarrhoea, cystitis, gastroenteritis, and bleeding. INTERPRETATION Full-spectrum endoscopy represents a technology advancement for colonoscopy and could improve the efficacy of colorectal cancer screening and surveillance. FUNDING EndoChoice.